Displaying One Session

Poster Area (Hall 4) Poster Display session
Date
30.09.2019
Time
12:00 - 13:00
Location
Poster Area (Hall 4)
Poster Display session 3 Poster Display session

Biomarkers (ID 6617)

Lecture Time
12:00 - 12:00
Speakers
  • Rodrigo Dienstmann (Barcelona, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00
Poster Display session 3 Poster Display session

94P - Two years of BRCA1 and BRCA2 somatic external quality assessment with Gen&Tiss scheme in France (ID 5578)

Presentation Number
94P
Lecture Time
12:00 - 12:00
Speakers
  • Kelly Dufraing (Leuven, Belgium)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Testing for germline BRCA1/2 mutations has an established predictive role in breast and ovarian cancer risk assessment and EQA on germline mutation testing have been performed for a long time. With the European extension of indication for the PARP inhibitors, the screening of tumors first is increasingly important. However, tumoral BRCA1/2 testing is a different analytical process on formalin-fixed, paraffin-embedded (FFPE) material and with some challenging variants as large rearrangements. Validation of the test method and participation in external quality assessment programs are therefore required.

Methods

In the French national quality control programs (Gen&tiss) of 2017 and 2018, laboratories received 5 samples from ovarian cancer patients and 1 educational artificial sample with mutations present at different variant allelic frequencies in BRCA1/2 and a large rearrangement in BRCA1.

Results

The number of participants was 21 in 2017 and 26 in 2018. The number of labs with severe error was 3 in 2017 (14%) and 4 in 2018 (15%). For BRCA1, the average score remained stable between 2017 [9.6/10 (N = 21)] and 2018 [9.6/10 (N = 26)]. In both years, 2 laboratories made severe errors (false positive/false negative). In 2017 only 11 laboratories (N = 20) identified the educational variant present at 7% VAF. For BRCA2 the score slightly decreased from 9.8/10 (N = 22) to 9.4/10 (N = 26) and the number of laboratories with severe errors increased from 1 to 3. Half of the laboratories (N = 20) detected all three mutations present in the educational sample (VAF 10% to 30%) in the 2017 scheme. In 2018 a large deletion in BRCA1 present in the educational sample was only detected by 4 out of 20 laboratories. Three out of 26 laboratories detected the additional RAD51C variant and none the RAD51D variant. The main methods applied in France focus on BRCA1 and BRCA2 genes and amplification-based enrichment.

Conclusions

The genotype results were very similar between 2017 and 2018: acceptable but there are still more than 14% with severe errors. The limit of detection is a critical point. Few labs are ready to extend testing beyond BRCA1/2 genes. The question of large rearrangements is not yet solved for tumoral screening. EQA on tumoral BRCA1/2 testing is therefore essential to improve laboratory performance.

Legal entity responsible for the study

Gen&tiss - GFCO and AFAQAP.

Funding

AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

95P - Evaluation of markers associated with efficacy of abiraterone acetate plus prednisone (AAP) in patients (pts) with castration-sensitive prostate cancer (mCSPC) from the LATITUDE study (ID 4868)

Presentation Number
95P
Lecture Time
12:00 - 12:00
Speakers
  • Kim N. Chi (Vancouver, British Columbia, Canada)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

AAP and androgen deprivation therapy (ADT) treatment significantly improved overall survival (OS) and radiological progression-free survival (rPFS) in mCSPC pts with adverse prognostic factors. This analysis was aimed to identify predictive markers associated with response or resistance to AAP to guide combination and subsequent therapies.

Methods

DNA (n = 43) and RNA (n = 48) extracted from archived tumor samples from the LATITUDE study were sequenced using next generation and targeted DNA sequencing. Androgen receptor (AR) anomalies (copy number changes and mutations), frequency of DNA repair deficient (DRD: BRCA1/2, ATM, BRIP1, CHEK2, PALB2, FANCA, HDAC2) tumors and other resistant markers were probed. ARV7 expression was assessed in archived tumors (n = 105) by immunohistochemistry. Associations of biomarkers with rPFS and OS were assessed using univariate cox proportional hazards models.

Results

Of 105 treatment-naïve tumor samples tested, none of them met previously defined H-score cut off for ARV7 staining of > 5%, while 4/105 (4%) showed >1% ARV7 staining. A non-synonymous AR mutation (E654K) was detected in one sample (1/43), while none of the samples showed AR amplification. Impact of ARV7 expression on clinical outcomes was inconclusive due to small sample size of positive results. DRD tumors were observed at an overall frequency of 6/42 pts (14.3%: 4 biallelic), 4/30 pts (13.3%; 3 biallelic) in the AAP arm and 2/12 pts (16.7%: 1 biallelic) in control arm. Incidences of BRCA1/2 were only observed in AAP arm at a frequency of 2/30 (6.7%). In the AAP arm, shorter PFS was observed for DRD+ vs DRD– cohort (median 21.01 vs 24.14 mo; HR: 3.9; 95% CI: 1.1-12.1; p = 0.03). Genomic alterations were observed in PTEN (32.5%), TMPRSS2 (30%), TP53 (25.55), SPOP (20.9%) and APC (13.9%) genes, however, associations with clinical outcomes were not meaningful due to fewer samples and events.

Conclusions

AR splice variants and mutations were absent/rare in treatment naïve tumor samples from men with castrate-sensitive prostate cancers. The DRD+ cohort appears to show poorer rPFS outcome in AAP treated men.

Clinical trial identification

NCT01715285.

Editorial acknowledgement

Shweta Pitre, MPharm, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd., India) provided writing assistance and Namit Ghildyal, PhD (Janssen Global Services, LLC) provided additional editorial support.

Legal entity responsible for the study

Janssen Research and Development, LLC.

Funding

Janssen Research and Development, LLC.

Disclosure

K.N. Chi: Research grant/Funding (self): Janssen Pharmaceuticals, Astellas Pharma, Amgen, Bayer, Novartis, Sanofi, Exelixis, Tokai Pharmaceuticals, Oncogenex, Teva; Advisory/Consultancy: ESSA, Astellas Pharma, Janssen Pharmaceuticals, Sanofi, Lilly/ImClone, Amgen, Bayer, Takeda Pharmaceuticals; Honoraria (self): Sanofi, Janssen Pharmaceuticals, Astellas Pharma. S. Thomas: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. M. Gormley: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. D. Shen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. S. Joshi: Full/Part-time employment: Janssen Research & Development. N. Tran: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. M. Smith: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. D. Ricci: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. K. Fizazi: Advisory/Consultancy, Received personal fees: Amgen; Advisory/Consultancy, Received personal fees: Astellas; Advisory/Consultancy, Received personal fees: AstraZeneca; Advisory/Consultancy, Received personal fees: Bayer; Advisory/Consultancy, Received personal fees: Clovis; Advisory/Consultancy, Received personal fees: Curevac; Advisory / Consultancy, Received personal fees: Essa; Advisory/Consultancy, Received personal fees: Genentech; Advisory/Consultancy, Received personal fees: Janssen; Advisory/Consultancy, Received personal fees: Merck Sharp and Dohme; Advisory/Consultancy, Received personal fees: Orion; Advisory/Consultancy, Received personal fees: Sanofi.

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Poster Display session 3 Poster Display session

96P - LRP2, a potential new biomarker for Chinese younger aged intrahepatic cholangiocarcinoma patients (ID 4837)

Presentation Number
96P
Lecture Time
12:00 - 12:00
Speakers
  • Xiaoliang Shi (Shanghai, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Cholangiocarcinoma (CCA), which includes extrahepatic cholangiocarcinoma (exCCA) and intrahepatic cholangiocarcinoma (iCCA), is a primary malignancy which is often diagnosed as advanced stage and inoperable. The poor sensitivity of clinical diagnosis and lack of effective biomarkers to guide treatment are the main problems to be tackled. Identification of new and effective biomarkers is necessary to assist early diagnosis and prognosis of CCA.

Methods

Deep sequencing targeting 450 cancer genes was performed on FFPE and matching blood samples were collected from 63 CCA patients. Genomic alterations (GAs) including single nucleotide variations, short and long insertions and deletions, copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. The correlation analysis was performed by One-way ANOVA.

Results

A total of 63 (35 male and 28 female) Chinese CCA patients, including 40 intrahepatic CCA (iCCA) and 23 extrahepatic CCA (exCCA), were analyzed in this study. The most commonly altered genes included TP53 (41.27%, 26/63), KRAS (31.75%, 20/63), ARIK1A and IDH1 (15.87%, 10/63, for both), SMAD4 (14.29%, 9/63), FGFR2 and BAP1 (12.70%, 8/63, for both) and CDKN2A (11.11%, 7/63). The mutation of LRP2 specifically occurred with low frequency (7.5%, 3/40) in iCCA patients. There were 24 patients aged 50 to 70 years, 6 patients aged more than 70 years and 10 patients aged less than 50 years (younger group). Notably, the mutations of LRP2 were detected only in the younger group, and statistical analysis showed the significant correlation between LRP2 and younger iCCA patients (P = 0.02). Also, 2 of the 3 patients with LRP2 mutations harbored high TMB (TMB-H, more than 10 Muts/Mb). Statistical analysis showed a significant association of LRP2 and TMB-H.

Conclusions

The mutation of LRP2 is associated with younger Chinese iCCA patients. The correlation of LRP2 and TMB-H represents a better mutational burden and probably a better prognosis of younger iCCA patients with LRP2 mutations. Our results support that LRP2 may be a potential biomarker for the diagnosis and prognosis of younger Chinese iCCA patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

97P - Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability (ID 1286)

Presentation Number
97P
Lecture Time
12:00 - 12:00
Speakers
  • Aurelie Moreira (Paris, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

SIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT.

Methods

All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test.All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test.

Results

The 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1 mo in IIIA; 1.7 mo in IIIB, and 3.2 mo in IVA (p = 0.13). Median OS was 11.7 mo in tier II, 11.2 mo in IIIA, 6.3 mo in IIIB, and 12.1 mo in IVA (p = 0.002).

Conclusions

The majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway.

Legal entity responsible for the study

Institut Curie.

Funding

ANR-10-EQPX-03 from the Agence Nationale de le Recherche (Investissements d’avenir) and SiRIC (Site de Recherche Intégré contre le Cancer).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

99P - Comparison of platforms for determining tumor mutational burden (TMB) from blood samples in patients with non-small cell lung cancer (NSCLC) (ID 2736)

Presentation Number
99P
Lecture Time
12:00 - 12:00
Speakers
  • Jonathan Baden (Princeton, NJ, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

TMB is a clinically relevant biomarker associated with response to immune checkpoint inhibitors in patients with NSCLC. Tumor TMB (tTMB) can be assessed by next-generation sequencing (NGS) gene panels; however, obtaining sufficient tumor tissue can be challenging, and NGS methods have been developed for TMB assessment from blood (bTMB). We compared bTMB values using 3 commercial NGS assays that differ in gene number, depth of coverage, and variant allele cutoff.

Methods

bTMB was assessed in 25 commercial NSCLC plasma samples with 3 NGS assays, and values were compared by Spearman’s correlation. For assay A, < 500 genes were sequenced to a depth of < 1000x. Assays B and C each comprised > 500 genes, sequenced to a depth of ∼ 1500x. To determine concordance between bTMB and tTMB we assessed 86 commercial NSCLC matched plasma and tumor samples using bTMB assays A and C and a clinically validated tTMB gene panel assay, and performed subgroup analysis by disease stage.

Results

bTMB in stage I–III NSCLC samples assessed by assays B and C showed greater correlation (r = 0.78) than by assays A and B (r = 0.59) and A and C (r = 0.53). Across 86 matched samples, tTMB and bTMB concordance was lower for assay A (r = 0.24) than assay C (r = 0.51) and was higher among stage IV NSCLC samples (A, r = 0.38; C, r = 0.72) than stage I–III (A, r = 0.24; C, r = 0.40). Using clinically relevant cutoffs, high bTMB was observed in 5/30 patients with assay A (range: 10.5–21.1), and 19/30 patients with assay C (range: 12.4–67.6); high tTMB ranged from 10.0 to 36.6.

Conclusions

In patients with NSCLC, bTMB was concordant (r > 0.5) between 3 NGS assays. Concordance between bTMB and tTMB varied and was improved for bTMB assays with increased coverage and sequencing depth, and in patients with higher stage metastatic disease. Assay parameters impact accurate and reproducible TMB assessment, with lower coverage and sequencing depth, and differing variant allele cutoff, risking false-negative results that may affect outcomes in response to immune checkpoint inhibitor therapy. These data underscore the need for demonstrating clinical utility of bTMB assays and for assessment of bridging analytical performance between assays.

Editorial acknowledgement

Amrita Dervan, PhD, and Jay Rathi, MA, of Spark Medica Inc, funded by BristolMyers Squibb.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

J. Baden: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb; Shareholder/Stockholder/Stock options: Johnson & Johnson. H. Chang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. D.M. Greenawalt: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. S. Kirov: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. S. Pant: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. A. Seminara: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. S. Srinivasan: Shareholder / Stockholder / Stock options, Full/Part-time employment: Bristol-Myers Squibb. G. Green: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb.

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Poster Display session 3 Poster Display session

100P - Comprehensive pan-cancer analysis of somatic mutations in drug transporters to reveal acquired and intrinsic drug resistance in 3149 metastatic cancer patients (ID 5045)

Presentation Number
100P
Lecture Time
12:00 - 12:00
Speakers
  • Sander Bins (Rotterdam, Netherlands)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Systemic anti-cancer treatment is hampered by drug resistance (DR). However, little is known about the pharmacokinetic consequences of genetic changes in tumor cells. We hypothesize that somatic point mutations, small indels, copy number variations (sCNV) and/or structural variations in genes encoding drug transporters are drivers of DR mechanisms in tumor cells. We therefore performed an explorative analysis to quantify somatic aberrations that could reflect DR mechanisms and, in parallel, identify their stressors.

Methods

We interrogated whole-genome sequencing (WGS) data from a Dutch pan-cancer cohort of metastatic cancer patients (N = 3149 at ∼118x and matched peripheral blood at∼38x read depth), of which more than half had failed previous systemic treatment. Somatic aberrations (germline filtered) were analyzed in drug transporters (N = 51), present on the Drug Metabolizing Enzymes and Transporters (DMET™ plus) panel (v.32). Enrichment of somatic DR variants was estimated by assessing nonsynonymous/synonymous mutation ratio deviations (dN/dS) and sCNV were detected with GISTIC2.

Results

In total, 5137 somatic variants (2645 in treatment-naive and 2484 in pretreated patients) in drug transporter genes were observed in 1651 patients (52.4%) of whom 55.1% were systemically pretreated. Three genes (ABCB4, ABCC5, SLCO1B1) showed dN/dS enrichment (p = 0.0142 - 0.0364). sCNVs (N = 7656; 5849 deep gene-level gains and 1807 deletions) were observed in 1906 patients (60.5%). Interestingly, we identified 20 somatic DR-related variants in 12 patients (58.3% pretreated), not present in the matching germline samples, that were identical to SNP variants on DMET™ plus.

Conclusions

In the largest metastatic pan-cancer WGS cohort worldwide, we characterized the pharmacogenomic drug transporter landscape in tumor cells. Potentially, the incidence of somatic variants in pharmacogenes accounts for acquired DR in pretreated patients and/or intrinsic DR. We will extend our study with analyses of prior treatments and germline variations, in order to assess the clinical consequences of the variations and improve clinical decision-making.

Clinical trial identification

NCT01855477.

Legal entity responsible for the study

The authors.

Funding

This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study.

Disclosure

C. van Herpen: Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (self): Servier. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

101P - Pan-cancer genomic landscape of the cyclin D1/FGF3,4,19 (11q13) amplicon including associations with HPV status, and ESR1 and AR alterations (ID 4577)

Presentation Number
101P
Lecture Time
12:00 - 12:00
Speakers
  • Jennifer M. Johnson (Philadelphia, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The amplicon of CCND1, FGF3, FGF4, and FGF19 on chromosome 11q13 encodes cyclinD1, regulator of the CDK4/6 cell cycle kinase and FGF ligands for FGFR kinases, which are targets for drug development. We sought to characterize the pan-cancer genomic landscape of this amplicon.

Methods

Tumor samples from 255,117 patients with clinically advanced cancers underwent comprehensive genomic profiling (CGP) with an adaptor-ligation/hybrid capture-based assay of coding DNA of up to 395 cancer-related genes and select introns of 28 genes that are frequently involved in genomic rearrangements to detect base substitutions, insertions and deletions, copy number alterations, and rearrangements.

Results

4% (10,202/255,117) of all cases harbored the 11q13 amplicon (+). The median copy number was 12 (range 6-176). Of the 10 cancers where 11q13+ was most frequent, five were squamous cell carcinomas (SCC) including esophagus SCC (ESCC) (47.3% 11q13+) as the most enriched, head and neck SCC (HNSCC) (17.0%), as well as lung SCC (LSCC) (10.8%). Given ESCC and LSCC are overwhelmingly HPV-, we assessed 11q13 occurrence by HPV status in HNSCC. 3.4% of the 11q13+ HNSCC cases were HPV+, compared to 36.8% of the 11q13- HNSCC samples (p = 9.4e-52). 2 (20%) of the 10 cancers most frequently 11q13+ were the classically ER+ breast invasive lobular carcinoma (17.7%) and breast carcinoma NOS (16.6%). In 441 ER+ breast cancers, 286 (19.8%) were 11q13+. Of these ER+/11q13+ cases, 19.2% also featured ESR1. In contrast, only 14.3% of the ER+/11q13- cases also had ESR1 mutations (p = 0.05). Similarly, in 7103 cases of predominantly castrate resistant prostate cancers, 210 (3.0%) featured 11q13+. 38.6% of the 11q13+ prostate cancer cases also harbored mutations in AR while only 19.9% of the 11q13- cases harbored AR mutations (p = 6.2e-11).

Conclusions

SCCs are enriched for 11q13+ with preliminary evidence for linking them to HPV- status. The co-occurrence of 11q13+ with both ESR1 and AR mutations suggests a co-operative role in acquired resistance to hormonal therapy, but not to TKIs. Further investigation will be 11q13+ in the development of SCC and acquired resistance to hormonal therapies appears warranted.

Legal entity responsible for the study

Foundation Medicine.

Funding

Foundation Medicine.

Disclosure

J.Johnson: Consultant: Foundation Medicine Consultant: Rakuten-Aspyrian. J. Lee: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. R. Madison: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Advisory / Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, Full / Part-time employment: Foundation Medicine; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Schlesinger Associates; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Precision Health Economics; Research grant / Funding (self): Puma; Research grant / Funding (self): Celgene; Research grant / Funding (self): Eli Lilly. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Officer / Board of Directors: Celsius Therapeutics. J. Chung: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Incysus Therapeutics; Advisory / Consultancy: Revolution Medicines.

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Poster Display session 3 Poster Display session

102P - Co-occurrence of NTRK fusions with other genomic biomarkers in cancer patients (ID 5366)

Presentation Number
102P
Lecture Time
12:00 - 12:00
Speakers
  • Xiaolong Jiao (Whippany, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Larotrectinib is the first therapy approved in the U.S. for locally advanced or metastatic solid tumors with neurotropic tyrosine receptor kinase (NTRK) gene fusions. NTRK gene fusions have been documented with variable frequency across numerous tumor types; limited data exist regarding the relationship of NTRK gene fusions with other targetable biomarkers. This study evaluated the co-occurrence of NTRK gene fusions with other therapy molecular markers in cancer patients.

Methods

This retrospective study included cancer patients from a de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) who had next-generation sequencing (NGS) between Jan 2011 and July 2018. The co-occurrence frequencies of NTRK gene fusions with the following markers was determined using NGS assays including FoundationOne and FoundationOne Heme: tumor mutation burden (TMB), microsatellite instability (MSI), ALK, BRAF, ERBB2, EGFR, ROS1, and KRAS.

Results

An evaluable sample of 15,971 of 33,398 patients in the CGDB had one of 18 histologies where at least one NTRK fusion patient was identified. NTRK gene fusions were identified in 29 patients: 55% (16/29) were female; 69% (20/29) were Caucasians. The median age was 60 years (Q1-Q3: 49.0-65.0). Fifteen different fusion partners were identified; the most frequent were ETV6-NTRK3 (n = 8), TPM3-NTRK1 (n = 6), and TPR-NTRK1 (n = 3). Co-occurring genomic alterations are shown in the table.

Co-occurring biomarkers*Patients with NTRK gene fusions (N = 29), % (n)
TMB High (>20 mut/mB) TMB Medium (<20, >5 mut/mB)20.7 (6/29) 10.3 (3/29)
MSI (high)17.6 (3/17)**
ALK rearrangement0.0 (0/29)
BRAF alteration3.5 (1/29)
ERBB2 amplification0.0 (0/29)
EGFR alteration3.5 (1/29)
ROS1 alteration0.0 (0/29)
KRAS alteration10.3 (3/29)

Variants of “known” or “likely” functional status were included

MSI status missing for 12 patients

Conclusions

The study confirmed the rarity of NTRK gene fusions in cancer patients. Co-occurrence of the biomarkers ALK, BRAF, ERBB2, EGFR, ROS1, or KRAS was uncommon. These results highlight the importance of identifying patients with NTRK gene fusion-driven cancers, through molecular testing, who will benefit from the use of selective TRK kinase inhibitors across different solid tumors.

Editorial acknowledgement

Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer.

Legal entity responsible for the study

Bayer.

Funding

Bayer.

Disclosure

X. Jiao: Full / Part-time employment: Bayer. A. Lokker: Full / Part-time employment: Flatiron Health; Shareholder / Stockholder / Stock options: CVS Health, Roche, Medtronic, Sangamo Therapeutics. J. Snider: Full / Part-time employment: Flatiron Health; Shareholder / Stockholder / Stock options: Roche. E. Castellanos: Full / Part-time employment: Flatiron Health. S. Nanda: Full / Part-time employment: Bayer. V. Fisher: Full / Part-time employment: Foundation Medicine. J. Zong: Full / Part-time employment: Bayer. K. Keating: Full / Part-time employment: Bayer. M. Fellous: Full / Part-time employment: Bayer.

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Poster Display session 3 Poster Display session

103P - Prospective comparative study of next-generation sequencing on fine needle aspirations versus core needle biopsies in cancer patients included in SHIVA02 trial (ID 4084)

Presentation Number
103P
Lecture Time
12:00 - 12:00
Speakers
  • Julien Masliah-Planchon (Paris, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

High throughput molecular screening of solid tumours using core needle biopsies (CNB) allows the identification of actionable molecular alterations. Several reports revealed that success rate of genomic analyses based on CNB is around 70% with failures being mostly related to low proportion of tumour cells. Although several studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to the sensitivity of CNB to detect actionable alterations compared to the less invasive fine needle aspiration (FNA). We aim to prospectively evaluate the ability of FNA to detect molecular alterations identified on CNB in cancer patients (pts) included in SHIVA02 trial.

Methods

In-house targeted sequencing amplicon based panel (Illumina TSCA 99.3 Kb, 1,504 amplicons covering 87 genes) was used to identify pathogenic variants and gene copy number alterations (CNVs) in both CNB and FNA for pts enrolled in the SHIVA02 trial (NCT03084757).

Results

CNB and FNA specimen from 39 pts enrolled in the SHIVA02 trial were assessed. Main tumour locations were breast (17pts, 44%), pancreatic (4pts, 10%), and colorectal cancers (3pts, 8%). 91 somatic variants were identified in both specimens with a good correlation of variants’ allelic ratios (r: 0.772). CNV profiles of CNB and FNA were concordant. When taking into account molecular alterations validated during the molecular biology board, 88 alterations (55 variants and 35 CNVs) were reported among which 69 alterations (78%) where concordant between CNB and FNA. Among the 50 actionable alterations, only 12 (3 variants and 9 CNVs) (24%) were discordant between FNA and CNB. Main discordances were related to homozygous deletions and amplifications but false negative results were not related to FNA samples alone (5 CNVs in favour of FNA versus 4 in favour of CNB).

Conclusions

Comparative analyses of molecular alterations in CNB compared to FNA showed high concordance in terms of variants as well as CNVs identified. FNA could therefore be easily used in routine diagnostics workflow and clinical trials for tumour molecular screening with the advantage of being minimally invasive.

Clinical trial identification

NCT03084757 SHIVA02; Trial release date: April 1, 2017.

Legal entity responsible for the study

Institut Curie.

Funding

MSD Avenir Fundation.

Disclosure

C. Le Tourneau: Advisory / Consultancy: MSD, BMS, Merck Serono, AstraZeneca, Novartis, Roche, Nanobiotix. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

104P - First national external quality assessment for the interpretation of somatic variants: Assessment of 25 variants in colorectal, lung, ovarian cancers and melanoma in France (ID 6017)

Presentation Number
104P
Lecture Time
12:00 - 12:00
Speakers
  • Etienne Rouleau (Villejuif, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The interpretation of testing results in molecular pathology is an essential phase. It is difficult to assesss this in external quality assessment on real samples. Here we propose a national measure of the concordance in the variant interpretation between laboratories participating in the national French quality control program Gen&tiss.

Methods

Laboratories were asked to interpret 5 variants each for melanoma, lung and colorectal cancers and 10 for ovarian cancer. These variants in KRAS, NRAS, BRAF, PIK3CA, PTEN, AKT1, TP53, EGFR, RAC1, KIT, BRCA1 and BRCA2 were not classical hotspots of mutation and 15 of these were annotated in OncoKB. A maximum of 25 variants was assessed per laboratories. Nine possible interpretations were proposed: from neutral to oncogenic and from no therapeutic impact to targeted by a drug. For each variant, a consensus score was determined based on public database as OncoKb and validated by 4 molecular experts with literature review. Three scores were possible: right answer (2 points), acceptable answer without clinical impact (1 point), wrong answer with clinical impact (0 points).

Results

60 laboratories participated to the program for variant interpretation. The average scores on 10 were 5.9 for colorectal (N = 52), 7.0 for lung (N = 49), 6.0 for melanoma (N = 49) and 7.0 for ovarian cancer (N = 25). For BRCA genes in ovarian cancer, there was a pilot project in 2017, in which 5 identical variants were proposed to interpretation. 18 laboratories participated both in 2017 and 2018: 50% performed better, 28% performed worse, 17% had similar results.

Conclusions

As test results have will have a direct impact on patient management, ensuring a correct interpretation becomes more and more important. This EQA could help to validate the interpretation process used in the laboratories (SOP and databases) and could be extend to the individual expertise.The average score is acceptable, yet improvable and it really depends on the variants proposed. International consensus guidelines equivalent to the ACMG classification of constitutional variants would be helpful to improve reproducibility and inter-laboratory homogeneity.

Legal entity responsible for the study

Gen&tiss - GFCO and AFAQAP.

Funding

AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

105P - Prospective testing of circulating tumour DNA in metastatic breast cancer facilitates clinical trial enrollment and precision oncology (ID 2283)

Presentation Number
105P
Lecture Time
12:00 - 12:00
Speakers
  • Andjelija Z. Bujak (Melbourne, Australia)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The increasing availability of targeted agents for treatment of metastatic breast cancer (mBC) necessitates accurate and timely molecular characterisation of disease. As a minimally invasive test, circulating tumour DNA (ctDNA) is well positioned to overcome many of the limitations associated with traditional tumor biopsies. Here, we established a program to assess the feasibility of routine prospective ctDNA testing for the clinical management of mBC patients.

Methods

Detection of somatic mutations from patient plasma was performed using a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2 and AKT1. In parallel, a subset of samples were also analysed via next generation sequencing (targeted amplicon (TA) sequencing and low-coverage whole-genome sequencing). Results were discussed at a multidisciplinary breast cancer meeting prior to therapy selection.

Results

234 mBC patients were enrolled on this study, with a median age at diagnosis of 54 years (28-80) and a median of 2 lines of prior therapy. The average turnaround time for ctDNA testing using ddPCR was 9 days (1-49). Using ddPCR, 80/234 (34.2%) patients had ≥1 mutation identified, with 52/234 (22.2%) patients having an alteration in PIK3CA, 35/234 (15.0%) in ESR1, 9/234 (3.8%) in AKT1 and 2/234 (0.9%) in ERBB2. TA sequencing performed in the first 159 patients, identified actionable mutations (classified using the OncoKB database) in 63 patients (39.6%) and showed that a mean variant allele fraction of > 5% was significantly associated with inferior overall survival (Hazard ratio: 1.8; 95% Confidence interval: 1.1-3.1; p < 0.02). Of 97/234 patients where an actionable alteration was identified, the result influenced clinical management in 41 (42.3%), including 18 who were enrolled in a clinical trial. In one patient initially diagnosed with ER+/HER2- disease, a HER2 gene amplification was identified through ctDNA analysis leading to the initiation of HER2-targeted treatment and a near complete metabolic response to treatment.

Conclusions

Prospective ctDNA testing of mBC patients is a practical and feasible approach to guide clinical trial enrolment and patient management.

Legal entity responsible for the study

The authors.

Funding

National Health and Medical Research Council Australia.

Disclosure

S.Q. Wong: Travel / Accommodation / Expenses: Bio-Rad Laboratories. S. Dawson: Research grant / Funding (self): Genentech. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

106P - Elevated driver mutational burden or number of perturbed pathways and poor response to abiraterone or enzalutamide in metastatic castration-resistant prostate cancer (ID 5218)

Presentation Number
106P
Lecture Time
12:00 - 12:00
Speakers
  • Bram De Laere (Stockholm, Sweden)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with rare driver gene alteration combinations in most men, requiring large sample sizes for stratified evaluations. We therefore hypothesized that the number of driver genes or pathways would affect prognosis in patients initiating androgen receptor signalling inhibitors (ARSi, i.e abiraterone acetate or enzalutamide).

Methods

We performed a post hoc analysis of the circulating tumor DNA (ctDNA) mutational landscape in ARSi-treated men with mCRPC (n = 342), recruited in our prospective, non-interventional, cohort study (n = 142) and the prospective NCT02125357 trial (n = 200). The driver gene mutational burden was defined as the number of detectable hotspot, pathogenic and/or function-affecting perturbations in 39 overlapping genes, which in turn were associated with 13 pathways. Progression-free survival (PFS) estimates were inferred by Kaplan-Meier analysis and multivariable Cox regression models, including the following covariates: PSA and ctDNA levels, prior chemotherapy, prior ARSi exposure, and presence of visceral metastases.

Results

Driver gene perturbations were detectedin 192/342 (56.1%) evaluable patients at baseline, with 152/192 (79.2%) and 40/192 (20.8%) perturbed patients having 1-3 and ≥ 4 significant events, respectively. PFS decreased as the driver mutational burden increased (0, 1-3, ≥ 4 drivers, median PFS 12.5 vs 5.6 vs 2.7 months, p < 0.0001). In multivariate analysis the driver burden reached significance once ≥ 4 driver hits were detected (HR 1.85, 95%CI 1.06-3.23, p = 0.03). The number of perturbed pathways reached independent prognostic value once ≥ 3 pathway or gene classes were affected (HR 1.7, 95%CI 1.02-2.84, p = 0.04). Additionally, in both models the presence of visceral metastases (p < 0.0001) and increasing PSA (p < 0.001) and plasma ctDNA (p < 0.001) levels were also independently associated with inferior outcome.

Conclusions

We demonstrate for the first time that the elevated driver mutational burden or number of affected pathways is independently associated with poor prognosis in mCRPC patients starting ARSi.

Legal entity responsible for the study

CORE-ARV-CTC and ProBio Investigators.

Funding

The Belgian Foundation Against Cancer, Kom op tegen Kanker (the Flemish Cancer Society), Royal College of Surgeons/Cancer Research UK, The Erling-Persson Family Foundation, the Swedish Research Council, and the Swedish Cancer Foundation.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

107P - High proportion of multiple KRAS mutations in circulating tumour DNA and tumour tissue of pancreatic ductal adenocarcinoma (ID 2452)

Presentation Number
107P
Lecture Time
12:00 - 12:00
Speakers
  • Min Kyeong Kim (Gyeonggi-do, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Circulating tumor DNA (ctDNA) has been known to be released from tumor cells and evaluated as potential biomarkers for therapeutic responses. In our previous study, we proved applicability for KRAS mutation as a prognostic marker in pancreatic ductal adenocarcinoma (PDA) through the quantitative analysis of ctDNA using KRAS multiplex kit which covers 7 sites. In this study, we analyzed distribution of each single mutation in tumor and ctDNA by performed droplet digital PCR (ddPCR).

Methods

Total of 126 PDA patients were enrolled and analyzed for tumor DNA. We found 94 patients have samples for matched ctDNA analysis. Plasma was separated by established method and ctDNA were extracted using QIAamp Circulating Nucleic Acid Kit. QX200 Droplet Digital PCR System was applied to measure frequency of KRAS mutations using KRAS screening multiplex kit and probe for G12D, G12V and G12C in ctDNA and tumor DNA. Then, we compared the frequency between multiplex and single point mutation of KRAS.

Results

The positivity of mutation of tumor and ctDNA in multiplex ddPCR were 96.0% (n = 121/126) and 60.3% (n = 76/126), respectively. Positive rates of G12D, G12V and G12C were 59.6%, 24.5% and 22.3% in tumor and 36.2%, 16.0% and 17.0% in ctDNA, respectively. There was a correlation between multiplex and the sum of single point mutation (r = 0.805). In the single point mutation results, 44 of the samples detected in both tumor and ctDNA mutations were detected in the same site (75.9%), 12 of them were partially identical (19.0%), and 3 were inconsistent (5.2%). Comparing the frequency with other studies, G12D and G12V showed no difference in frequency, but G12C showed a higher positive rate than the previous studies even though we did not analysis for G12R. Multiple KRAS mutations were found in 17% and 6.4% in tumor and ctDNA.

Conclusions

These results show that the frequency of KRAS mutation correlated with tumor tissue and ctDNA. Also multiple mutations were detected high proportion compared to the previous studies. Further studies are needed to determine G12R proportion. We further evaluate whether the single point mutation detected by single probe is more valuable than sum of mutations from KRAS multiplex kit as a biomarker for predicting the prognosis of PDA.

Legal entity responsible for the study

Sun-Young Kong.

Funding

National Cancer Center and the Ministry of Health & Welfare, Republic of Korea.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

108P - Biological difference of tumour mutational burden (TMB) and microsatellite instability (MSI) status in patients (pts) with somatic vs germline BRCA1/2-mutated advanced gastrointestinal (GI) cancers using cell-free DNA (cfDNA) sequencing analysis in the GOZILA study (ID 3328)

Presentation Number
108P
Lecture Time
12:00 - 12:00
Speakers
  • Yasuyuki Kawamoto (Sapporo, Hokkaido, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

A novel approach to differentiate somatic vs. germline BRCA1/2 mutations in cfDNA using a beta binomial model (AACR 2018, abst #4272) may enable identification of pts with advanced GI tumors who are likely to benefit from a PARP inhibitor. The results from the GOZILA study, the Nationwide Cancer Genome Screening Project utilizing Guardant360, are presented here.

Methods

Pts with advanced GI tumors who were appropriate for any systemic therapy and had progressed following at least one prior treatment were eligible. We investigated the prevalence of somatic vs. germline BRCA1/2 mutations and the association between BRCA1/2 mutations, TMB and MSI.

Results

From Jan 2018 to Mar 2019, 850 pts were prospectively enrolled among 26 major cancer centers in Japan. Of 40 (4.7%) actionable BRCA1/2 mutations, 14 were germline: esophagus (squamous cell carcinoma only), 2 pts (N = 62, 3.2%); stomach, 2 pts (N = 131, 1.5%); colorectum, 3 pts (N = 377, 0.8%); pancreas, 3 pts (N = 157, 1.9%); biliary tract, 4 pts (N = 77, 5.2%); and others, none (N = 31, 0%). Notably, the majority of BRCA1/2 mutations (75%) in pts with esophageal, pancreas and biliary tract cancers were germline, while 81% of BRCA1/2 mutations in pts with stomach and colorectal cancers were somatic (p = 0.001). Median TMB of pts with germline BRCA1/2 mutations was significantly lower than those with somatic BRCA1/2 mutations (p = 0.042). In addition, all pts with germline BRCA1/2 mutations were microsatellite stable, while 19% of pts with somatic BRCA1/2 mutations were MSI-high.

Conclusions

Analysis of cfDNA identified a unique subset of pts with germline BRCA1/2 mutations in advanced GI cancers. Given the association of these findings with efficacy of PARP inhibitor and immune-based therapies, these findings suggest that the identification of BRCA1/2 mutations and their germline-somatic origin may have future implications for therapy selection.

Clinical trial identification

UMIN000029315.

Legal entity responsible for the study

SCRUM-Japan GI-SCREEN.

Funding

Guardant Health, Ono Pharmaceutical.

Disclosure

Y. Kawamoto: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Daiichi Sankyo Co., Ltd.; Honoraria (self): Takeda Pharmaceutical Co., Ltd.; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Merck Biopharma Co., Ltd.; Honoraria (self): Eli Lilly Japan K.K.. Y. Nakamura: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho Pharmaceutical. M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Yakult; Advisory / Consultancy: Otsuka Pharmaceutical; Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Honoraria (self): EA Pharma; Honoraria (self): MSD; Advisory / Consultancy, Research grant / Funding (institution): ASLAN Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nano Carrier; Honoraria (self): Gilead. H. Bando: Honoraria (self): Taiho Pharmaceutical company; Honoraria (self): Eli Lilly; Research grant / Funding (self): Sysmex; Research grant / Funding (self): AstraZeneca. T. Esaki: Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self): Chugai; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Eli Lilly; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Novartis. M. Ueno: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Shire; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): MSD; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): ASLAN Pharmaceuticals. T. Nishina: Honoraria (self), Research grant / Funding (institution): Taiho pharmaceutinal; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Suibb; Honoraria (self): Nihonkayaku; Honoraria (self), Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Diichi Sankyo. E. Oki: Speaker Bureau / Expert testimony: Taiho Pham; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Chugai Pham; Speaker Bureau / Expert testimony: Takeda Pharm; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Bayer. T. Denda: Speaker Bureau / Expert testimony: DAIICHI SANKYO COMPANY, LIMITED. T. Mizukami: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly Japan; Advisory / Consultancy: Bristol-Myers Squibb Company; Speaker Bureau / Expert testimony: Takeda Pharmaceutical; Research grant / Funding (institution): TAIHO Pharmaceutical. N. Okano: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Eisai; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Yakult Honsha; Honoraria (self): Takeda; Honoraria (self): J-Pharma; Honoraria (self): Kyowa Hakko Kirin. M.I. Lefterova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. J.I. Odegaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. H. Taniguchi: Honoraria (self): Chugai; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): Taiho; Honoraria (self): Eli Lilly; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Sysmex. C. Morizane: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Yakult Honsha; Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (institution): Nobelpharma; Honoraria (self): Fujifilm; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Eisai; Advisory / Consultancy: Abbvie; Research grant / Funding (institution): ONO PHARMACEUTICAL; Research grant / Funding (institution): J-Pharma. T. Yoshino: Research grant / Funding (self): Novartis Pharma K.K.; Research grant / Funding (self): MSD.K.K.; Research grant / Funding (self): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (self): CHUGAI PHARMACEUTICAL Co., Ltd.; Research grant / Funding (self): Sanofi K.K.; Research grant / Funding (self): DAIICHI SANKYO Co., Ltd.; Research grant / Funding (self): PAREXEL International Inc.; Research grant / Funding (self): ONO PHARMACEUTICAL Co., Ltd. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

109P - Cell-Free DNA to detect focal versus non-focal MET amplification in metastatic colorectal cancer patients: Combined analysis from Japan and the United States (ID 3022)

Presentation Number
109P
Lecture Time
12:00 - 12:00
Speakers
  • Mishima Saori (Kashiwa, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

MET amplification (amp) is rare in untreated metastatic colorectal cancer (mCRC), but cell-free DNA (cfDNA) analysis identifies it in ∼20% with anti-EGFR monoclonal antibody (mAb)-refractory disease. CfDNA analysis reveals both focal gene amp and gene copy number gain due to chromosomal aneuploidy (non-focal MET amp). We analyzed cfDNA from Japanese (JPN) and United States (US) patients (pts) with anti-EGFR mAb-refractory mCRC to investigate the prevalence of focal and non-focal MET amp.

Methods

We studied MET amp in pts with mCRC in the Nationwide Cancer Genome Screening Project in JPN (GOZILA; UMIN000029315; JPN cohort) and in a phase I/II trial of cabozantinib (C) +/- panitumumab (P) in pts with RAS wild-type mCRC (NCT02008383; US cohort). MET amp was detected with the Guardant360 assay. Focal MET amp was defined as either the only amp on chromosome (chr) 7q or MET copy number ³4. Non-focal MET amp was defined as co-amp with ³1 other genes (CDK6 or BRAF) located on chr 7q and MET copy number <4.

Results

244 JPN cohort pts were analyzed from 2/2018-12/2018, and 81 pts in the US cohort, from 8/2014-2/2018. In pts with prior anti-EGFR mAb (JPN: n = 184; US: n = 70), focal and non-focal MET amp were detected in 8 (4.3%) and 30 (16.3%) pts in the JPN cohort, and in 9 (12.9%) and 4 (5.7%) US pts. Without prior anti-EGFR mAb (JPN: n = 60; US: n = 11), focal and non-focal MET amp were detected in 1 (1.7%) and 4 (6.7%) pts in the JPN cohort, and 0 (0%) and 1 (9.1%) US pts. The focal MET amp rate combined was 6.7% (17/254) with prior anti-EGFR mAb. In the US cohort, 4/6 pts with focal MET amp treated with C or C+P had a reduction in RECIST lesions as best response, with one PR, while 2 pts with non-focal MET amp had tumor growth as best response.

Conclusions

The prevalence of focal MET amp detected by cfDNA analysis in mCRC pts was similar in the JPN and US cohorts. Given preliminary efficacy results from the US trial, focal MET amp may be a [A1] predictor of benefit from a MET inhibitor. A clinical trial evaluating a MET inhibitor in mCRC pts with focal MET amp is underway.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Kawazoe: Honoraria (self), Research grant / Funding (institution): Ono Oharmaceutical; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Takeda Pharmaceutical; Research grant / Funding (institution): Astellas Pharmaceutical; Research grant / Funding (institution): MSD. Y. Nakamura: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho Pharmaceutical. J.I. Odegaard: Full / Part-time employment: Guardant Health. M.I. Lefterova: Full / Part-time employment: Guardant Health. R. Lanman: Full / Part-time employment: Guardant Health. T. Yoshino: Research grant / Funding (institution): Novartis Pharma K.K.; Research grant / Funding (institution): MSD.K.K.; Research grant / Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (institution): CHUGAI PHARMACEUTICAL CO., LTD.; Research grant / Funding (institution): Sanofi K.K.; Research grant / Funding (institution): DAIICHI SANKYO COMPANY, LIMITED; Research grant / Funding (institution): PAREXEL International Inc.; Research grant / Funding (institution): ONO PHARMACEUTICAL CO., LTD.. J.H. Strickler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Chugai; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Leadership role, Research grant / Funding (institution): OncoMed; Advisory / Consultancy: Celgene; Advisory / Consultancy: Proteus Digital Health; Advisory / Consultancy: Chengdu Kanghong Biotechnology Co., Ltd; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Leap Therapeutics; Research grant / Funding (institution): MedImmune. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

110P - Presence of circulating tumour DNA in surgically resected renal cell carcinoma is associated with advanced disease and poor patient prognosis (ID 2833)

Presentation Number
110P
Lecture Time
12:00 - 12:00
Speakers
  • Andres Correa (Philadelphia, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Circulating tumor DNA (ctDNA) is a promising, non-invasive biomarker for preclinical detection and monitoring of various cancers. The utility of ctDNA assessment in renal cell carcinoma (RCC) in not well established. Here, we evaluate the potential of a bespoke, multiplex PCR, whole exome sequencing (WES)-based approach for ctDNA detection.

Methods

The cohort consisted of 42 patients with stage Ib-IV RCC who underwent complete surgical resection. ctDNA was measured in plasma samples drawn pre-surgery (n = 34; baseline) and at post-operative time points (n = 41) using the bespoke assay targeting patient-specific tumor variants.

Results

A median of 11.7 ng (1.4-175 ng) of cfDNA was extracted from a median plasma volume of 3.2 mL (1.2-3.8 mL). ctDNA was detected with a mean mutant molecules/mL of 5.3 (0.22-62). Baseline ctDNA was detected in 41% (14/34) of patients. Presence of ctDNA was significantly associated with increased tumor size (mean 9.7 vs 7.1cm, p < 0.05), advanced tumor stage (stage III-IV vs I-II, p < 0.05) and poorly differentiated tumors (grade III-IV vs II, p < 0.0001). In the postoperative setting, 8/8 ctDNA-positive patients relapsed (positive predictive value (PPV=100%), while 16/33 ctDNA-negative patients relapsed (NPV=52%). Positive ctDNA status was associated with reduced relapse-free survival at post-surgical timepoints (HR: 2.8; 95% CI:1.2-6.6). None of the post-surgical samples from a control cohort of 17 non-relapsing patients were ctDNA-positive (specificity of 100%; median follow up of 64 months).

Conclusions

Presence of presurgical ctDNA strongly correlates with advanced stage RCC. Despite low plasma volumes, the bespoke assay detected ctDNA in 41% of baseline samples. Postoperative ctDNA presence is correlated with clinical relapse. However, absence of ctDNA does not preclude recurrence as RCC is known to shed limited amounts of ctDNA. Higher sample volumes and multiregion tumor biopsies could enhance detection rates. This personalized approach has the potential to be used for ctDNA-based detection of relapse in patients with advanced stage RCC.

Legal entity responsible for the study

Natera, Inc.; Fox Chase Cancer Center.

Funding

Natera, Inc.; Fox Chase Cancer Center.

Disclosure

M. Balcioglu: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. H. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. S. Dashner: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. E. Kalashnikova: Full / Part-time employment: Natera, Inc. H. Pawar: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. R.G. Uzzo: Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Argos. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. R. Salari: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. B. Zimmermann: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. P. Abbosh: Advisory / Consultancy, Advisory: Janssen; Advisory / Consultancy, Advisory: AstraZeneca. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

111P - Combined genomic and epigenomic assessment of cell-free circulating tumour DNA (cfDNA) for cancer diagnosis and recurrence-risk assessment in early-stage lung cancer (ID 1376)

Presentation Number
111P
Lecture Time
12:00 - 12:00
Speakers
  • Junghee Lee (Seoul, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Circulating tumor DNA (ctDNA) analysis has been successfully applied to therapy selection and treatment monitoring in advanced cancer patients. However, it is not yet established whether ctDNA can be used clinically for early cancer detection or recurrence prediction in early stage lung cancer patients.

Methods

We analyzed pre-operative plasma samples from 55 early stage NSCLC patients (stages I-IIIA) using next-generation sequencing assay incorporating somatic and epigenomic analysis, and a bioinformatic classifier to filter non-tumor derived variants.

Cell typeStageSomatic mutationEpigenetic patternTotal numberRecurrence+, n (%)Site of recurrence
Adenocarcinomastage 1ctDNA-methylation-91 (11)Lung
n = 17methylation+62 (33.3)Stump, bone
ctDNA+21 (50)lung
stage 2ctDNA-methylation-00 (0)
n = 2methylation+00(0)
ctDNA+11 (100)multiple
stage 3ctDNA-methylation-00 (0)
n = 4methylation+20 (0)
ctDNA+22 (100)brain, multiple
Sqaumous cell carcinomastage1ctDNA-methylation-00 (0)
n = 7methylation+30 (0)
ctDNA+41 (25)multiple
stage2ctDNA-methylation-00 (0)
n = 9methylation+00 (0)
ctDNA+92 (22.2)multiple, lung
stage3ctDNA-methylation-00 (0)
n = 4methylation+10 (0)
ctDNA+31 (33.3)Mediastinal LNs

Results

Somatic mutation analysis alone detected ctDNA in 42% (23/55) of patients, whereas combined mutational and epigenomic analysis detected ctDNA in 67% (37/55). ctDNA detection rate varied by pathological subtypes; using combined approach, ctDNA was detected in all squamous cell carcinoma patients, while only 55% (12/22) in adenocarcinoma (ADC) (p=0.006). Within the ADC subgroup, ctDNA detection rates using the combined approach were dependent on disease stage: 47% (8/17) in stage I, 100% (2/2) in stage II, and 100% (2/2) in stage IIIA. Importantly, within 2 years of follow-up, pre-operative ctDNA status was correlated with tumor recurrence after resection; among 17 stage I ADC patients, three of eight (38%) ctDNA-positive cases showed recurrence, while only one of nine (11%) ctDNA-negative cased did (p=0.29). Interestingly, patients with somatic mutation in their ctDNA have shown higher recurrence rate.

Conclusions

Utilizing a plasma-only sequencing assay incorporating somatic genomic and epigenomic analysis, ctDNA detection rate in early stage lung cancer (stage I-III) can far outperform the detection rate of somatic sequence variant detection alone. And, the presence of pre-operative ctDNA in patients with early stage lung adenocarcinoma may identify those who are more likely to have disease recurrence.

Legal entity responsible for the study: Guradant Health, Inc.

Funding

Guardant Health, Redwood City, CA, USA.

Disclosure

I. Kim: Full / Part-time employment, Officer / Board of Directors: Guardant Health. M. Shultz: Officer / Board of Directors: Guardant Health. A. Jaimovich: Officer / Board of Directors: Guardant Health. J. Odegaard: Officer / Board of Directors: Guardant health, Inc. S. Olsen: Officer / Board of Directors: Guardant Health, Inc. A. Talasaz: Officer / Board of Directors: Guardant health. J. Kim: Research grant / Funding (self): Guardant health, Inc. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

112P - DEMo: A prospective evaluation of a prognostic clinico-molecular composite score in NSCLC patients treated with immunotherapy (ID 4050)

Presentation Number
112P
Lecture Time
12:00 - 12:00
Speakers
  • Arsela Prelaj (Milan, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The DiMaio (D), EPSILoN (E) and plasma microRNA signature classifier (MSC), are 3 diverse clinico-biochemical and molecular scores able to independently predict prognosis in advanced non-small cell lung cancer (aNSCLC) patients (pts) treated with immunotherapy (IO). By assessing the ability of each test a combined score (SC) called DEMo was developed. The study aims to prospectively evaluate the prognostic value of DEMo in aNSCLC pts treated with IO.

Methods

We included in the analyses 166 aNSCLC pts treated in 1L (n = 47) and further-lines (n = 119) with IO at Istituto Nazionale Tumori of Milan. For all pts we obtained complete necessary data for both clinical SC: D (sex, histology, ECOG-PS stage, uses of platinum-based therapy at 1L and response to 1L) and E (ECOG-PS, Smoke, Liver, LDH, NL-ratio). MSC was prospectively evaluated in plasma samples collected at baseline IO and the risk level was assessed. Endpoints were median overall survival (mOS), progression-free survival (mPFS) and overall response rate (ORR). Kaplan-Meier and Cox model were used to generate survival curves and multivariate analyses, respectively.

Results

In multivariate analysis adjusted for age, sex, smoke and ECOG-PS each score remain independently significant for both PFS (D: HR = 1.99, CI95% 1.21–3.03, p = 0.007; E: HR = 1.87 CI95% 1.12 – 3.10, p = 0.016; MSC: HR = 1.56, CI95% 1.03–2.37, p = 0.0370) and OS (D: HR = 3.12, CI95% 1.80–5.41, p = 0.0001; E: HR = 2.21, CI95% 1.28–3.79, p = 0.0041; MSC: HR = 2.03, CI95% 1.30–3.17, p = 0.0019). DEMo separated patients in 4-risk groups (gr) based on the presence of 3–2–1–0 poor prognostic SC. Strata had 0%–7%–20%–46% 18 months (mo) PFS (p < 0.0001) and 0%–23%–44%–78% 18 mo OS (p < 0.0001). We further combined DEMo gr 3/2 and 0/1 for multivariate analysis: mPFS and mOS for gr 3/2 vs 0/1 were 2.1 vs 6.4 mo (HR = 2.06, CI95% 1.26–3.36, p = 0.0038) and 4.1 vs 20.3 mo (HR 3.17, CI95% 1.91–5.24, p < 0.0001). The ORR was 2.9 (CI95% 1.4–6.0) fold higher for gr 0/1 compare to 3/2 (p = 0.0034).

Conclusions

We created a composite clinic-molecular combined biomarker classifier able to better predict prognosis compared to each single SC and to select patients who less likely benefit from IO. DEMo could be a useful tool to guide choices in aNSCLC.

Clinical trial identification

The authors.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale Tumori of Milan, Italy.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

113P - Bespoke circulating tumor DNA (ctDNA) analysis as a predictive biomarker in solid tumor patients (pts) treated with single agent pembrolizumab (P) (ID 4727)

Presentation Number
113P
Lecture Time
12:00 - 12:00
Speakers
  • Cindy Yang (Toronto, Canada)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Limited data exist in the clonal dynamics of serial ctDNA as a predictive biomarker in advanced solid tumor pts receiving immune checkpoint blockade.

Methods

Pts with mixed solid tumors received single agent P (anti-PD-1) 200 mg IV Q3wks in the investigator-initiated phase II INSPIRE trial (NCT02644369). ctDNA was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera™). Samples were considered ctDNA positive if ≥ 2 of 16 pt-specific targets met the qualifying confidence score threshold.

Results

Of 94 pts are presented. Demographics: male 38%; median age=55 yrs (range 21–81); triple negative breast (19%), ovarian (19%) and head and neck (17%) cancers comprised the major malignancies. Median no. of P cycles=3 (range 1–35); follow up was 14m (range 0.6-35.4); RECIST responses: CR 3.2% (n = 3), PR 14% (n = 13), CBR (CR+PR+SD>6 cycles) 28% (n = 26), RECIST/clinical PD (n = 61/18; 65%/19%). Median PFS=2.5m and median OS = 14m. In all 94 pts, ctDNAB correlated with PFS (adjusted HR 0.53, 95% CI 0.34-0.84, p = 0.01) and OS (adjusted HR 0.47, 95% CI 0.28-0.8, p = 0.01). Among 74 pts with both ctDNAB and ctDNAC3, the change (ΔctDNA) correlated with clinical efficacy parameters (Table).

EndpointORR N = 72*CBR N = 72*EndpointPFS N = 73*OS N = 73*
SubgroupCR/PR N = 15SD/PD N = 57CR/PR/SD≥6 cycles N = 22CR/PR/SD<6 cycles N = 50Subgroup↑ from baseline N = 33↓ from baseline N = 40↑ from baseline N = 33↓ from baseline N = 40
ΔctDNA (% change)Median = -91.5% Range = -100% to 60%Median = 40% Range = -98.4% to 2458%Median = -75% Range = -100% to 96%Median = 52% Range = -94.6% to 2458%Results based on ΔctDNAMedian = 7.9m 6m = 51.5%Median = 2.8m 6m = 10.0%Median = not reached 6m = 91% 12m = 82%Median = 9.1m 6m = 73% 12m = 45%
P-valueP < 0.001P < 0.001Adjusted HR (95% CI)^0.43 (0.25-0.75) P = 0.0030.35 (0.18–0.67) P = 0.002

Adjustment on cohorts;

2 pts were excluded from ORR/CBR analyses as baseline ctDNA = 0; 1 of these 2 pts (with PR) excluded from PFS/OS analyses as C3 ctDNA = 0

Conclusions

Strong correlations exist between both ctDNAB and ΔctDNA with clinical outcome, suggesting both prognostic and predictive values in pts with mixed solid tumors.

Clinical trial identification

NCT02644369, December 31, 2015.

Legal entity responsible for the study

University Health Network, Toronto.

Funding

Merck, Netera, Terry Fox Research Institute, Princess Margaret Cancer Foundation.

Disclosure

S. Dashner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A.R. Hansen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Karyopharm. P. Bedard: Honoraria (institution), Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Oncothyreon. S. Lheureux: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Tesaro. A. Spreafico: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Oncology/Johnson & Johnson; Research grant / Funding (institution): Array Biopharma. A.A. Razak: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): CASI Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Adaptimmune. H. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. P.S. Ohashi: Honoraria (self), Advisory / Consultancy: Symphogen Inc; Honoraria (self), Advisory / Consultancy: Providence Therapeutics. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. L.L. Siu: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfiser; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Honoraria (self), Advisory / Consultancy: Morphosys; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy: GeneSeeq; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: Oncorus; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boerhinger-Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Intensity Therapeutics; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Shattucks; Spouse / Financial dependant: Agios. S. Bratman: Research grant / Funding (self): Nektar Therapeutics; Licensing / Royalties, Co-inventor of a patent relating to circulating tumor DNA detection technology: Roche Molecular Diagnostics. T.J. Pugh: Honoraria (self): Merck; Honoraria (self): Prosigna; Honoraria (self): Chrysalis Medical Advisors; Advisory / Consultancy: DynaCare; Research grant / Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

114P - Dynamic changes in whole-genome cell-free DNA (cfDNA) to identify disease progression prior to imaging in advanced solid tumours (ID 3662)

Presentation Number
114P
Lecture Time
12:00 - 12:00
Speakers
  • Andrew A. Davis (Chicago, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Liquid biopsies have potential clinical utility as dynamic biomarkers for treatment response. We analyzed serial changes in whole-genome (WG) cfDNA to identify patients with disease progression prior to routine imaging.

Methods

We prospectively collected clinical data and blood from 93 advanced cancer patients (40 lung, 25 breast, 28 other). Blood was collected prior to initiation of a new treatment and at one or two additional timepoints (median 21 and 42 days). We isolated plasma cfDNA and prepared sequencing libraries for each patient’s series for either WG sequencing or WG bisulfite sequencing. We quantified changes in the fraction of tumor-derived cfDNA over the initial course of treatment to predict progression vs. no progression. Treatment response at first follow-up imaging (FUI) was determined by RECIST 1.1 and clinical assessment. Study endpoints were agreement with FUI and progression-free survival (PFS) by cfDNA prediction.

Results

Patients were treated with chemo- (34), immuno- (33), targeted- (16), or endocrine therapy (10). Patients with predicted progression by cfDNA (16), indicated by an increase in tumor fraction in either post-treatment blood sample, had shorter PFS (median 64 days) compared to patients without an increase (77; median 263 days), with a hazard ratio of 8.0 (95% confidence interval 4.1-15.6, log-rank P = 8x10-13). For cases where progression was correctly predicted using cfDNA (14), blood collection preceded imaging by a median of 40 days. Positive predictive value was 88% for disease progression and negative predictive value was 84%. Sensitivity for the assay was 54% and specificity was 97%. These findings were consistent in the subset of patients on immunotherapy (sensitivity 71%, specificity 100%, log-rank P = 5x10-12).

Conclusions

Our results show the ability to detect early disease progression with high specificity using liquid biopsy prior to first imaging. These findings were consistent across a variety of tumor histologies and types of treatment. This technology may enable early switching from ineffective therapy to a potentially effective alternative, increasing the value proposition of all delivered treatment.

Legal entity responsible for the study

The authors.

Funding

Lexent Bio, Inc.

Disclosure

A.A. Davis: Travel / Accommodation / Expenses: Menarini Silicon Biosystems. W. Iams: Travel / Accommodation / Expenses, Clinical Trial Visit: EMD Serono. N. Peterman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. A. Robertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Full / Part-time employment, 2016-2017: Color Genomics; Shareholder / Stockholder / Stock options, 2015-2018: Counsyl. A. Shah: Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Myriad. R. Srivas: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. N. Lambert: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Sequenom. T. Wilson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options, Full / Part-time employment, Prior employment: Illumina; Shareholder / Stockholder / Stock options: Counsyl. P. George: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Hologic. B. Wong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. J. Close: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. H. Wood: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. A. Tezcan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. J.C. Spinosa: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Full / Part-time employment: San Diego Blood Bank; Advisory / Consultancy: Gestalt Diagnostics; Advisory / Consultancy: SonicHealthUS. H. Tezcan: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options, 2015-2018: Counsyl. Y.K. Chae: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Biodesix; Advisory / Consultancy: Counsyl; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Advisory / Consultancy: ImmuneOncia; Advisory / Consultancy: Hamni; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Eli Lilly; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Lexent Bio, Inc.; Research grant / Funding (institution): Freenome. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

115P - Evaluation of microsatellite instability testing through cell-free DNA sequencing (ID 3817)

Presentation Number
115P
Lecture Time
12:00 - 12:00
Speakers
  • Shile Zhang (San Diego, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Microsatellite instability (MSI) status has been approved by FDA to select for patients with metastatic tumors for cancer immunotherapy treatments. Additionally, MSI status is used in assessment of prognosis and treatment choices in certain cancer types, as well as the first step in the genetic diagnosis for Lynch syndrome. Circulating tumor DNA (ctDNA) is a noninvasive, real-time approach used for comprehensive genomic profiling of cancer. However, only a small fraction of cell-free DNA (cfDNA) fragments originate from tumor cells, requiring an ultra-sensitive method to detect MSI status from cfDNA. Here we evaluate the performance of Illumina TruSight™ Oncology 500 panel for MSI testing through cfDNA sequencing.

Methods

We developed a robust method to assess MSI status in cfDNA. For each MSI locus, we assessed the repeat length distribution of the test subject and a cohort of normal samples. By comparing allele distributions with information-theory based approach, we determined if each of the MSI locus was unstable. Final MSI score was calculated using the number of unstable sites divided by total tested sites. To assess the analytical performance of our method, we titrated MSI-high (MSI-H) cell lines into MSI stable (MSS) background at a series of concentrations ranging from 0.31% to 5.0%, representing low tumor fractions in cfDNA samples. Additionally, we processed 94 clinical samples with matched FFPE tumor and cfDNA to examine the concordance of MSI testing between FFPE and cfDNA.

Results

For titrated MSI-H samples with low tumor fraction, we achieved 100% sensitivity in samples at 0.625% MSI-H content titration into MSS background. Moreover, we achieved 98.9% overall percent agreement (93/94) for MSI status between matched FFPE and cfDNA samples with a wide range of tumor content.

Conclusions

Our evaluation indicates that we can accurately determine MSI status in cfDNA samples with a wide range of tumor content.

Legal entity responsible for the study

The authors.

Funding

Illumina.

Disclosure

S. Zhang: Full / Part-time employment: Illumina. J.S. LoCoco: Full / Part-time employment: Illumina. A. Mentzer: Full / Part-time employment: Illumina. B.M. Crain: Full / Part-time employment: Illumina. S. Katz: Full / Part-time employment: Illumina. G. Berry: Full / Part-time employment: Illumina. Y. Fu: Full / Part-time employment: Illumina. T. Jiang: Full / Part-time employment: Illumina. C. Zhao: Full / Part-time employment: Illumina. S. Bilke: Full / Part-time employment: Illumina. T. Pawlowski: Full / Part-time employment: Illumina. K. Kruglyak: Full / Part-time employment: Illumina.

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Poster Display session 3 Poster Display session

116P - Longitudinal changes in cell-free DNA (cfDNA) methylation levels identify early non-responders to treatment in advanced solid tumours (ID 3664)

Presentation Number
116P
Lecture Time
12:00 - 12:00
Speakers
  • Andrew A. Davis (Chicago, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Aberrant methylation changes are present in nearly all cancers. The goal of this study was to determine if changes in cfDNA methylation patterns during the course of treatment could predict non-response prior to routine imaging.

Methods

We prospectively collected clinical data and blood from 52 patients with advanced malignancies (25 lung, 11 breast, 16 other). Blood was drawn prior to start of a new treatment, after first cycle (median 23 days), and/or second cycle (median 43 days). We performed whole-genome (WG) bisulfite sequencing (median depth 18X) on plasma cfDNA to determine methylation levels. By tracking how methylation levels change across 19,710 regions throughout the genome, from baseline to subsequent timepoints, we classified patients as either progressors or non-progressors. Treatment response at first follow-up imaging (FUI) was determined by RECIST 1.1 or clinical assessment. Study endpoints were agreement with first FUI and progression-free survival (PFS) by cfDNA classification.

Results

The cohort consisted of 58% females and the median age was 71. Main treatment regimens were immuno- (22), chemo- (20), targeted- (7) or endocrine therapy (3). PFS was significantly shorter (log-rank p = 0.003) in patients classified as progressors by cfDNA (N = 10; median: 90 days) compared to non-progressors (42, median: 263 days). 6 out of 10 patients classified as cfDNA progressors were later confirmed to progress at first follow-up evaluation (60% positive predictive value). The cfDNA assay for these 6 patients preceded imaging and clinical evaluation by a median of 40 days. For the remaining patients, 39 of 42 did not progress (93% negative predictive value). Thus, sensitivity for the assay for identifying progression was 67% and specificity was 91%.

Conclusions

Our results show that WG cfDNA methylation change is a novel cancer signature with potential to identify patients whose treatment regimen is ineffective prior to imaging, and allow switching to a more effective alternative at an earlier time. Moreover, integrating methylation-based changes with information about genomic alterations may increase performance of cfDNA-based response monitoring.

Legal entity responsible for the study

The authors.

Funding

Lexent Bio, Inc.

Disclosure

A.A. Davis: Travel / Accommodation / Expenses: Menarini Silicon Biosystems. W. Iams: Travel / Accommodation / Expenses, Clinical Trials Visit: EMD Serono. R. Srivas: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. N. Lambert: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Sequenom. A. Robertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Full / Part-time employment, Prior employment: Color Genomics; Shareholder / Stockholder / Stock options, 2015-2018: Counsyl. N. Peterman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. A. Shah: Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Myriad. T. Wilson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options, Full / Part-time employment, Prior employment: Illumina; Shareholder / Stockholder / Stock options: Counsyl; Licensing / Royalties: Gen-Probe. J. Close: Full / Part-time employment: Lexent Bio, Inc. P. George: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Hologic. H. Wood: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. B. Wong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. A. Tezcan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. J.C. Spinosa: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Full / Part-time employment: San Diego Blood Bank; Advisory / Consultancy: Gestalt Diagnostics; Advisory / Consultancy: SonicHealthUSA. H. Tezcan: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options, 2015-2018: Counsyl. Y.K. Chae: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Biodesix; Advisory / Consultancy: Counsyl; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Advisory / Consultancy: ImmuneOncia; Advisory / Consultancy: Hanmi; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Eli Lilly; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Lexent Bio; Research grant / Funding (institution): Freenome. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

117P - Multigene panel testing results for hereditary breast cancer in 1325 individuals: Implications for gene selection and considerations for guidelines (ID 3212)

Presentation Number
117P
Lecture Time
12:00 - 12:00
Speakers
  • Georgios N. Tsaousis (Athens, Greece)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The application of the Next Generation Sequencing (NGS) technology has facilitated multigene panel testing for hereditary breast cancer (BC) in clinical practice. We performed a retrospective analysis of individuals referred for testing in our lab aiming to investigate the contribution of included genes and evaluate current genetic testing guidelines in BC.

Methods

In total, 1141 BC patients and 184 unaffected individuals with family history (FH) of BC were referred from physicians for testing using a multigene panel. Genomic DNA was enriched for targeted regions of 33 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated computationally and by Multiplex Ligation-dependent Probe Amplification (MLPA).

Results

A pathogenic variant (PV) was identified in 22% (291/1325) of analyzed individuals and in specific in 23.2% of BC patients and 14.1% of unaffected individuals (P = 0.006). Among individuals with PVs, 49.1% were located in the BRCA1/2 genes whereas 8.6%, 22.7% and 19.6% occurred in other high, moderate and low-risk genes respectively. Notably, 21 of the 291 positive individuals (7.2%) carried clinically significant variants in two different genes and 6.5% had a LGR. A retrospective analysis of positive individuals showed that 88.3% of BC patients met the NCCN criteria for further genetic risk evaluation compared to 80.8% of unaffected individuals with FH of BC (P = 0.269). In BRCA-positive cases, NCCN criteria were met in 92.3% of the referrals compared to 81.8% in individuals positive for other genes (P = 0.008).

Conclusions

Extended multigene panel testing in hereditary BC facilitates the detection of nearly twice as many individuals that could benefit from personalized management. In our cohort, the currently used selection criteria for HBOC failed to identify only 12.7% of individuals positive for pathogenic variants, suggesting strong selection strategies from physicians. However, our results indicate that selection criteria perform better for the identification of BRCA-positive BC patients and should be revised to facilitate towards the inclusion of BC patients with PVs in other genes.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

118P - PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors (ID 2591)

Presentation Number
118P
Lecture Time
12:00 - 12:00
Speakers
  • Julia C. Quintanilha (Chapel Hill, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Hypertension is one of the major side effect of VEGF-pathway inhibitors. There are no validated biomarkers to predict which cancer patients will develop hypertension. This study aimed to identify genetic predictors of hypertension induced by VEGF-pathway inhibitors.

Methods

A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) (PMID 30385613) and genotyped for 1,040 germline variants in 56 genes. The most statistically significant variant from the discovery set (chi-squared test) was tested in a validation set (cause-specific Cox model) consisting of 1,041 cancer patients treated with bevacizumab (10-15 mg/kg every two-three weeks) and genotyped using GWAS microarray platforms. For both studies, grade ≥2 hypertension (CTCAE v. 3.0) was used as the endpoint. Genetic associations were adjusted for age and sex.

Results

In the discovery set, the most statistically significant variant associated with hypertension in sorafenib-treated patients was rs444904 (G>A, P = 0.006). The A allele of rs444904 (minor allele frequency, MAF 0.14) increased the risk of hypertension. In the validation set, the A allele of rs427554 (G>A, in complete linkage disequilibrium with rs444904) increased the risk of hypertension in bevacizumab-treated patients (P = 0.008, MAF 0.11). rs444904 and rs427554 are intronic variants in PIK3R5. PIK3R5 encodes the regulatory subunit of PI3Kγ, which, when activated by VEGF, leads to nitric oxide (NO) production and vasodilation. These variants have been associated with decreased expression of PIK3R5 in blood (PMID 25954001), consistent with their effect in increasing the risk of hypertension.

Conclusions

Common genetic variants that could reduce PIK3R5 activity increase the risk of sorafenib- and bevacizumab-induced hypertension. In patients treated with these drugs, reduced activity or expression of PIK3R5 may lead to a reduction in NO production, resulting in vasoconstriction and hypertension. This study, for the first time, provides evidence for new predictive genetic markers of drug-induced hypertension that should be further evaluated for other VEGF-pathway inhibitors.

Clinical trial identification

TARGET CALGB 80303 NCT00088894 CALGB 40503 NCT00601900 CALGB 40502 NCT00785291 CALGB 90401 NCT00110214.

Legal entity responsible for the study

Federico Innocenti.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

119P - ERBB2 mRNA as a predictor in HER2-positive (HER2+)/hormone receptor-positive (HR+) metastatic breast cancer (BC) treated with HER2 blockade in combination with endocrine therapy (ET): A retrospective analysis of the ALTERNATIVE and SOLTI-PAMELA trials (ID 4377)

Presentation Number
119P
Lecture Time
12:00 - 12:00
Speakers
  • Nuria Chic (Barcelona, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The ALTERNATIVE trial randomized 355 patients (pts) with HER2+/HR+ metastatic BC to receive as 1st-line therapy lapatinib (L) + trastuzumab (T) + aromatase inhibitors (AI) or T + AI or L + AI. The neoadjuvant PAMELA trial tested a chemo-free regimen of L + T on HER2+ pts, combined with letrozole or tamoxifen in HR+ tumors. We explored the hypothesis that gene expression may help predicting benefit from anti-HER2 therapy in combination with ET.

Methods

The expression of 55 BC-related genes was evaluated from FFPE tumors using the nCounter. The PAM50 subtype distribution and the association of the expression of each gene (continuous variable) with progression-free survival (PFS) was evaluated using univariate Cox-models. Median PFS was calculated using the Kaplan-Meier method. Clinical benefit (CB) was defined as complete or partial response or stable disease at 6 months. The Cutoff Finder tool was used to find an optimal gene expression cut-off with CB as the endpoint. Logistic regression was used to evaluate the association of gene expression with pathologic complete resonse (pCR) and CB.

Results

In ALTERNATIVE, 60 tumors (16.9%) were analyzed: 57% HER2-enriched, 20% Luminal B, 12% Luminal A, 8% Normal-like and 3% Basal-like. Median PFS in ERBB2-high group (above the median) was higher compared to ERBB2-low group (11.0 vs 5.6 months; Hazard Ratio [HazR]=0.49; p = 0.006). ERBB2 was found more expressed in pts with CB. CB rate was higher in the ERBB2-high group compared to ERBB2-low group (54% vs 22%; p = 0.013). An optimal ERBB2 mRNA cutoff (2.923) for predicting CB (AUC=0.68; odds ratio [OR]=1.49, p = 0.014; PFS HazR=0.46, p = 0.022) was then identified. The same ERBB2 cutoff in PAMELA baseline tumor samples (n = 77) was found significantly associated with pCR (43.8% in ERBB2-high vs. 11.5% in ERBB2-low; adjusted OR = 4.45; p = 0.041).

Conclusions

ERBB2 mRNA expression is a robust predictor of response and survival outcome in HER2+/HR+ BC following HER2-blockade and ET. Our study identifies a common biomarker between pCR improvement (OR ∼4.5) in early disease and CB in the advanced setting (PFS HazR of ∼0.50).

Legal entity responsible for the study

Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).

Funding

Has not received any funding.

Disclosure

N. Chic: Travel / Accommodation / Expenses: Eisai. F. Schettini: Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Pfizer. M. Vidal: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Daiichi Sankyo. M. Muñoz: Travel / Accommodation / Expenses: Roche. J. Cortés: Honoraria (self): Novartis; Honoraria (self): Eisai; Honoraria (self): Roche; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Celgene; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biothera Pharmaceutical; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics. A. Llombart-Cussac: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche/Genentech. M. Rimawi: Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: MacroGenics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Daiichi Sankyo. A. Prat: Advisory / Consultancy: Nanostring Techonologies. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

120P - Early on-treatment vs pre-treatment tumour transcriptomes as predictors of response to neoadjuvant therapy for HER2-positive inflammatory breast cancer (ID 3439)

Presentation Number
120P
Lecture Time
12:00 - 12:00
Speakers
  • Sonia Pernas (Hospitalet de Llobregat, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Inflammatory breast cancer (IBC) is an understudied form of breast cancer (BC). The incidence of HER2-positive disease in IBC is 2-fold greater than that in non-IBC. Several studies evaluating dual-HER2 blockade in HER2-positive BC have demonstrated an association of specific gene expression signatures with response. Those analyses were based on pretreatment tumor characteristics and did not focus specifically on IBC. We used RNA-Seq to elucidate the impact of short term neoadjuvant dual-HER2 blockade on IBC transcriptomic profile and to identify early predictors of response.

Methods

We analyzed fresh frozen tumor samples prospectively obtained from 23 patients (pts) with HER2-positive IBC, treated at a single institution in a phase 2 trial (NCT01796197) with neoadjuvant trastuzumab, pertuzumab (HP) and paclitaxel for 16 weeks (wk). Breast biopsies were performed at baseline (D1) and 1 wk later (D8) after a single dose of dual blockade with HP before adding paclitaxel. Primary endpoint was pathologic complete response (pCR) defined as no evidence of invasive disease in breast or lymph nodes. Tumors from D1 and D8 were used for RNA-Seq analysis and assessment of tumor-infiltrating lymphocytes (TILs) and CelTIL score.

Results

Paired breast tumor biopsies (D1, D8) were obtained in all pts; 2 pts did not have surgery. In the intent-to-treat analysis, 10/23 (43%) pts achieved a pCR. Across all metrics, D8 biopsies were significantly better predictors of response than D1 (p-value: 1.0X10-15). Upregulation of immune signatures by RNA-Seq was observed at D1 and D8. D8 biopsies showed a greater upregulation of anti-tumor immunity and changes in multiple signalling pathways. Neither TILs nor CelTIL were associated with pCR.

Conclusions

We identified an accurate predictor of response based on transcriptomic profiling by RNAseq, following a single dose of neoadjuvant dual-HER2 blockade in HER2-positive IBC. It outperforms a similar predictor constructed on a pretreatment profile in the same cohort. Assessing early-changes in gene expression level by RNA-seq following one dose of treatment may provide insights for the molecular mechanisms underlying response or resistance to anti-HER2 therapy.

Clinical trial identification

NCT01796197.

Legal entity responsible for the study

Dana-Farber Cancer Institute.

Funding

Genentech, Inc and the Inflammatory Breast Cancer (IBC) Network.

Disclosure

S. Pernas: Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Polyphor. S. Goel: Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: G1 Therapeutics; Research grant / Funding (institution): Merck. J.L. Guerriero: Advisory / Consultancy, Research grant / Funding (institution): Glaxo-Smith Kline; Research grant / Funding (self): Eli Lilly. E.A. Mittendorf: Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Merck; Advisory / Consultancy: Peregrine Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Sellas Lifesciences; Advisory / Consultancy: Tapimmune. B. Overmoyer: Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Eisai. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

121P - AXL expression predicts poor prognosis and lack of efficacy of anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents in patients (pts) with RAS wild type (WT) metastatic colorectal cancer (mCRC) (ID 2512)

Presentation Number
121P
Lecture Time
12:00 - 12:00
Speakers
  • Claudia Cardone (Napoli, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Activation of AXL receptor tyrosine kinase is a key mediator of epithelial to mesenchymal transition (EMT). AXL is overexpressed in several human cancers, including CRC.

Methods

AXL expression was assessed by immunohistochemistry in tumor samples from 346 mCRC pts treated at three Institutions and enrolled in different clinical trials (CAPRI, MACBETH, MOMA, TRIBE2). In silico data of AXL RNA levels were obtained from GSE5851 dataset, including 80 pts with advanced mCRC treated with cetuximab in a later line.

Results

AXL expression was found in 18% of cases within tumor cells, with no difference among RAS cohorts. In the RAS WT group, AXL positive pts had a worse mPFS whether treated with chemotherapy (CT) + anti-EGFR [6.2 m (CI95% 4.2- 8.2) vs 12.1 m (CI95% 10.6 – 13.6) p 0.012] or CT+anti-angiogenic agent [6.7 m (CI95% 8.9- 19.3) vs 14.1 m (CI95% 9.4– 13.0) p 0.007], whereas in RAS mutant pts no impact on PFS was observed. AXL expression correlated with worse mOS in both cohorts; notably, in RAS WT pts mOS was 19.9 m (CI95% 10.5- 29.2) vs 37.6 m (CI95% 31.1– 44.1) p 0.006]. In tumor stroma, assessable in 334 samples, AXL was expressed in 80% of cases, with no difference among RAS groups. AXL expression correlated with lower mOS in both cohorts. (Table) Intriguingly, AXL expression in tumor and stroma (+/+) correlated with shorter mOS; in particular, RAS WT pts (+/+) had a mOS of 19.9 m (CI95% 8.0- 31.7) vs (-/-) 50.1 m (CI95% 43.9- 56.2) p 0.004]. In silico analyses showed high AXL RNA levels in 50% of pts. Moreover, in this population treated with cetuximab, in the KRAS exon2 WT cohort (N = 43) AXL high pts had worse mPFS [1.9 m (CI95% 1.7 -2.0) vs 3.8 m (CI95% 0.7-6.7) p 0.59].

CohortAXL expression in tumor cells
AXL expression in stroma
NNegative <1% (%)Positive ≥1% (%)PFS months p valueOS months p valueNNegative <1% (%)Positive ≥1% (%)PFS months p valueOS months p value
Overall population346285 (82)61 (18)10.7 vs 8.0 0.00832.4 vs 23.0 0.00733466 (20)268 (80)10.7 vs 8.0 0.1141.1 vs 28.5 0.004
RAS WT (overall)175147 (84)28 (16)12.3 vs 6.6 <0.00037.6 vs 19.9 0.00616733 (20)134 (80)15.0 vs 10.7 0.03449.8 vs 33.5 0.031
RAS WT CT + anti-EGFR136114 (84)22 (16)12.1 vs 6.2 0.01235.8 vs 23.0 0.08712918 (14)111 (86)14.3 vs 10.4 0.3744.4 vs 33.5 0.11
RAS WT CT + anti-angiogenic3933 (85)6 (15)14.1 vs 6.7 0.00744.8 vs 13.2 0.0043815 (39)23 (61)15.0 vs 11.0 0.1250.1 vs 40.6 0.17
RAS mut (overall) CT + anti-angiogenic171138 (81)33 (19)9.6 vs 8.9 0.7827.6 vs 23.7 0.3316733 (20)134 (80)9.7 vs 9.2 0.9835.5 vs 24.7 0.056

Conclusions

AXL expression in tumor and stroma might have a negative prognostic relevance in mCRC. In RAS WT pts, AXL expression might represent a predictive biomarker of lack of efficacy for both anti-EGFR and anti-angiogenic agents.

Legal entity responsible for the study

Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli".

Funding

AIRC MFAG-2015-ID: 7778.

Disclosure

F. Ciardiello: Advisory / Consultancy, Advisory Board: Merck KgA, Bayer, Amgen, Roche, Servier, Pfizer. E. Martinelli: Advisory / Consultancy: Merck KgA, Amgen, Bayer, Roche, Sanofi, Servier. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

122P - Prevalence of EGFR mutations and its correlation with Egyptian patients’ human kinetics (PEEK Study) (ID 4061)

Presentation Number
122P
Lecture Time
12:00 - 12:00
Speakers
  • Adel I. Khalil (Cairo, Egypt)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Lung cancer is a leading cause of cancer-related deaths. Knowledge is evolving regarding cancer driver genes. In Egypt, very limited data exist about cancer driver genes for non-small cell lung cancer. EGFR mutation testing was initiated in Egypt through a collaboration between Colors lab and AstraZeneca. Data collection was planned to detect the prevalence of EGFR and determine consequent medical decisions. In this real-world evidence context, we tried to sketch out the Egyptian EGFR gene mutations and correlatie them to patient demographics regarding gender, age, smoking history and pathological sub-types.

Methods

A total of 2017 formalin-fixed, paraffin-embedded (FFPE) tumors from patients diagnosed with non-small cell lung cancer were tested for EGFR mutation during the period between 2016 & 2018, following all aspects of GLP procedures including human rights, legal regulatory requirements, and AstraZeneca’s policy on bioethics. Patients were consented to collect their demographic and clinico-pathological data anonymously. DNA extraction was carried out using QIAamp DNA FFPE Tissue Kit. Extracted samples were tested by use of Therascreen EGFR RGQ PCR Kit on Rotorgene®, Qiagen.

Results

A total of 353 (17.5%) out of 2017 tested samples were positive for EGFR mutations. Mutations subtypes were detected in EGFR mutations presenting 151 (42.78%) for ex19 del, 106 (30.0%) for L858R point mutation, 39 (11.05%) for T790M mutations, 12 (3.4%) for insertions in exon 20, 8 (2.27%) for L861Q mutation, 8 (2.27%) for S768I mutation and 29 (8.22%) for other mutations. The older the patient age showed higher significance in prevalence rate (P < 0.001) than in younger age. EGFR prevalence was numerically (NS) higher among females than males. Both current and formerly smoking patients showed highly significant (P < 0.001) mutation frequencies compared with non-smokers. Adenocarcinoma showed a frequency of 55.8% with higher significance than other pathological cell types.

Conclusions

This is the first and largest study on EGFR mutation prevalence among Egyptian patients showing a slightly higher percentage than in European patients. Age, smoking status and pathological reports define significant impact on EGFR mutation pattern in Egyptian patients.

Legal entity responsible for the study

AstraZeneca Egypt.

Funding

AstraZeneca Egypt.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

123P - Evaluation of tumour microenvironment identifies immune correlates of response to combination immunotherapy with margetuximab (M) and pembrolizumab (P) in HER2+ gastroesophageal adenocarcinoma (GEA) (ID 2547)

Presentation Number
123P
Lecture Time
12:00 - 12:00
Speakers
  • Sergio Rutella (Nottingham, United Kingdom)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Despite improvements in treatments, the 5-year survival of GEA patients (pts) is disappointing. Individual molecular subtypes display preferential responses to PD-1 blockade. M, an investigational Fc-optimized anti-HER2 monoclonal antibody, is being tested in combination with P in HER2+ GEA post trastuzumab. We present gene expression data from archival FFPE biopsies.

Methods

55 pt samples were assessed by NanoString PanCancer IO360™ assay. Immune signature scores are presented as fold changes (FC) and analyzed by unpaired t-test. Associations examined include baseline IHC PD-L1 (pos vs neg) and HER2 expression (IHC3+ vs 2+), ERBB2 mRNA, inflamed tumor microenvironment (TME), radiographic response, and GC vs GEJ.

Results

ERBB2 mRNA was increased in pts with HER2 IHC3+ vs 2 + (5.6 FC, p < 0.001); IHC3+ was also associated with an inflamed TME (higher IFN-γ signaling, cell proliferation, PD-L2 and inflammatory chemokine expression). ERBB2 expression significantly correlated with response; pts with CR/PR had a 5.13 FC ERBB2 expression compared to PD (p < 0.001). Importantly, ERBB2 expression was associated with anti-tumor activity (ROC-AUC=0.754), with a 3.1 FC between SD/PR/CR vs PD (p = 0.004). TME gene signatures, including PD-1/PD-L1, CTLA4, cytotoxic CD56dim NK cells and DR5 abundance, also trended higher in responders. GC tumors expressed higher levels of ERBB2 (5.25 FC, p < 0.001), with a trend towards a more inflamed TME (higher PD-L1, IFNγ), and had increased clinical response-- this differed from GEJ tumors, which showed lower ERBB2 expression, higher expression of IFITM1, MYC and STAT3, and less clinical responses. Lastly, in PD-L1pos vs PD-L1neg samples, PD-L1 gene expression (1.3 FC, p = 0.013), IFN-γ signaling (1.5 FC, p < 0.001), LAG3 expression (1.4 FC, p = 0.045), IDO1 expression (1.7 FC, p = 0.031), inflammatory chemokines (1.7, p = 0.005), and tumor inflammation signature (1.5 FC, p = 0.0064) were all significantly elevated.

Conclusions

Our study documents for the first time ERBB2 expression and inflamed TME in GEA, which can help differentiate immunologically between GC and GEJ tumors.

Clinical trial identification

NCT02689284.

Legal entity responsible for the study

MacroGenics, Inc.

Funding

MacroGenics, Inc.

Disclosure

S. Rutella: Leadership role: Society for Immunotherapy of Cancer; Research grant / Funding (institution): John and Lucille van Geest Foundation. S.E. Church: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. A.H. Sullivan: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. S. Warren: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. J. Baughman: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Muth: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. H. Park: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex. H. Uronis: Shareholder / Stockholder / Stock options, Full / Part-time employment: GeneCentric; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Macrogenics. Y. Kang: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): DAE HWA Pharmaceutical; Advisory / Consultancy: Lilly/ImClone; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Taiho Pharmaceutical; Research grant / Funding (self): LSK Biopharma. M.C.H. Ng: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self), Travel / Accommodation / Expenses: Taiho Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): ASLAN Pharmaceuticals. P. Enzinger: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho Pharmaceutical. K.W. Lee: Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics. K. Huber: Full / Part-time employment: Macrogenics, Inc. A. Wynter-Horton: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. D. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy, Research grant / Funding (institution): Green Cross; Advisory / Consultancy: Hanmi; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): MSD Oncology; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Samyang; Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): CKD; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda. J. Davidson-Moncada: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Five Prime Therapeutics; Honoraria (self), Speaker Bureau / Expert testimony: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Genentech/Roche; Honoraria (self): Genmab; Honoraria (self): Gritstone Oncology; Honoraria (self), Speaker Bureau / Expert testimony: Guardant Health; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): NantOmics; Honoraria (self): OncoPlex Diagnostics; Honoraria (self), Advisory / Consultancy: Taiho Pharmaceuticsal; Advisory / Consultancy: Astellas Pharma. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

124P - Clinicopathological and molecular criteria assessment for the screening of hypermutated proficient mismatch repair (pMMR) colorectal cancers (CRC) with exonucleasic domain POLE (edPOLE) mutations (mt) (ID 4671)

Presentation Number
124P
Lecture Time
12:00 - 12:00
Speakers
  • Benoit J. Rousseau (Créteil, CEDEX, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

MMR Deficiency (dMMR) and edPOLE mutations (mt) are responsible for hypermutated tumoral phenotype. Immunotherapy have shown efficacy in dMMR/high mutation burden patients (pts). One of the French AcSé Nivolumab trial cohorts aims to assess Nivolumab in advanced edPOLE mt tumors. These mt occur in 1-2% of Colorectal Cancer (CRC). We aimed to define the most relevant criterias in CRC to facilitate the screening for inclusion in the AcSé Nivolumab edPOLE cohort.

Methods

edPOLE mutational status was evaluated in a cohort of locally advanced/metastatic (LA/M) CRC cancers enriched for BRAF mt, RAS mt, and unusual BRAF/RAS mt using High Resolution Melting PCR on the three hotspots described in the literature (codons 286, 411 and 459). Patients harboring edPOLE mt were then analyzed using FoundationOne genomic testing including tumor mutational burden (TMB).

Results

386 CRC pts were analysed between 2012 and 2018 (208 with atypical RAS or BRAF mutation, 119 with classical RAS or BRAF mutation, 59 RAS/BRAF wild type): 11 edPOLE mutated tumors were identified, most frequently in young male pts (Sex ratio 4,5, mean age: 54 years), pMMR (91%, 10/11), with left-sided tumors (73%, 8/11). The prevalence of edPOLE mt in atypical KRAS/BRAF mutated tumor was 5.3% (11/208) vs 0% (0/178) in other cases (p = 0.02). Among the 11 edPOLE mt cases, 2 had a low TMB ( < 12mt/Mb) 3 were hypermutated (TMB≥12- < 100 mt/Mb) and 6 ultramutated (TMB≥100mt/Mb). High TMB (mean 172 mt/Mb) was observed in 8 pMMR cases: 7 mt in hotspots (4, 2 and 1 respectively in codons 286, 411 and 459); 1 mt outside hotspots (codon 461). Codons 464 and 425 pMMR edPOLE mt cases had a low TMB (4 mt/Mb) and one was hypermutated dMMR case had a silent POLE codon 464 mt.

Conclusions

A screening strategy based on clinicopathological (male gender, young age, left-sided tumors), and molecular criterias (pMMR, unusual BRAF/KRAS mutations) may help to identify pathogenic edPOLE mt (codons 286, 411, 459 and 461) associated with a high TMB in LA/M CRC. The use of these criterias could help to select patients for POLE mt screening and facilitate their access to immunotherapy.

Clinical trial identification

NCT03012581.

Legal entity responsible for the study

The authors.

Funding

Roche.

Disclosure

B.J. Rousseau: Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

125P - Tumour mutation burden and microsatellite instability in colorectal cancer (ID 3862)

Presentation Number
125P
Lecture Time
12:00 - 12:00
Speakers
  • Francesca Fenizia (Napoli, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The role of tumour mutation burden (TMB) as predictive biomarker of response to immune checkpoint inhibitors (ICI) is being explored in colorectal cancer (CRC). Microsatellite instability status (MSI) is currently used to identify CRC patients who may benefit from ICI. However, TMB values vary significantly among MSI CRC. In addition, selected microsatellite stable (MSS) with high TMB might also benefit treatment with ICI.

Methods

TMB evaluation was performed with the Oncomine Tumor Mutation Load Assay (OTML, Thermofisher) on the Ion S5XL platform. Data analysis was carried out using Ion Reporter Software v5.10. TMB was calculated as the total number of non-synonymous somatic single nucleotide variants (SNVs) and indels divided by number of bases sequenced. MSI status was analysed by means of the Idylla MSI assay (Biocartis), which evaluates the presence of mutations in 7 novel MSI loci.

Results

TMB analysis was performed on 106 formalin-fixed paraffin embedded CRC samples and the data were compared with the MSI results. The Idylla assay classified 68 samples as MSS and 38 samples as microsatellite instable (MSI-H). The TMB values ranged from zero to 21.22 (median: 5.005) in the MSS and from 13.42 to 204.8 in the MSI-H group (median: 25.66), with a significant difference in median values (P < 0.0001). A significant difference in TMB values was also observed when the number of mutated MSI-associated loci was ≥2 versus <2. We next correlated the presence of mutations in a group of driver genes with the TMB values. Significantly different median TMB values were registered when a BRAF (Mann Whitney p value: 0.0023) or PIK3CA mutation (p value: 0.0082) was present, but not when KRAS alterations were detected.

Conclusions

The TMB values assessed with the OTML assay strongly correlated with MSI status in CRC. However, significant heterogeneity in TMB levels were detected among both MSI and MSS tumors, suggesting that TMB testing might provide additional information on sensitivity to ICI in CRC. The correlations with driver gene alterations might help in selecting tumors to be tested for TMB.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

126P - Predictors of response to checkpoint inhibitors in naïve and ipilimumab-refractory melanoma (ID 4614)

Presentation Number
126P
Lecture Time
12:00 - 12:00
Speakers
  • Domenico Mallardo (Napoli, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Response to checkpoint inhibitors (CI) is governed by the tumor immune environment and understanding this immune contexture can predict response. Therapeutic intervention can change this environment even in the absence of clinical response. Patients failing initial immunotherapy may respond to a second line of CI; however, these cohorts show lower overall response rates (ORR). This study identifies transcriptional signatures associated with response to first- and second-line CI monotherapy in melanoma.

Methods

CI-naïve or ipilimumab-refractory patients were treated with ipilimumab, nivolumab or pembrolizumab at the Instituto Nazionale Tumori and clinical response was evaluated by irRECIST 1.1 criteria. Pretreatment tumor biopsies (n = 82) from metastatic lesions were collected and RNA was profiled with the NanoString® IO360 gene expression panel.

Results

Compared to CI-naïve cohorts, ipilimumab-refractory cohorts had reduced ORR to nivolumab (naïve: 35%, n = 6; refractory: 20%, n = 10) or pembrolizumab (naive: 67%, n = 6; refractory: 20%, n = 10) with multiple genes differentially expressed between groups. The Tumor Inflammation Signature, an investigational 18 gene signature of suppressed adaptive immune response enriching for pembrolizumab response, was higher in responders versus non-responders in first-line (log2 fold change: 1.56, p = 0.21), but not second-line pembrolizumab (log2 fold change: 0.41, p = 0.60). First-line pembrolizumab responders had elevated MHC2 (log2 fold change: 1.35, p = 0.02) and B cell (log2 fold change: 2.14, p = 0.02) signatures. Upon stratifying the CI-naïve cohort between no prior treatment versus prior targeted/chemotherapy, the latter had increased immune expression suggesting these therapies prime the tumor immune environment.

Conclusions

Correlating patterns of tumor gene expression with clinical response can lead to the development of biomarkers enriching for CI response in both first-line and CI-refractory patients. Utilization of a clinical grade platform such as the NanoString nCounter® may speed the development of diagnostic assays used to predict and monitor patient response to immunotherapy.

Legal entity responsible for the study

The authors.

Funding

NanoString Technologies.

Disclosure

S. Ong: Full / Part-time employment: NanoString Technologies. S. Warren: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. A. Cesano: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. J.M. Beechem: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. P.A. Ascierto: Advisory / Consultancy: Amgen; Advisory / Consultancy: Array; Advisory / Consultancy: BMS; Advisory / Consultancy: Incyte; Advisory / Consultancy: Immunocore; Advisory / Consultancy: MedImmune; Advisory / Consultancy: IDERA; Advisory / Consultancy: Genmab; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

127P - IFN-γ/IL-10 ratio as predictive biomarker for response to anti-PD-1 therapy in metastatic melanoma patients (ID 2901)

Presentation Number
127P
Lecture Time
12:00 - 12:00
Speakers
  • Emilio F. Giunta (Napoli, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Anti-PD-1 antibodies represent nowadays a first-choice therapy for metastatic melanoma patients. Despite impressive results in terms of PFS and OS, a proportion of patients does not respond to anti-PD-1 therapy with an overall poor prognosis. Identification of predictive biomarkers is considered an important unmet clinical need to avoid expensive and potentially harmful drugs in patients who will not respond to them. In the last years, many studies have evaluated the role of cytokines on both blood and tissue samples as predictive biomarkers for immunotherapy, with encouraging results.

Methods

Blood samples from 18 patients with metastatic melanoma treated with anti-PD-1 antibodies as first line therapy were collected at baseline. 8 patients were classified as non-responders (best response: PD excluding pseudo-progression with median PFS of 2 months) and 10 patients as responders (best response: PR or CR, with median PFS of 17 months). mRNA expression levels of the main pro- and anti-inflammatory cytokines were evaluated by Real time quantitative PCR in PBMCs obtained from baseline blood samples. Unpaired two-tailed t-test was used for statistical analysis.

Results

IFN-γ mRNA expression levels were higher in responder patients (p < 0.01) whereas IL-10 levels tended to be higher in non-responders (p > 0.05). Combining data for each patient, we noticed a correlation between higher levels of IFN-γ and lower levels of IL-10 for responders and vice versa. Starting from these findings, we observed that the IFN-γ/IL-10 ratio was higher (median: 43,3 vs 5,2) in responders (p < 0.01), with high negative and positive predictive value (NPV:100% and PPV:91% using a threshold of 18). The main lymphocyte subpopulations producing these cytokines were also identified.

Conclusions

Our data suggest an interesting correlation between IFN-γ/IL-10 ratio and response to anti-PD-1 therapy in melanoma patients. This correlation seems to be stronger than using IFN-γ expression levels alone probably because of the influence of anti-inflammatory cytokines. Since this is an exploratory and retrospective analysis of 18 patients, a larger population should be tested to validate our results.

Legal entity responsible for the study

Dipartimento di Medicina di Precisione, Università degli studi della Campania Luigi Vanvitelli.

Funding

Has not received any funding.

Disclosure

F. Ciardiello: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Servier; Advisory / Consultancy: BMS; Advisory / Consultancy: Cellgene; Advisory / Consultancy: Lilly; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Takeda. T. Troiani: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

128P - Multiplex chromogenic Immunohistochemistry (IHC) for spatial analysis of checkpoint-positive tumour infiltrating lymphocytes (TILs) (ID 2306)

Presentation Number
128P
Lecture Time
12:00 - 12:00
Speakers
  • Scott Ely (Princeton, NJ, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Spatial localization of TILs has been shown to correlate with immunotherapy response. Chromogenic IHC (cIHC) enables assessment of lineage (eg, CD8) or immune checkpoint expression (eg, T-cell immunoglobulin and mucin-domain–containing-3 [TIM-3]). Codetection of lineage and checkpoint molecules may help to better inform responders to checkpoint inhibitors, but colocalization is challenging by cIHC. Fluorescence (fIHC) allows colocalization but not spatial assessment and is not an approved CDx platform. Consequently, CDxs have been limited to single-plex cIHC assays. We developed a multiplex cIHC platform that enables image analysis colocalization and spatial assessment of TILs.

Methods

Image analysis of cIHC via HALO software was performed to detect colocalized CD8 and TIM-3. We compared % TIM-3+/CD8+ by cIHC to TIL multiparameter flow cytometry (MFC) on 10 procured renal cell carcinoma (RCC) samples. Pathologist annotation and a trained random forest machine-learning tissue classifier were used to determine spatial localization (tumor vs peritumoral vs nontumor) of CD8+ and TIM-3+/CD8+ TIL subsets. We also performed a validated fIHC assay, including CD8 and TIM-3, on 5 additional procured RCC samples.

Results

High concordance (r = 0.92) was observed between % TIM3+/CD8+ TILs measured by cIHC and MFC. Image analysis showed that within the CD8+ population, median % TIM-3+/CD8+ TILs were primarily intratumoral (18.0%), with fewer in peritumoral (9.4%) and nontumoral (6.4%) regions (intratumoral vs peritumoral, and intratumoral vs nontumor, both P = 0.015). TIM-3/CD8 coexpression detection appeared similar between cIHC and fIHC.

Conclusions

We developed a multiplex cIHC method that enables simultaneous quantitation of TIL subpopulations, checkpoint expression, and spatial analysis. cIHC, fIHC and MFC performed similarly in coexpression detection, but only multiplex cIHC enabled spatial localization. Specifications of this assay show promise for development as a CDx. Additional data will demonstrate the capability to substitute TIM-3 with other markers, suggesting an assay template for other lineage/target combinations.

Editorial acknowledgement

Amrita Dervan, MSc, and Jay Rathi, MA, of Spark Medica Inc, funded by Bristol-Myers Squibb.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

S. Ely: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. G. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. L. Menard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Yan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. P. Fischer: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. B. Kakrecha: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. D. Locke: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. P. Patah: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. K. Urbanska: Full / Part-time employment: Bristol-Myers Squibb.

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Poster Display session 3 Poster Display session

129P - The role of PD-L1 expression as a predictive biomarker in advanced renal cell carcinoma: A meta-analysis of randomized clinical trials (ID 1678)

Presentation Number
129P
Lecture Time
12:00 - 12:00
Speakers
  • Alberto Carretero-Gonzalez (Madrid, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Immune checkpoint inhibitors (ICIs) are beneficial in a subset of metastatic renal cell carcinoma (mRCC) patients. However, no biomarker has been shown to be useful to select which patient benefits and the role of programmed death-ligand 1 (PD-L1) expression on tumor samples is controversial.

Methods

We assessed the potential role of PD-L1 expression according to Cochrane Collaboration’s Guidelines. Search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care (SoC) in mRCC patients was performed. Trials must have included subgroup analysis evaluating the selected outcomes (progression-free survival-PFS- and overall survival-OS-) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios (HR) with confidence intervals (CI) were used as the measure of efficacy between groups.

Results

A total of 3,720 patients (5 studies) were included (ICIs arm: 1,913 patients; SoC arm: 1,807 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: 0.003) but it did not seem to impact in OS results (p-value for difference: 0.29).

Value of PD-L1 expression as a predictive biomarker for ICIs. HR: Hazard ratio. CI: Confidence interval

Total populationHigh PD-L1Low PD-L1p-value for difference
PFSHR 0.72; 95% CI 0.58-0.90HR 0.63; 95% CI 0.51-0.77HR 0.96; 95% CI 0,79-1.160.003
OSHR 0.69; 95% CI 0.61-0.78HR 0.64; 95% CI 0.54-0.77HR 0.73; 95% CI 0.62-0.870.29

Conclusions

PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

130P - Radiomic features as a non-invasive biomarker to predict response to immunotherapy in recurrent or metastatic urothelial carcinoma (ID 5138)

Presentation Number
130P
Lecture Time
12:00 - 12:00
Speakers
  • Kye Jin Park (Seoul, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Reliable biomarkers to predict response to immunotherapy is crucial for patients’ counseling and decision making. This study was aimed to identify the role of CT radiomic features in predicting response to immunotherapy in patients with recurrent or metastatic urothelial carcinoma.

Methods

A total of 62 patients with their 224 lesions who underwent PD-1 and PD-L1 immunotherapy between March 2015 and November 2017 were retrospectively analyzed. The patients were temporally divided into training sets (n = 41; 155 lesions) and independent test set (n = 21; 69 lesions). For radiomics feature extraction, two radiologists independently segmented the region of interest at baseline CT on portal venous phase. A radiomics signature (RAD score) was built by using the least absolute shrinkage and selection operator (LASSO) method. The diagnostic performance of RAD score for prediction of response to immunotherapy was evaluated by C statistics.

Results

The overall response rate of immunotherapy was 36.6% in the training set and 28.8% in the test set. RAD score revealed the C statistics of 0.83 (95% CI, 0.68–0.93) in the training set and a corresponding C statistics of 0.71 (95% CI, 0.48–0.89) in the test set.

Conclusions

This study suggests that radiomic features extracted from metastatic masses at baseline CT are predictive of response to immunotherapy in patients with recurrent or metastatic urothelial carcinoma.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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Poster Display session 3 Poster Display session

131P - Integrative combination of high-plex digital profiling techniques and cluster analysis to reveal complex immune biology in the tumour microenvironment of mesothelioma (ID 5800)

Presentation Number
131P
Lecture Time
12:00 - 12:00
Speakers
  • Carmen Ballesteros-Merino (Portland, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Malignant mesothelioma is an aggressive cancer with poor prognosis and few effective therapies. Due to its derivation from the mesothelium of the lung, immune cells in the tumor microenvironment (TME) may behave differently than in other solid tumors. We describe the combination of two techniques to spatially characterize the tumor-immune profile in mesothelioma.

Methods

47 FFPE mesothelioma tumors were characterized by Definiens’ Immune-Oncology Panel (IOP) and NanoString’s GeoMx™ Digital Spatial Profiling (DSP). Three alternating sequential sections were stained with IOP (CD8/PD-1/FOXP3, CD68/PD-L1/CD3, Granzyme B (GRZMB)). DSP was performed on 12 IOP-derived regions-of-interest (ROIs) on the interleaving slide by a combination of a fluorescent antibodies stain (pan-CK, CD3, CD68) and a panel of 38 UV-photocleavable DNA barcoded antibodies quantified on the nCounter® platform. Gene expression was assessed using NanoString’s PanCancer IO 360™ (IO360) assay.

Results

Cluster analysis based on the IOP revealed 6 distinct immune groups. Two of these had high IOP CD68 density, distinguished by an inhibitory phenotype (PD-L1+) and activated macrophage profile. Subsequent DSP analysis showed that e.g. VISTA, B7-H4 amongst others were higher in the active vs. inhibitory macrophage group. Overall survival (OS) was not associated with density of T cell marker expression measured by IOP/DSP. The IO360 analysis confirmed that and showed tumor-related gene signatures (e.g. proliferation, hypoxia), but not lymphoid-related ones were upregulated in patients with <12 months OS. DSP analysis of VISTA, B2M[BM1] , β-catenin and GRZMB were significantly associated with >12 months OS.

Conclusions

Based on a novel combination of two high-plex spatial analysis techniques, we propose mesothelioma subtypes where macrophages act as immune inhibitory or activated with the latter displaying a possible T-cell excluded phenotype. We also show that deep-profiling of biology within the TME identifies prognostic markers of OS. Thus, we hypothesize that this approach may guide a better understanding and help to develop effective immunotherapies.

Legal entity responsible for the study

Bernard A. Fox.

Funding

Nanostring and Definiens.

Disclosure

T. Herz: Full / Part-time employment: Definiens. S.E. Church: Shareholder / Stockholder / Stock options, Full / Part-time employment: Nanostring. M. Widmaier: Full / Part-time employment: Definiens. A. Budco: Full / Part-time employment: Definiens. D. Medrikova: Full / Part-time employment: Definiens. I. Kanchev: Full / Part-time employment: Definiens. A. Spitzmueller: Full / Part-time employment: Definiens. A. Shaepe: Full / Part-time employment: Definiens. A. White: Shareholder / Stockholder / Stock options, Full / Part-time employment: Nanostring. J. Reeves: Shareholder / Stockholder / Stock options, Full / Part-time employment: Nanostring. A.H. Sullivan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Nanostring. M. Bailey: Shareholder / Stockholder / Stock options, Full / Part-time employment: Nanostring. R. Sanborn: Advisory / Consultancy: CellDex. C. Bifulco: Advisory / Consultancy: Ventana/Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: HalioDx; Advisory / Consultancy, Shareholder / Stockholder / Stock options: PrimeVax. S. Warren: Shareholder / Stockholder / Stock options, Full / Part-time employment: Nanostring. J.M. Beechem: Shareholder / Stockholder / Stock options, Full / Part-time employment: Nanostring. B. Fox: Advisory / Consultancy: Argos; Advisory / Consultancy: AstraZeneca/MedImmune; Advisory / Consultancy, Research support: Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy: CellDex; Advisory / Consultancy: Clearlight; Advisory / Consultancy, Research support: Definiens; Advisory / Consultancy, Research support: Janssen; Advisory / Consultancy, Research support: Macrogenics; Advisory / Consultancy, Research support: Nanostring; Advisory / Consultancy, Research support: OncoSec; Advisory / Consultancy, Research support: PerkinElmer/Akoya; Advisory / Consultancy, Shareholder / Stockholder / Stock options: PrimeVax; Advisory / Consultancy, Research support: Quanterix; Advisory / Consultancy, Research support: Shimadzu; Advisory / Consultancy: Ultivue; Advisory / Consultancy, Research support: Ventana/Roche; Advisory / Consultancy, Research support: Viralytics/Merck; Leadership role, Shareholder / Stockholder / Stock options: UbiVac. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

132P - Predictive factors of response to immunotherapy in 198 patients with metastatic non-microcytic lung cancer (mNSCLC): Real world data from 2 university hospitals in Spain (ID 5736)

Presentation Number
132P
Lecture Time
12:00 - 12:00
Speakers
  • Juan Felipe Cordoba Ortega (Lleida, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Patients with mNSCLC benefit in terms PFS and OS of treatment with immunotherapy (IO) in first (1L) and second line (2L); However, the majority of patients do not respond to IO, which, due to the high cost of these new treatments, makes identifying predictive factors of response imperative in order to select the patients who will really respond to this therapy. Bearing in mind that most hospitals do not have the technology to perform high sensitivity techniques such as NGS, it seems prudent to be able to identify these patients using more common, cheap and affordable methods in any hospital.

Methods

In all mNSCLC treated with IO in monotherapy in two university hospitals in Spain, from February 2012 to January 2018, a RWD study of predictive factors of response was performed. 198 patients from the University Hospital Arnau de Vilanova of Lleida and the University Hospital Dr. Josep Trueta (ICO Girona) were analyzed. Statistical analysis of the data was performed using IBM SPSS Statistics 23.0 software.

Results

With a median follow-up from the start of treatment with IO of 217 days, it was found that in all treated patients, the overall response rate (ORR = CR + PR) was 26.6%. In 1L the ORR was 56%, in 2L 22.8%, in 3L 15% and in 4L 0%. In 1L, the factor that is associated with a better response is the absence of liver mets: ORR 66.7% vs 16.7% (p: 0.03). The factor associated with a better OS is Hb ≥ 12.5 gr/dl (p 0.001): 495 vs 241 days. Analyzing by treatment lines, we objectify that in 1L, the factors that influence better OS are the absence of liver mets (p 0.003): 421 (CI: 345-497) vs 138 days (CI: 65-212) ) and Hb ≥ 12.5gr dl (p 0.027) 440 (CI: 368-512) vs 215 days (CI: 111-319). In 2L the factors that influence a better OS are younger age with a cutoff point of 70 years (p 0.008): 328 vs 239 days; Hb ≥ 12.5 gr/dl (p 0.001): 512 vs 325 days and lymphocytes > 1450 (p 0.013): 353 vs 241 days.

Conclusions

Methods that are easily available in any hospital can help select the patients that benefit most from immunotherapy in monotherapy. In our series, patients older than 70 years, with Hb ≤ 12.5 gr/dl and lymphocytes ≤1.450, have worse overall survival independently of PDL1.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

133P - Evaluating lung ct density changes among patients with extensive stage small cell lung cancer (ES-SCLC) treated with thoracic radiotherapy (TRT) alone or TRT followed by combined ipilimumab (IPI) and nivolumab (NIVO) (ID 5645)

Presentation Number
133P
Lecture Time
12:00 - 12:00
Speakers
  • Kujtim Latifi (Tampa, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Radiation induced CT changes may be apparent following completion of TRT. We sought to quantify differences in radiation-associated densities on serial CT scans of patients with ES-SCLC treated with TRT alone versus TRT followed by combined IPI and NIVO.

Methods

Between 2016 and 2018, patients at a single institution with ES-SCLC who achieved stable disease or better following initial treatment with platinum doublet chemotherapy were offered TRT and prescribed a total dose of 30Gy in 10 fractions targeting initially involved thoracic tumor sites. Combined IPI 3mg/kg and NIVO 1mg/kg was administered every 3 weeks for up to 4 doses. We evaluated an irradiated region of interest (ROI) within the lungs and a volume of lung (outside the Planning Target Volume) receiving > 20 Gy. Within the ROI, we calculated the Hounsfield unit (HU) mean for each patient prior to therapy and at subsequent follow-up CT thorax at least 60 days and closest to 120 days after commencing TRT. To quantify CT density change, we measured the difference in HU mean within the irradiated ROI before and after treatment.

Results

Seventeen patients enrolled on NCT03043599 received TRT followed by combined IPI/NIVO. Two additional patients received the same treatment off protocol. Eleven patients received TRT alone (no IPI/NIVO). The average increase in HU mean within 20Gy irradiated ROI before and after treatment was 9% (max 59%, min -19%) across the study cohort (n = 30). CTCAE grade 3 or higher pulmonary toxicity (N = 8 of 30) was significantly associated with increased CT density change within the ROI (mean 28% vs 2%, p = 0.001). Treatment with TRT and IPI/NIVO (N = 19 of 30) demonstrated a trend towards increased mean CT density change within the ROI compared to patients treated with TRT alone (mean 13% vs. 0%, p = 0.1).

Conclusions

Quantifying CT density change within irradiated lung parenchyma may offer a novel approach to predict radiation associated pulmonary toxicities. Measuring density changes across patient cohorts receiving TRT with novel systemic therapies may help to identify combined treatment strategies likely to be associated with diminished risk of toxicity.

Legal entity responsible for the study

The authors.

Funding

Bristol-Myers Squibb.

Disclosure

S. Kim: Research grant / Funding (institution): Bristol-Myers Squibb. S.A. Rosenberg: Advisory / Consultancy: Novocure. J.E. Gray: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Triptych Health Partners. S.J. Antonia: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck; Advisory / Consultancy: CBMG; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca/MedImmune; Advisory / Consultancy: Memgen; Advisory / Consultancy: FLX Bio; Advisory / Consultancy: Nektar; Advisory / Consultancy: Venn. B. Perez: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

134P - Immuno-oncology therapy biomarkers differences between polyoma-virus positive and negative Merkel cell carcinomas (ID 1540)

Presentation Number
134P
Lecture Time
12:00 - 12:00
Speakers
  • Zoran Gatalica (New York, Arizona, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) is detected in the majority of MCCs while MCPyV-negative cases are thought to arise through progressive accumulation of ultraviolet-light induced somatic mutations. In a non-selected cohort of stage IV MCC patients, treatment with Avelumab (an anti-PD-L1 monoclonal antibody), showed durable responses in less than a third of patients, regardless of their PD-L1 or MCV status. We hypothesized that there are significant differences in other predictors of response to I-O therapy in MCC related to their oncogenic origins.

Methods

48 MCC samples were analyzed for the presence of MCPyV using immunohistochemistry for detection of the large T-antigen (CM2B4 clone). Biomarkers of I-O therapy response included: expression of PD-L1 (IHC), total mutational burden (TMB) and microsatellite instability (MSI).

Results

Overall, MCPyV was detected in 18/48 cases using IHC (37.5%). In MCPyV-positive cases (N = 9) average TMB was 6/Mb (range 4-11/Mb), while MCPyV-negative cases (N = 21) had a significantly (p < 0.0001) higher average TMB of 25/Mb (range 4-68/Mb). No microsatellite instability was detected in any of the cases (0/22). The most commonly mutated gene in MCPyV-negative cohort was TP53 detected in 20 cases, with co-mutation of RB1 in 11 cases. Only one pathogenic mutation (ARID1A) was detected in any of the 9 MCPyV-positive cases. A single (MCPyV-positive) case exhibited PD-L1 expression in 5% of tumor cells.

Conclusions

MCPyV associated MCC was present in a significantly lower proportion of cases in our data set (37.5%) than has been reported in the general population (70-80%), potentially due to preselection of advanced disease cases. Successes of Avelumab therapy in MCC may be related to the high mutational load in MCPyV-negative cases and mediated through PD-L1+ immune cell infiltrate (IC) influence on effector (PD-1) lymphocytes, or some other mechanism. Further analysis of the status of these (and potentially other) biomarkers of response to immune check point inhibitors is recommended to refine the subgroups of patients responding to therapy.

Legal entity responsible for the study

Caris Life Sciences.

Funding

Caris Life Sciences.

Disclosure

Z. Gatalica: Leadership role: Caris Life Sciences. J. Xiu: Leadership role, employment: Caris Life Sciences. J. Swensen: Leadership role, employment: Caris Life Sciences. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

135P - Can we improve patient selection for phase I clinical trials (phI1) based on immuno-oncology score prognostic index (VIO)? (ID 4538)

Presentation Number
135P
Lecture Time
12:00 - 12:00
Speakers
  • Ignacio Matos Garcia (Barcelona, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Life expectancy longer than 12 weeks(w) is a common inclusion criteria for most Ph1. Despite the presence of several prognostic indeces in drug development, their value for patient selection in clinical trials is not well established. VIO is a immune-oncology score validated in patients treated in Ph1 with immunotherapy (Hierro C. ESMO 2018), which includes 5 variables: albumin<35g/L, lactate dehydrogenase > upper limit normal, dNLR (derived neutrophil/(leukocytes minus neutrophils) ratio) >3, >2 sites of metastases, and presence of liver metastases.

Methods

VIO variables were retrospectively collected from 384 patients with advanced disease treated in Ph1 with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) since 2011 to 2017 at Vall d´Hebron Hospital. The following VIO clusters were defined based on Kaplan Meier OS estimates: good prognosis (0‐1), intermediate (2‐3) and poor prognosis (4‐5). We aimed to improve patient selection for Ph1 (independent of treatment type) by developing a composite VIO score that is associated with overall survival (OS), progression free survival (PFS) and objectively estimated life expectancy at 12 w.

Results

From the 384 patients treated with ICIs (53.6%) or TAs (45.4%) in Ph1, 206 (53.6%) were female, 210 were treated with monotherapy (54.7%). Most frequent tumor types were: colorectal (17.4%), breast (14.1%) and lung (9.4%). The median follow-up was of 8.4 months (m) [IC95% 7.3-9.5]. Estimated median OS in good prognosis (33.3% of all pts), intermediate (54.2%) and poor prognosis (12.5%) was 16.2 m (13.3‐19.1), 7.8 m (6.9‐8.6) and 2.9 m (2.1-3.8), respectively (log rank test, p < 0.001), while the median PFS was 3.3 m (2.6‐3.9), 1.9 m (1.7‐2.1) and 1.2 m (0.8-1.6), respectively (log rank test, p < 0.001). Proportions of patients with life expectancy < 12 w were 52.2%, 13.1% and 4.3% in poor, intermediate and good prognosis VIO score groups, respectively (chi square<0.001).

Conclusions

VIO score is a strong prognostic index independent of the treatment type and it could be useful as a tool to estimate objectively life expectancy <12 w. More than 50% of patients with VIO score 4-5 (poor prognosis) died within 12 w, an estimate that can guide recruitment in phase 1 trials.

Legal entity responsible for the study

The authors.

Funding

This research has been funded by the Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) supported by the Banco Bilbao Vizcaya Argentaria Foundation (FBBVA) (grant 89/2017).

Disclosure

J. Martin-Liberal: Advisory / Consultancy: Bristol-Myers Squibb, Novartis, Pierre Fabre, Roche; Speaker Bureau / Expert testimony: Astellas, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche; Honoraria (self): Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Ipsen. A. Azaro: Honoraria (self), Advisory / Consultancy: Novartis, Roche, Orion. I. Brana: Advisory / Consultancy: Orion pharma; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Merck Serono; Research grant / Funding (self): AstraZeneca, BMS, Celgene, Gliknik, GSK, Janssen, KURA, MSD, Novartis, Northern Biologics, Orion Pharma, Pfizer, Roche.. M. Vieito Villar: Honoraria (self), Travel grant: Roche. E. Muñoz-Couselo: Advisory / Consultancy: Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche; Honoraria (self): Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche. E. Elez Fernández: Honoraria (institution): Array, MSD, Abbvie, Amgen, GSK, AstraZeneca,Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche; Advisory / Consultancy: Hoffman La-Roche, Bristol-Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime; Research grant / Funding (self): Fundación Merck Salud, Grant for Oncology Innovation EMD Serono.. J. Carles: Research grant / Funding (self): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol-Myers Squibb Inter; Advisory / Consultancy: Bayer / Johnson & Johnson / Bristol-Myers Squibb / Astellas Pharma / Pfizer / Sanofi / MSD Oncology / Roche/ AstraZéneca; Speaker Bureau / Expert testimony: Bayer / Johnson & Johnson / Asofarma / Astellas Pharma. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. R. Dienstmann: Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Roche, Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Research grant / Funding (self): Merck. E. Garralda: Advisory / Consultancy: F.Hoffmann-La Roche,Ellipses Pharma ,Neomed Therapeutics1 Inc,Boehringer Ingelheim ,Janssen Global Services; Speaker Bureau / Expert testimony: Bristol-Mayers Squibb; Honoraria (self): Menarini, Glycotope, Menirarini. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

136P - Evaluation of a radiomic signature of CD8 cells in patients treated with immunotherapy-radiotherapy in three clinical trials (ID 5544)

Presentation Number
136P
Lecture Time
12:00 - 12:00
Speakers
  • Roger Sun (Villejuif, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Several studies have suggested that combining radiotherapy (RT) to immunotherapy (IO) may be synergistic but many questions are still pending regarding the radiation modalities to optimize this combination, such as the choice of the lesion to irradiate. Radiomics consists in the analysis of quantitative data extracted from standard medical imaging to generate imaging biomarkers. A previous study published in The Lancet Oncology has shown that a radiomic signature could predict the CD8 cells infiltration, which is associated with the activity of anti-PD-1/PD-L1. We aimed to assess whether this biomarker could help to guide IO-RT combinations.

Methods

Patients from three clinical studies of IO-RT combinations with advanced solid tumors in two institutions were screened. Patients with available baseline (E0) and first evaluation (E1) CTs were included. Immunotherapy consisted in 4 different drugs. Hypofractionated conformal RT or stereotactic RT of one tumor lesion was delivered after the start of IO for most of the patients. The irradiated lesion and a sample of non-irradiated lesions were delineated from E0 and E1 CTs. Radiomics features were extracted and the published radiomic signature was applied to estimate the CD8 cells.

Results

84 patients were included. 244 tumor lesions were delineated on the E0 CT, including the 84 lesions which were selected for irradiation. Median time between IO and RT start was 21 days (IQR: 9-24), and 2.4 mo between E0 and E1 (IQR: 1.3 - 3). 80 irradiated lesions and 152 non irradiated lesions remained at E1. At baseline, the volume and the radiomic score of TIL (RS) were not different between the two groups (irradiation or no) (p = 0.94 and 0.50). While the mean volume of the analyzed lesions was not different from E1 to E0 (p = 0.15), irradiated lesions were significantly smaller at E1 (p = 0.03). A high RS in the irradiated lesion at E1 (compared to the median value) was associated with PFS (HR = 0.57, IC95%: 0.345-0.95, p = 0.031) irrespective of the volume in multivariate analysis but was not significantly associated with OS.

Conclusions

Radiomic score of the irradiated lesion was associated with PFS. Such biomarker may help to guide the selection of the lesion to irradiate in IO-RT combinations.

Legal entity responsible for the study

Gustave Roussy Cancer Campus.

Funding

Fondation pour la Recherche Médicale, SIRIC-SOCRATE 2.0, Fondation ARC, Amazon.

Disclosure

R. Sun: Travel / Accommodation / Expenses: AstraZeneca. N.L. Sundahl: Travel / Accommodation / Expenses: Merck Sharpe & Dohme; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb. P. Ost: Research grant / Funding (institution): Merck Sharpe & Dohme; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Janssen; Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Travel / Accommodation / Expenses: Ferring Pharmaceuticals; Honoraria (self): Bayer. C. Massard: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Jansen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Orion. E. Deutsch: Advisory / Consultancy, Research grant / Funding (institution): Roche Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

137P - Biomarkers predictive of overall survival in advanced cancer patients treated with a peptide-based cancer vaccine (ID 1117)

Presentation Number
137P
Lecture Time
12:00 - 12:00
Speakers
  • Shigetaka Suekane (Kurume, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

To determine biomarkers predictive of overall survival (OS) in advanced cancer patients treated with a peptide-based cancer vaccine.

Methods

The samples from two randomized, double-blind, placebo-controlled, phase III trials of personalized peptide vaccine (PPV) for advanced prostate cancer patients (n = 306) and recurrent glioblastoma (n = 88) patients, those from one single arm phase II trial of PPV for various types of advanced cancer patients (n = 2588), and those from one randomized placebo-controlled non-personalized phase II trial (n = 51) were provided for this retrospective biomarker study.

Results

No significant differences in clinical benefit (overall survival, OS) were found between the patients receiving PPV and those receiving placebo in each of the two randomized, double-blind, placebo-controlled, phase III trials. The neutrophil or lymphocyte proportion in advanced prostate cancer patients prior to study entry was a biomarker discriminating the PPV patients (70%) who showed significantly shorter OS relative to placebo patients from the remaining PPV patients who showed significantly longer OS relative to placebo patients. The CCL2 level prior to the study entry in recurrent glioblastoma patients was the other biomarker discriminating the PPV patients (40%) who showed significantly shorter OS relative to placebo patients from the remaining PPV patients who showed significantly longer OS relative to placebo patients. The neutrophil or lymphocyte proportion prior to study entry was also a biomarker discriminating the PPV patients (60%) with significantly shorter OS from the remaining PPV patients entered in the single arm phase II study in all the advanced cancer patients other than gastric cancer or glioblastoma patients. This marker could also discriminate patients who showed significantly shorter OS from the remaining patients in the non-personalized peptide vaccine phase II study for prostate cancer patients.

Conclusions

Peptide-based cancer vaccine shortened the OS of a large portion, but not all, of advanced cancer patients with various types of cancer. Prospective clinical studies of peptide-based cancer vaccines using the newly defined prognostic markers may be warranted.

Clinical trial identification

UMIN Clinical Trials Registry, 6970, 113088, 11028, 1482, 1839, 1844, 1847, 1850, 1854, 1855, 1856, 1875, 1881, 1882, 1883, 1884, 2282, 3590, 5631, 6249, 6295, 6493, 7493, 8126, 8823, 8824, 8825, 8826, 8827, 8828, 10068, 19390, 2906, 2907, 2908, 2984, 2985, 2987, 3027, 3028, 3029, 3059, 3060, 3081, 3082, 3083, 5329, 10290, 11593, 14855, 19802, 19879, 6927,11230.

Legal entity responsible for the study

President Kyogo Itoh,M.D., Ph.D., Cancer vaccine center, Kurume University School of Medicine, Japan.

Funding

Grants from the Japan Agency for Medical Research and Development (16ck0106086h0003, 18im0110802h0008), the Ministry of Health, Labor and Welfare of Japan, and FUJIFILM Corporation.

Disclosure

M. Noguchi: Advisory / Consultancy: BrightPath Biotherapeutics Co. Ltd. A. Yamada: Advisory / Consultancy: BrightPath Biotherapeutics Co. Ltd. K. Itoh: Advisory / Consultancy, Research grant / Funding (self): Taiho Pharmaceutical Company. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

138P - Expression of PD-L1 in plasma exosomes of NSCLC patients and its associations with PD-L1 expression of corresponding tumour tissues (ID 1922)

Presentation Number
138P
Lecture Time
12:00 - 12:00
Speakers
  • Shaorong Yu (Nanjing, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The aim of this study was to research whether there was expression of PD-L1 in plasma exosome of NSCLC patients and whether its expression can partly represent PD-L1 expression of corresponding lung tumor tissues.

Methods

Plasma was collected before and after surgery of NSCLC patients with stage II to stage III. Plasma of NSCLC patients with stage IV was also collected before and after anti-PD-1/PD-L1 therapy. Digital PCR was used to detect PD-L1 and β-actin mRNA expression of plasma exosomes. Expression of PD-L1 in tumor tissues was determined by immunohistochemical staining (22C3). Pearson correlation analysis and wilcoxon rank sum test was performed by SPSS 22.0.

Results

A total of 126 patients (54 patients with surgery and 72 patients with non-surgery therapy) were participated in this study. Exosomal PD-L1 expression can be detected in all plasma samples. Exosomal expression of PD-L1 calculated by both absolute quantification method and relative quantification method showed a positive correlation with PD-L1 expression of tumor tissues (absolute quantification method: r2=0.289, P = 0.001; relative quantification method: r2=0.547, P = 0.000). However, expression of exosomal PD-L1 calculated by relative quantification calculation showed higher correlation. Exosomal PD-L1 expression significantly decreased after surgery (P < 0.001) and three patients who showed good response (PR) to anti-PD-1/PD-L1 therapy also showed significantly decreasing exosomal PD-L1 expression after anti-PD-1/PD-L1 therapy (P < 0.001).

Conclusions

Plasma exosomes of NSCLC patients contains substantial expression of PD-L1. Plasma exosomal PD-L1 expression showed high correlation with PD-L1 expression of tumor tissues. Exosomal PD-L1 expression could represent PD-L1 expression of tumor tissues and might be a potential predictive marker for anti-PD-1/PD-L1 therapy.

Legal entity responsible for the study

Jifeng Feng.

Funding

The National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

139P - Patient’s perspective on digital biomarkers in advanced urologic malignancies (ID 5495)

Presentation Number
139P
Lecture Time
12:00 - 12:00
Speakers
  • Severin Rodler (Munich, Germany)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Digital biomarkers allow for continuous remote patient monitoring and will potentially change the way healthcare is provided and clinical trials are designed. We conducted a study to identify current preferences and interest in digital biomarkers in patients with advanced urological cancers.

Methods

We included 80 patients undergoing systemic therapy for advanced urologic malignancies at our institution. A questionnaire was developed to survey the current access to online information and digital technologies and to rate preferences on a scale from 1 (does not apply) to 5 (fully applies). Statistical analysis was performed by Chi-square test and unpaired t-test.

Results

26% of the cohort presented with prostate cancer (PC), 38% with urothelial cancer (UC) and 36% with renal cell carcinoma (RCC). 69% of patients researched medical information about their disease online, 85% of PC patients, 72% of RCC patients, and 53% of UC respectively. 63% of all patients use smartphones and 9% wearables. Smartphone usage is most common in RCC patients (76%) followed by PC (66%) and UC (46%) patients while wearables are used by 7% of RCC, 5% of PC, and 13% of UC patients, respectively. In our cohort RCC patients are younger (Mean 63.3 years) than PC patients (Mean 69.3 years) and UC patients (Mean 68.3 years). The percentage of patients seeking information online and using smartphones or wearables is significantly higher in patients under the age of 75 (p < 0.05). With respect to the information generated by wearables, patients’ interest in activity data is significantly higher (3.5/5) than interest in sleeping profiles (2.5/5; p < 0.01). Patients are more likely to use wearables in clinical trials when they have access to the generated activity data (2.8/5) than using them without gaining access to the information (2.1/5; p < 0.01). Interest in wearable data and willingness to wear them as part of clinical trials are significantly higher for male gender (p < 0.01), and is independent of age and distance between home and the clinical trial site.

Conclusions

Our study demonstrates a high engagement of patients in digital technologies. Even though there is a lower penetration rate for digital technologies in older people, interest in digital biomarker data is high in regardless of age group.

Legal entity responsible for the study

Severin Rodler.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

141P - A comprehensive pan-cancer study of FGFR aberrations in Chinese cancer patients (ID 3166)

Presentation Number
141P
Lecture Time
12:00 - 12:00
Speakers
  • Yang Gao (Changsha, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Aberrations in fibroblast growth factor receptors (FGFR) are common in multiple cancers, making them highly promising therapeutic targets. Optimal application of FGFR inhibitors requires a comprehensive understanding of the prevalence and types of FGFR mutations, which may vary significantly among ethnicities. Such analysis has not been conducted in Chinese pan-cancer. This study investigated the prevalence and the distribution of FGFR aberrations in Chinese cancer patients.

Methods

We screened genomic profiling results of plasma or tissue samples from 10,582 patients spanning 16 cancer types: lung, breast, gastric, hepatobiliary, pancreatic, soft tissue sarcoma, esophageal, ovarian, colorectal, head and neck, renal, endometrial, osteogenic sarcoma, cervical, melanoma and lymphoma.

Results

Of the 10,582 patients screened, we observed 745 patients with FGFR aberrations, revealing an overall prevalence of 7.03%. Approximately, 3.78% harbored FGFR amplification, 2.73% had other mutations and 0.53% had fusions. A majority (56.78%) of patients had FGFR1 aberrations, followed by 17.72%, 14.43% and 2.82% with FGFR3, FGFR2 and FGFR4 aberrations, respectively. Furthermore, 8.46% of patients with aberrations in more than 1 FGFR gene. The most common type of aberrations was amplification (53.69%), followed by other mutations (38.79%) and fusions (5.64%). Concurrent FGFR fusion and amplification occurred in 1.88% patients. Of the 16 cancer types, except for head and neck cancer, osteogenic sarcoma, renal carcinoma, and lymphoma, all other cancer types had FGFR aberrations detected with colorectal cancer (31.03%) having the highest prevalence. Other relatively commonly affected cancers included: gastric cancer (16.78%), breast cancer (14.27%) and esophageal cancer (12.68%). FGFR1 amplification was the most common genetic alteration in CRC, breast cancer and lung cancer. FGFR2 amplification was more commonly seen in gastric cancer. Of the patients with FGFR aberrations, 57 patients, spanning 9 cancer types, had fusions. Among them, breast cancer patients are more likely to have concurrent FGFR amplification than other cancer types (p < 0.001).

Conclusions

Our study provides a comprehensive view of FGFR aberrations in Chinese cancer patients.

Legal entity responsible for the study

Yang Gao.

Funding

Key Research and Development Program of Hunan province (2016JC2039).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

143P - A systemic inflammation response index (SIRI) correlates with survival and could be a predictive factor for mFOLFIRINOX in metastatic pancreatic cancer (PC) (ID 3277)

Presentation Number
143P
Lecture Time
12:00 - 12:00
Speakers
  • Vilma E. Pacheco-Barcia (Madrid, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Cancer-related inflammation is a distinctive feature of the development and progression of PC. However, the relationship between the systemic inflammatory response and survival has not been evaluated as a predictive factor of chemotherapy. The aim of this study was to evaluate the prognostic and predictive value of a baseline SIRI based on peripheral neutrophil, monocyte, and lymphocyte counts in metastatic PC.

Methods

Retrospective review of 178 metastatic pancreatic cancer patients. Associations between overall survival (OS), time to progression (TTP), chemotherapy schedule and SIRI at diagnosis were analyzed.

Results

Median age 67 years, 52% were male. First line chemotherapy regimens: 41% Gemcitabine, 31% Gemcitabine plus Nab-Paclitaxel and 17% mFOLFIRINOX. Patients with SIRI<2.3x109 showed a statistically significant improvement in OS compared to SIRI≥2.3x109 [16 months versus 4.8 months, Hazard Ratio (HR) 2.87, Confidence Interval (CI) 95% 2.02-4.07, p < 0.0001] that was confirmed in multivariate analysis. In addition, patients with SIRI<2.3x109 showed a longer TTP (12 versus 6 months, HR 1.92, IC 95% 1.314-2.800, P = 0.001). Furthermore, we observed that patients with SIRI ≥2.3x109 are more likely to benefit from mFOLFIRINOX therapy. Patients with an elevated SIRI treated with mFOLFIRINOX versus Gemcitabine plus Nab-Paclitaxel and Gemcitabine showed a clinically and statistically significant difference in median OS of 17 months compared to 6 and 4 months respectively (p < 0.001). Conversely, the difference was not clinically significant in the SIRI<2.3x109 subgroup: 15.9 months versus 16.5 and 16, respectively.

Conclusions

An elevated SIRI (≥2.3x109) is an independent prognostic factor for survival in patients with metastatic pancreatic cancer. Patients with an elevated SIRI (≥2.3x109) show an increased benefit from mFOLFIRINOX in comparison to other first line chemotherapy regimens. These results raise the issue of appropriately selecting patients who would benefit of a more intensive first-line chemotherapy regimen.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

144P - Circulating biomarkers and risk of immune-related adverse events (irAEs) in patients (pts) with advanced non-small cell lung cancer (aNSCLC) and metastatic melanoma (mMel) (ID 2680)

Presentation Number
144P
Lecture Time
12:00 - 12:00
Speakers
  • Alberto Pavan (Padova, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Immune checkpoint inhibitors (ICIs) have changed the treatment of pts with aNSCLC and mMel. No predictive markers of development of irAEs are available. Aim of the study is to evaluate the role of circulating markers in predicting irAE onset.

Methods

We reviewed clinical data of aNSCLC and mMel pts treated with ICIs at Istituto Oncologico Veneto (Padova, Italy) and San Bortolo Hospital (Vicenza, Italy) between January 2012 and January 2019. We collected data on type and grading (G) of irAEs and calculated neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) before first ICI administration and at irAE onset. Values were dichotomized in: high (H) and low (L) NLR and H- and L-PLR, using pre-identified cut-offs of 3 and 180 for aNSCLC, 3 and 120 for mMel.

Results

Analysis included 377 pts (252 aNSCLC and 125 mMel). In aNSCLC cohort, median PFS and OS were 4.9 months (m) (95% CI: 3.6-6.1) and 8.6m (95% CI: 6.3-10.8). Ninety-seven pts (38%) developed irAEs, mainly G1-2 (72%), with permanent ICI discontinuation in 29 (29.9%) cases; 26 pts (26.8%) experienced more than one irAE. Pts with baseline L-NLR or L-PLR had a higher risk of irAE (OR = 2.3, 95% CI: 1.3-3.9, p = 0.002 | OR = 2.4, 95% CI: 1.3-4.1, p = 0.02). Multivariate analysis confirmed NLR and PLR as independent predictive markers (OR = 1.8, 95%CI: 1.0-3.2, p = 0.04 | OR = 1.9, 95%CI: 1.0-3.4, p = 0.03). L-PLR at irAE onset was associated with risk of irAE recurrence or second irAE development (OR = 4.2, 95% CI: 1.4-12.9, p = 0.01). In mMel pts, median PFS and OS were 5.1m (95% CI: 3.6-6.5) and 18.1m (95% CI: 11-25.2). Fifty-four pts (43%) developed irAEs, mainly G1-2 (76%), with permanent ICI discontinuation in 10 (18.5%) cases; 14 pts (25.9%) had multiple irAEs. Pts with baseline L-NLR had higher risk of irAE (OR = 2.2, 95% CI: 1.1-4.6, p = 0.04). NLR and PLR at time of irAE onset were not associated with the risk of irAE recurrence or second irAE development.

Conclusions

Baseline NLR and PLR may be reliable and inexpensive predictive tools of irAE risk. For aNSCLC pts L-PLR at irAE onset correlates with risk of further toxicity. If validated, these biomarkers may help pts’ management during ICIs and treatment handling after a first irAE.

Legal entity responsible for the study

IRCCS Istituto Oncologico Veneto - IOV - Padua – Italy.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

145P - Breast cancer in young women of Kazakh population depending on germline mutations: Results of next-generation sequencing (ID 4066)

Presentation Number
145P
Lecture Time
12:00 - 12:00
Speakers
  • Dilyara Kaidarova (almaty, Kazakhstan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Breast cancer (BC) represents the most common malignancy and has the highest mortality among women, both in the world and in Kazakhstan. Approximately 20-30% of cases of hereditary breast cancer are caused by presence of BRCA1 and BRCA2 genes defects. Also, there are additional genes which can increase the risk of BC and they are still under study.The aim of this study was to identify new, detectable and objective markers of key cancer genes by next-generation sequencing (NGS) in BC patients.

Methods

The study included 194 unrelated patients (the av/age 34.25 ± 4.56) with BC. Genomic DNA was obtained from peripheral blood,next-generation sequencing was performed using TruSightCancer Kit on the MiSeq platform,studio Variant was used to annotate genetic variants.

Results

In total, 61 pathogenic variants (all in heterozygous state) were found in 56 (28.9%) patients,the vast majority of variants located in BRCA1 (n = 19/56; 33.9%), 15 in BRCA2 (26.8%). The frequency of pathogenic variants in genes TP53 (8.9%), PALB2 (5.4%), MSH6 (5.4%), CHEK2 (3.6%), SDHB (3.6%), and WRN (3.6%) were higher than those genes APC, ATM, FANCA, FANCM, MSH2, NBN, NF1, PMS1, PMS2, and XPA which include only one deleterious variants. The analysis of mutation type has revealed 28 frameshift mutations, 15 stop-gain mutations, 8 missense mutations, 8 splice site variants, 1 start lost variant, and 1 synonymous variant. In total, 43 mutations were unique, 15 of them represented novel variants. Those new mutations have not been previously mentioned in the LOVD and ClinVar databases and have not been described in publications. Population frequency of all detected pathogenic mutations in 1000G, ESP6500 and ExAC databases were less than 1%. 73.8% of the mutations were available in the dbSNP database. The most common pathogenic variants were c.5329dupC and c.5341-2delA (c.5278-2delA) in BRCA1 gene, accounting for 10.7% (n = 6/56) and 8.9% of patients (n = 5/56), respectively.

Conclusions

NGS showed frequent and novel germline mutations in BRCA1/2, CHEK2, TP53 and PALB2. After the final statistical data processing, diagnostic and prevention tools for key genes will be developed and included in the National guidelines for cancer diseases.

Legal entity responsible for the study

Kazakh Institute of Oncology and Radiology Institute of General Genetics and Cytology.

Funding

The Ministry of Healthcare of the Republic of Kazakhstan.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

146P - Discovery of an immunotranscriptomics signature in blood for early colorectal cancer detection (ID 5514)

Presentation Number
146P
Lecture Time
12:00 - 12:00
Speakers
  • Paolo Angelino (Lausanne, Switzerland)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Colorectal Cancer (CRC) is the second leading cause of cancer mortality worldwide. An effective and convenient blood test for early detection of CRC is urgently needed to increase screening compliance and reduce mortality. The development of a new blood test for early CRC detection was initiated that leverage the transcriptome analysis of circulating immune cells (ImmunoTranscriptomics) using artificial intelligence and machine learning tools.

Methods

To identify new transcriptional biomarkers for CRC and adenoma detections, peripheral blood mononuclear cells (PBMC) transcriptome were analyzed by RNA-sequencing of 561 subjects (300 Caucasians and 261 Asians) enrolled in the DGNP-COL-0310 study (Ciarloni et al., 2016), a multi-centers case-control study. The cohort included 189 subjects with CRC, 115 with advanced adenoma (AA), 39 with other types of cancer (OC) as well as 218 individuals without any colorectal lesions (CON). Several univariate and multivariate methods were applied to the discovery set (n = 282) and results were integrated into a ranking system. Top ranked genes were selected for further validation and algorithm development in an independent set (n = 279).

Results

A large panel of differentially expressed genes were identified in non-metastatic CRC (I-II-III) and AA compared to CON and OC with significantly high power of discrimination (P-value = 10-13). The novel developed data analytics pipeline was used to analyse the transcriptomic data measurements and the diagnostic accuracy of the new gene signature for CRC, through application of Machine Learning (ML) and bootstrap, was 82% sensitivity and 88% specificity and AUC of 90%. The signature was enriched in genes associated with myeloid cells activation, inflammation and hemostasis, suggesting a key role of the innate immunity in the early response to cancer.

Conclusions

Mapping the reaction of the immune system to onset of cancer and disease identification through application ML methods is a new approach to ensure an unbiased, genome-wide, unsupervised gene expression analysis for a highly specific biomarker identification.

Legal entity responsible for the study

Novigenix SA.

Funding

Novigenix SA.

Disclosure

S. Hosseinian Ehrensberger: Shareholder / Stockholder / Stock options: Novigenix SA. L. Ciarloni: Shareholder / Stockholder / Stock options: Novigenix. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

147P - Serum netrin-1 as a biomarker for colorectal cancer detection (ID 1595)

Presentation Number
147P
Lecture Time
12:00 - 12:00
Speakers
  • Jinzhou Zhu (Suzhou, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Recent evidence supported that netrin-1 involves in colorectal carcinogenesis. This study was to evaluate the performance of serum netrin-1 for detection of colorectal cancer (CRC) in both a clinical set and a screening set.

Methods

A total of 115 consecutive patients with CRC and matched healthy controls were included in Clinical Set. Fifty subjects with CRC, 50 subjects with advanced adenoma (AA), and 150 matched control participants free of neoplasia were included in Screening Set. Circulating levels of netrin-1 were evaluated with commercial ELISA kits.

Results

In Clinical set, subjects with CRC presented higher levels of serum netrin-1 (513.9 ± 22.6 pg/mL) than controls (347.8 ± 20.3 pg/mL, p < 0.0001). Similar in Screening set, serum levels of netrin-1 was higher in CRC (644.5 ± 37.0 pg/mL), in comparison with controls (407.7 ± 14.8 pg/mL, p < 0.0001) and AA (416.5 ± 18.5 pg/mL, p < 0.0001). However, there was no difference between controls and AA (p = 0.752). Compared with the low netrin-1 group, the high group presented increased risk of CRC (Clinical set: OR = 4.300 [95% CI 2.473 – 7.477], p < 0.001); Screening set: OR = 7.731 [95% CI 3.618 – 16.519], p < 0.001). ROC curve of netrin-1 was developed to detect CRC (Clinical set: AUC 0.703 [95% CI 0.636 – 0.770]; Screening set: AUC 0.759 [95% CI 0.680 – 0.837]).

Study population characteristics

Clinical set
Screening set
ControlsCRCControlsAACRC
Number1151151505050
Netrin-1 levels (pg/ml)347.8 ± 20.3*513.9 ± 22.6*407.7 ± 14.8#416.5 ± 18.5^644.5 ± 37.0#^
Age (years)53.8 ± 8.755.9 ± 9.154.2 ± 9.251.9 ± 10.055.8 ± 9.6
Sex
Male92921113737
Female2323391313
BMI (kg/m2)22.8 ± 3.024.6 ± 3.922.4 ± 2.923.1 ± 3.123.7 ± 3.1
WHR0.89 ± 0.080.92 ± 0.060.88 ± 0.080.94 ± 0.090.99 ± 0.07
TNM stage
I1610
II4322
III4213
IV145
Location
Colon8334
Rectum3216

Data are mean ± SD for continuous variables.

p < 0.001; #p < 0.001; p < 0.001. AA, advanced adenomas; BMI, body mass index; WHR, waist-to-hip circumference ratio.

Conclusions

It suggests netrin-1 as a potential biomarker in the screening and detection of CRC.

Legal entity responsible for the study

The First Affiliated Hospital of Soochow University.

Funding

Jiangsu Provincial Key Research and Development Plan (No. BE2018659) and Provincial Key Laboratory Program of Higher Education (No. KJS1867).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

148P - Salivary metabolomics for colorectal cancer detection (ID 2036)

Presentation Number
148P
Lecture Time
12:00 - 12:00
Speakers
  • Hiroshi Kuwabara (Tokyo, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

As the worldwide prevalence of colorectal cancer (CRC) is increasing, it is of vital importance to reduce its morbidity and mortality by early detection. Saliva is a noninvasively accessible fluid that potentially reflects both oral and systemic diseases. We report here the investigation and validation of salivary biomarkers to distinguish patients with CRC from those with polyps and healthy controls.

Methods

Saliva samples from subjects with CRC, polyps, and healthy controls were collected after 9 hours of fasting, and were split into training and validation data. Capillary electrophoresis-mass spectrometry-based metabolomics was used to quantify numerous hydrophilic metabolites.

Results

A total of 2,602 unstimulated saliva samples were collected from 231 subjects with CRC, 99 subjects with polyps, and 2272 subjects with healthy controls. The data were randomly divided into training (n = 1,301) and validation data (n = 1301). Biomarkers for distinguishing subjects with CRC from the others, as well as metabolites that normalize whole saliva concentration were identified. Analysis of these metabolites using machine learning-based artificial intelligence showed a high area under the receiver operating characteristic curve (AUC = 0.876; P < 0.0001) in the training dataset. This combination also showed high AUC values using the validation dataset (AUC = 0.861; P < 0.0001). Saliva samples were also collected multiple times from identical subjects and the robustness of these biomarkers were confirmed.

Conclusions

Combinations of salivary metabolites show high potential as a screening tool for CRC.

Legal entity responsible for the study

Hiroshi Kuwabara.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

149P - Evaluation and diagnostic potential of plasma biomarkers in bladder cancer (ID 1868)

Presentation Number
149P
Lecture Time
12:00 - 12:00
Speakers
  • Veronika Voronova (Moscow, Russian Federation)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

While urine biomarkers are widely used to diagnose bladder cancer (BLC), little is known about plasma protein levels in patients with BLC. The current research is aimed to evaluate diagnostic potential of 13 plasma markers including tumor antigens, inflammatory markers and apolipoproteins (Apo) as well as combinations of thereof.

Methods

In total 203 healthy volunteers (HV) and 59 patients with BLC were enrolled into the study. Concentrations of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (СА 19-9), prostate-specific antigen (PSA), beta 2 microglobulin (B2M), human-specific C-reactive protein (hsCRP), D-dimer, сytokeratin 19-fragments (CYFRA 21-1), ApoA1, ApoA2, ApoВ, transthyretin (TTR), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in plasma were measured via ELISA. t-test after log-transformation was used to identify between-group differences in biomarker levels. Diagnostic accuracy of the single biomarkers as well as trained random forest (RF), linear discriminant analysis (LDA) and support vector machine (SVM) classifiers was assessed by ROC analysis.

Results

Plasma levels of ApoB, B2M, CA 19-9, CYFRA 21-1, D-dimer, hsCRP, sVCAM-1 and TTR were significantly higher (p-value<0.001) whereas ApoA1 and ApoA2 levels were significantly lower (p-value<0.0005) in patients with BLC vs HV. No differences in AFP, CEA and PSA was found between the groups. The highest discriminative power was shown for sVCAM-1 and ApoA1 with area under ROC curve (AUROC) 0.92 and 0.90, respectively, whereas AUROC for several classifiers based on measurements of 2-12 biomarkers was higher than 0.95.

Conclusions

Numerous abnormalities in plasma biomarker levels were detected in patients with BLC, hence, blood-based tests represent a promising strategy to improve performance of urinary-based tests and cystoscopy in BLC detection and prognosis. Combining several biomarkers allows to increase diagnostic test accuracy.

Legal entity responsible for the study

I.M. Sechenov First Moscow State Medical University.

Funding

I.M. Sechenov First Moscow State Medical University.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

150P - Liquid biopsy assays using combined circulating tumour cells and circulating tumour DNA in the same patients for the diagnosis of primary lung cancer (ID 3655)

Presentation Number
150P
Lecture Time
12:00 - 12:00
Speakers
  • Yongjoon Suh (Seoul, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Lung cancer is the most common cause of cancer-related mortality worldwide. Early diagnosis and surgery may be one of the most important strategy for the treatment of lung cancer patients. However, the procedure of lung cancer diagnosis from initial suspicion to final confirmation is not efficient due to low sensitivity of current diagnostic methods and difficulties involved in tumor tissue biopsy in lung cancer compared to other cancer types. Therefore, we investigated the feasibility of liquid biopsy using circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) analysis for the better diagnosis of lung cancer.

Methods

In this study, we blindly analyzed both CTCs and ctDNA in the blood samples derived from 109 patients including histology-proven and clinically suspicious lung cancer patients to test the sensitivity of liquid biopsy methods. CTC analysis was done by CytoGen’s liquid biopsy platform, in which viable CTCs were isolated by size-based filtration with gravity and validated by immunostaining of EpCAM or CK, excluding CD45 positive cells and enumerated by CytoGen’s cell imaging software. Lung cancer diagnosis was predicted by a cut-off, 2 ≥ CTC in 5 ml peripheral blood. For ctDNA analysis, EDGC F-Can platform was used to analyze single nucleotide variations of very low variant allele frequencies by utilizing unique molecular indexes and a novel read error correction algorithm. For comparison, we also analyzed the levels of conventional tumor markers (CEA, cyfra21-1 and NSE) in the patient cohort.

Results

Compared to the diagnostic sensitivities of conventional tumor markers (CEA 29%; cyfra21-1 41%; NSE 39%), both assays of CTCs and ctDNA showed higher diagnostic sensitivity in predicting primary lung cancer (CTCs 67%; ctDNA 83%). When the assays of CTCs and ctDNA were combined for the diagnosis, the sensitivity was increased up to 98%.

Conclusions

Collectively, this study suggests that combined CTCs and ctDNA assay would be useful for the diagnosis of primary lung cancer.

Legal entity responsible for the study

Cytogen, Inc., EDGC, Inc., Department of Medicine, Samsung Medical Center

Funding

Has not received any funding

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

151P - Peripheral cytotoxic T cell correlates with tumor mutational burden and is predictive for progression free survival in advanced breast cancer (ID 3685)

Presentation Number
151P
Lecture Time
12:00 - 12:00
Speakers
  • Xiao-ran Liu (Beijing, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The clinical relevance of the host immune system in breast cancer has long been studied. Peripheral blood lymphocytes show a great potential due to the advantages of minimal invasiveness, ease of access and high homogeneity. Peripheral blood lymphocytes consists of varying subpopulations. Each subpopulation of peripheral lymphocytes plays a different part in anti-tumor immunity and thus may have different clinical relevance. However, the related studies have rarely been reported.

Methods

A total of 264 advanced breast cancer patients (ABCs) were consecutively recruited at our center between January 2015 and September 2018. All patients received the conventional regimen for advanced breast cancer. Detection of peripheral blood lymphocytes at baseline was accomplished in all 264 patients with 118 patients having ctDNA detection simultaneously. The median survival was estimated by Kaplan-Meier curve, with difference detection by log-rank test and Cox proportional hazards regression model.

Results

The median follow-up time of the study was 13.0 months. Multivariate analysis confirmed that cytotoxic T cell (CTL) was an independent prognostic factor of PFS (P = 0.024). Pierson correlation analysis showed one and only positive correlation between tumor mutational burden (TMB) and CTL level at baseline (P = 0.015). Furthermore, baseline CTL level was only confirmed in the HER2-positive subgroup (P < 0.001) but not in the HR-positive (P = 0.333) or in the TNBC subgroup (P = 0.322). For the entire cohort, the TMB high (>75%) group had a signifiantly shorter PFS (P = 0.004) than TMB low. In the HER2-positive subgroup, the PFS of the TMB high group was shorter than for the TMB low group (P < 0.001). We further use survival data obtained from the TCGA database as a validation set to confirm our findings. As expected, 24 out of 105 HER2-positive patients with TMB high were found to have shorter PFS than TMB low (HR = 0.2, 95% CI: 0.06∼0.71, P = 0.005).

Conclusions

Pheripheral CTL to total lymphocyte proportion is predictive for PFS in HER2-positive ABCs but not in TNBC or HR positive. Since CTL proportion was found to positively correlate with TMB and high TMB indicates shorter PFS. Thus, the negative prognositc role of CTL was, at least, partly due to the TMB of ABCs.

Legal entity responsible for the study

Peking University Cancer Hospital-Beijing Cancer Hospital.

Funding

National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

154P - Splenic metabolic activity as biomarker in cervical cancer (ID 1050)

Presentation Number
154P
Lecture Time
12:00 - 12:00
Speakers
  • Emiel A. De Jaeghere (Gent, Belgium)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Inflammation has a significant impact on cervical cancer (CC) development and therapy response. We sought to determine if splenic metabolic activity reflects host immune status and could improve prognostic and predictive categorization of CC.

Methods

Ninety-two consecutive patients with FIGO stage IB1 to IVB CC who received neo-adjuvant (chemo)radiation (NA-CRT) with curative intent were included. PET scans were performed at diagnosis and after completion of the NA-CRT. PET images were retrospectively assessed for pretreatment spleen-to-liver SUV ratio (preSLR), posttreatment spleen-to-liver SUV ratio (postSLR) and ΔSLR (post-pre) on Oasis Nuclear Medicine Workstations. (Δ)SLR was calculated as both (Δ)SLRmaxand (Δ)SLRmean. The prognostic (DFS) and predictive (pCR) abilities of these variables together with established predictors were calculated by C-index and ROC analysis, respectively. The optimal long-rank statistic and Youden index determined cutoff values. Multivariate Cox proportional hazard regression models were ranked based on their Akaike information criterion (AIC). Clinicopathological differences between patients with low or high SLR were performed by chi-square and Mann-Whitney U tests.

Results

For preSLRmaxand preSLRmean, association with DFS was found for preSLRmax>0.92 with HR = 2.25 (95% CI (1.08-4.66); p = 0.026) and for preSLRmean>0.94 with HR = 2.79 (95% CI (1.33-5.86); p = 0.005), respectively. The selected multivariate model consisted of three factors: preSLRmax, ΔSLRmaxand parametrial invasion (dichotomized; HR = 6.40 95% CI (2.70-15.20); p < 0.001). The model’s prognostic ability was quite favorable compared to FIGO staging (C-index 0.69 vs. 0.64). Further, uni- and multivariate analyses suggest that both low preSLRmaxand low preSLRmean influence pCR. Patients (n = 31) with high preSLRmaxhad a higher density of CD3+,CD4+, CD8+, CD20+(77.8% vs. 36.4%; p = 0.036), CD68+ (88.9% vs. 40.9%; p = 0.015), CD163+, FoxP3+and PD-L1+immune cells, as well as PD-L1+tumor cells (85.7% vs. 55.6%; p = 0.019) in the primary tumor using IHC; the same trends were observed for preSLRmean

Conclusions

SLR is a promising prognostic and predictive biomarker in CC and is associated with the tumor immune infiltrate.

Legal entity responsible for the study

Ghent University Hospital.

Funding

Research Foundation-Flanders (FWO).

Disclosure

E.A. De Jaeghere: Travel / Accommodation / Expenses: PharmaMar. F. Laloo: Honoraria (institution): Bayer. K. De Man: Travel / Accommodation / Expenses: Bayer. H. Denys: Honoraria (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Teva; Honoraria (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (institution): Eli Lilly and Company; Honoraria (institution): Novartis; Honoraria (institution): Amgen; Honoraria (institution): Tesaro. K. Vandecasteele: Travel / Accommodation / Expenses: PharmaMar. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

155P - Identification of distinct subtypes revealing prognostic and therapeutic relevance in diffuse type gastric cancer (ID 1413)

Presentation Number
155P
Lecture Time
12:00 - 12:00
Speakers
  • Seon-Kyu Kim (Daejeon, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for handling diffuse type GC are identified. Here, we aim to identify a prognostic and predictive signature predicting heterogeneous clinical courses of diffuse type GC.

Methods

We analysed RNA-seq based transcriptome data to identify a molecular signature in 150 gastric tissue samples including 107 diffuse type GCs. The predictive value of the signature was verified using other diffuse type GCs in three independent cohorts (n = 466). Various statistical methods, including log-rank and Cox regression analyses, were used to estimate an association between the signature and prognosis. The signature was also characterized by somatic variant assessments and tissue microarray analysis between diffuse type GC subtypes.

Results

Transcriptomic profiling revealed two distinct subtypes of diffuse type GC including intestinal-like (INT) and core diffuse type (COD) subgroups. We generated a signature, namely COD-signature, reflecting the best characteristics of subtypes. When estimating prognostic value in other cohorts, COD-signature showed a strong predictability and an independent clinical utility in diffuse type GC prognosis (hazard ratio = 2.058, 95% confidence interval = 1.53-2.77, P < 0.001; Table). Integrative mutation and gene expression analyses demonstrated that COD subtype was responsive to chemotherapy, whereas INT subtype showed responsiveness to immunotherapy with immune-check point inhibitor (ICI). Tissue microarray analysis showed practical utility of IGF1 and NXPE2 proteins for predicting diffuse type GC’s heterogeneity.

Univariate and multivariate Cox regression analysis of overall survival in diffuse type gastric cancer

VariablesUnivariate
Multivariate
nHR (95% CI)P-valuenHR (95% CI)P-value
Age4021.013 (1.001 - 1.025)0.0374021.02 (1.007 - 1.032)0.003
Gender (Male or Female)4021.074 (0.805 - 1.433)0.625
AJCC Stage (I, II, III or IV)4022.516 (2.088 - 3.032)<0.0012.67 (2.204 - 3.235)<0.001
Tumour site (cardia, body, antrum or whole)4020.985 (0.777 - 1.248)0.9
COD-signature (INT or COD subtypes)4021.675 (1.257 - 2.234)<0.0012.058 (1.53 - 2.766)<0.001

Abbreviations: HR, hazard ratio; CI, confidence interval; INT, intestinal-like; COD, core diffuse type.

Conclusions

The COD-signature represents a promising diagnostic tool for the identification of diffuse type GC patients who would display different clinical behaviours as well as response to chemotherapy or ICI treatment.

Legal entity responsible for the study

Korea Research Institute of Bioscience and Biotechnology Chungnam National University, College of Medicine Seoul National University, Faculty of Medicine.

Funding

Korea Research Institute of Bioscience and Biotechnology.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

156P - Recurrence risk evaluation in stage IB/IIA gastric cancer with TP53 codon 72 polymorphisms (ID 2140)

Presentation Number
156P
Lecture Time
12:00 - 12:00
Speakers
  • Satoshi S. Nishizuka (Morioka, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Post-operative adjuvant chemotherapy is not indicated for stage IB/IIA gastric cancer. However, approximately 10-30% of these patients experience recurrence and metastasis. In this study, we investigated the risk of recurrence after treatment of stage IB/IIA gastric cancer patients carrying the TP53 codon 72 polymorphism and attempted to identify a subpopulation that should receive post-operative adjuvant chemotherapy.

Methods

Among 658 gastric cancer patients who received gastrectomy with curative-intent, 130 stage IB and 73 stage IIA patients were enrolled in the present study. Overall survival rate (OS) and relapse-free survival rate (RFS) were analyzed based on the status of TP53 codon 72 polymorphism Arg/Arg, Arg/Pro, and Pro/Pro. The hazard ratio for each subgroup was compared by TP53 codon 72 polymorphism. All interaction p values were calculated using the likelihood test.

Results

Of the 189 patients for whom polymorphism analysis results were available, the 5- and 10-year OS was 84.9% and 65.1%, respectively. The 5- and 10-year RFS was 81.8% and 65.4%, respectively. When the study cohort was divided into two groups according to polymorphism status (i.e., "Arg/Arg and Arg/Pro" vs. Pro/Pro), both the OS (hazard ratio [HR], 2.799; 95% confidence interval [CI], 1.071-7.315, p = 0.036) and RFS (HR, 2.639; 95% CI, 1.025-6.794, p = 0.044) of the Pro/Pro group were significantly lower than those for the Arg/Arg and Arg/Pro groups across the entire observation period.

Conclusions

Among stage IB/IIA gastric cancer patients that underwent gastrectomy with curative-intent, post-operative adjuvant chemotherapy may be considered for patients carrying the TP53 codon 72 Pro/Pro polymorphism.

Clinical trial identification

NCT01905969.

Editorial acknowledgement

Christopher Brooks of Bioscience Editing Solutions.

Legal entity responsible for the study

The authors.

Funding

Ministry of Education, Culture, Sports, Science and Technology, Japan.

Disclosure

Y. Ohmori: Full / Part-time employment: Astellas Pharma Inc.

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Poster Display session 3 Poster Display session

157P - Identification and validation of a prognostic 4 genes signature for hepatocellular carcinoma: Integrated ceRNA network analysis (ID 1573)

Presentation Number
157P
Lecture Time
12:00 - 12:00
Speakers
  • Yongcong Yan (Guangzhou, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC. However, reliable molecular signatures predicting overall survival (OS) lacks of systematic research and validation.

Methods

A total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA (ceRNA) network from The Cancer Genome Atlas (TCGA) database. The prognostic signature was established with the least absolute shrinkage and selection operator (LASSO) algorithm. Multivariate Cox regression analysis and subgroup analysis was used to screen for independent prognostic factors. A time-dependent ROC curve analysis was performed to compare predictive value of the prognostic signature. The robustness of the prognostic signature was validated in validation cohorts.

Results

There were 39 differentially expressed mRNAs (DEmRNAs), 83 differentially expressed lncRNAs and 20 differentially expressed miRNAs involved in the ceRNA network. Twenty DEmRNAs were found to be significantly associated with OS. We identified a 4-gene signature (PBK, CBX2, CLSPN and CPEB3) using LASSO regression in the training set. Patients in the high-score group exhibited worse survival than those in the low-score group (HR = 2.444, P = 0.0004), and median OS was significantly shorter in the high-score group than in the low-score group (1005 days versus 2456 days). The 4-gene signature was an independent prognostic factor in multivariate Cox regression and subgroup analysis, particularly for patients with serum AFP ≥ 20 ng/ml. The results were validated in internal validation set (P = 0.0057) and two external validation cohorts (HR = 1.505 and 2.626). The signature (AUCs of one, two, three years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy.

Conclusions

We constructed a novel lncRNA-miRNA-mRNA ceRNA network for HCC based on genome-wide analysis. Then we identified a 4-gene signature as a new candidate therapeutic decision marker that yields great promise in the prediction of HCC OS.

Legal entity responsible for the study

Sun Yat-Sen University.

Funding

National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

158P - Plasma KIM-1 is associated with clinical outcomes after resection for localized renal cell carcinoma: A trial of the ECOG-ACRIN Research Group (E2805) (ID 1196)

Presentation Number
158P
Lecture Time
12:00 - 12:00
Speakers
  • Wenxin Xu (Boston, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

There is currently no circulating biomarker for renal cell carcinoma (RCC). The use of adjuvant sunitinib for RCC after nephrectomy is controversial, and a biomarker could help to select the patients at highest risk for recurrence. Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain can be detected in circulating plasma. We therefore investigated whether KIM-1 is associated with worse outcomes in patients with localized RCC after nephrectomy.

Methods

In the ECOG-ACRIN 2805 (ASSURE) trial, 1943 patients with resected high-risk RCC were randomized 1:1:1 to sunitinib, sorafenib, or placebo. Post-nephrectomy baseline samples from 182 randomly selected patients (9.4% of the study population) was available for this post-hoc biomarker analysis. Samples were analyzed using a previously validated microbead-based assay. Kaplan-Meier and Cox proportional hazards models were used to test for association between circulating KIM-1 and disease free survival (DFS) as well as overall survival (OS). ROC analysis was performed to evaluate test characteristics for KIM-1 in predicting RCC recurrence within 6 months after nephrectomy.

Results

Higher KIM-1 levels were associated with worse DFS and OS after nephrectomy. This association remained independently significant after controlling for pathologic stage, sarcomatoid features, and Fuhrman grade (DFS: HR 1.20 per log increase in KIM-1, 95% CI 1.09-1.33, p < 0.001; OS: HR 1.27 per log increase in KIM-1, 95% CI 1.11-1.45, p < 0.001). These associations were independent of treatment arm. In Kaplan-Meier analysis using KIM-1 quartiles, higher quartiles of KIM-1 were associated with worse DFS and OS (log-rank p = 0.02 for both). Post-nephrectomy KIM-1 was a prognostic marker for disease recurrence within 6 months after nephrectomy (AUC 0.85).

Conclusions

Elevated plasma KIM-1 is associated with worse DFS and OS in patients with resected RCC, and therefore has potential as an adjuvant biomarker. Analysis of larger cohorts to confirm this association is underway.

Clinical trial identification

NCT00326898.

Legal entity responsible for the study

ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs).

Funding

National Cancer Institute of the National Institutes of Health under the following award numbers: CA180820, CA180794, CA180867, CA189859.

Disclosure

K.T. Flaherty: Officer / Board of Directors: Loxo Oncology; Officer / Board of Directors: Clovis Oncology; Officer / Board of Directors: Strata Oncology; Officer / Board of Directors: Vivid Biosciences; Advisory / Consultancy, Corporate Advisory Board: X4 Pharmaceuticals; Advisory / Consultancy, Corporate Advisory Board: PIC Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Asana; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Fount; Advisory / Consultancy: Aeglea; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Shattuck Labs; Advisory / Consultancy: Arch Oncology; Advisory / Consultancy: Tolero; Advisory / Consultancy: Apricity; Advisory / Consultancy: Oncoceutics; Advisory / Consultancy: Fog Pharma; Advisory / Consultancy, Checkmate, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm.: Others; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Tvardi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: Takeda; Advisory / Consultancy: Verastem. V. Sabbisetti: Non-remunerated activity/ies, Patents on blood KIM-1 is a diagnostic, prognostic and predictive biomarker of RCC: Other. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

159P - Prognostic immunoprofiling of muscle invasive bladder cancer (MIBC) patients in a multicentre setting (ID 2657)

Presentation Number
159P
Lecture Time
12:00 - 12:00
Speakers
  • Katharina Nekolla (Munich, Germany)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Introduction of checkpoint inhibitors (anti PD-1/PD-L1) have resulted in improved survival for bladder cancer patients, however, only a subset will benefit. The utility of PD-L1 expression as a prognostic or predictive biomarker is limited, motivating the search for more robust biomarkers. Here, we examined the prognostic value of densities of PD-L1, CD3, CD8 or CD68 positive cells and studied the reproducibility of the findings across two patient cohorts in a multi-assay and multicentre setting.

Methods

MIBC specimens (T stage 2/3) from two patient cohorts collected at Melbourne, Australia (n = 39) and University of St Andrews, UK (n = 63) were studied. Two consecutive slides were stained with a brightfield immunohistochemistry or an immunofluorescence assay in the first and second cohorts, respectively. The densities of positive cells within the tumour core were determined using assay-specific image analysis algorithms. Within each cohort, the prognostic value of each cell density was assessed using univariate and multivariate Cox regression including age, T stage, N stage and adjuvant chemotherapy as covariates.

Results

The Melbourne cohort is slightly older, with a poorer prognosis and a higher proportion of N2/N3 disease compared to the St Andrews cohort. Univariate and multivariate analyses identified the density of CD8 positive cells as an important prognostic factor across both cohorts (p < 0.05). PD-L1 is significant in the St Andrews cohort and trends towards significance (p < 0.1) in the Melbourne cohort, whilst the reverse is seen with CD3. The significance level of CD68 cannot be reproduced across cohorts. Cohort statistics, hazard ratios and p values from univariate and multivariate survival analysis. .p < 0.1, *p<0.05, **p<0.01

Cohort 1: MelbourneCohort 2: St Andrews
Median age71.6466
Median survival time (months)23.7 - Overall32.57 - Disease Related
T stage
T216 (41%)26 (41%)
T323 (59%)37 (59%)
N stage
N13 (8%)52 (88%)
N28 (20%)7 (11%)
N328 (72%)0 (0%)
Univariate Cox regression
CD8HR 0.93 (0.88 0.98), p = 0.007 **HR 0.90 (0.83 0.97), p = 0.005 **
PD-L1HR 0.97 (0.94 1.00), p = 0.065 .HR 0.86 (0.75 0.98), p = 0.023 *
CD3HR 0.92 (0.87 0.97), p = 0.003 **HR 0.92 (0.87 0.98), p = 0.010 *
CD68HR 0.93 (0.88 0.99), p = 0.025 *HR 0.97 (0.93 1.00), p = 0.088 .
Multivariate Cox regression
CD8HR 0.92 (0.88 0.97), p = 0.003 **HR 0.92 (0.86 0.99), p = 0.029 *
PD-L1HR 0.96 (0.92 1.00), p = 0.053 .HR 0.84 (0.74 0.97), p = 0.015 *
CD3HR 0.90 (0.85 0.95), p = 0.0004**HR 0.94 (0.88 1.00), p = 0.060 .
CD68HR 0.92 (0.86 0.99), p = 0.023 *HR 0.98 (0.94 1.02), p = 0.294

Conclusions

Our multicentre and multi-assay study suggests that the density of CD8 positive cells in the tumour core is a robust prognostic factor in MIBC. Further investigation of PD-L1 and CD3 cell density is warranted.

Legal entity responsible for the study

Definiens AG; The Walter and Eliza Hall Institute of Medical Research; University of St Andrews.

Funding

Definiens AG.

Disclosure

K. Nekolla: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. N. Brieu: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. C.G. Gavriel: Research grant / Funding (self), Definiens is a full subsidiary of AstraZeneca: Definiens AG. M. Widmaier: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. A. Budco: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. D. Medrikova: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. I. Kanchev: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. M. Testori: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. J. Chan: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. D.J. Harrison: Advisory / Consultancy, Member: Scientific Advisory Board: Definiens AG; Full / Part-time employment: NuCana plc; Leadership role, Director: Industrial Centre for AI Research in Digital Diagnostics. M. Baehner: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. P.D. Caie: Research grant / Funding (institution): Definiens AG. B. Tran: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Non-remunerated activity/ies: Janssen-Cilag; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy: Tolmar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ipsen; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): Servier; Research grant / Funding (institution): Aslan; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Akeso; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Aptevo; Leadership role, Chair - GU Tumour Group: Cancer Trials Australia; Leadership role, Chair - Germ Cell Tumour Subcommittee, Member - Scientific Advisory Committee: ANZUP; Leadership role, Member - Scientific Advisory Committee: Biogrid; Leadership role, Member - Scientific Advisory Committee: Parkville Cancer Clinical Trials Unit; Leadership role, Co-Chair - Molecular Tumour Board: Victorian Comprehensive Cancer Centre. G. Schmidt: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG; Shareholder / Stockholder / Stock options: AstraZeneca; Licensing / Royalties, Royalities "Tissue Phenomics" ISBN 9789814774888: Pan Stanford Publishing. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

160P - Molecular profiling and prognostic significance of TP53 mutations in diffuse large b cell lymphoma: Identifying a high-risk subgroup (ID 4900)

Presentation Number
160P
Lecture Time
12:00 - 12:00
Speakers
  • Yuan-Kai Shi (Beijing, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Diffuse large B-cell lymphoma (DLBCL) is heterogenous morphologically, clinically and genetically. Although half of patients could be cured by frontline R-CHOP, approximately 10%-15% are refractory or relapse within the 1st year. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP.

Methods

Targeted sequencing was performed on baseline samples of 105 DLBCL patients. After a median follow-up of 67 months, 63 (60.0%) patients had refractory or relapsed disease. All patients received R-CHOP(-like) regimen as the first-line treatment. After excluding double-hit and primary central system lymphoma, 81 patients with measurable disease before initial treatment and followed over 1 year were included for survival analysis. Patients who received less than a partial remission in the first-line setting or those relapsed within the first 12 months since the initiation of the treatment were defined as having primary refractory.

Results

Collectively, we identified 1162 mutations spanning 103 genes from this cohort. The most commonly seen mutations included PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (41.7% vs 7.4%, p = 0.002). For those with TP53 disruptive mutations, primary refractory is also more common (22.9% vs. 0%, p = 0.006). Interestingly, BCL-2 somatic hypermutation (SHM) was only seen in patients without primary refractory disease (p = 0.014). The International prognostic index (IPI) score and other clinical characteristics were comparable between the 2 groups. Furthermore, TP53 mutations were correlated with shorter PFS (p = 0.001) and OS (p = 0.049). Next, we investigated mutation landscape in patients with WT TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior PFS than those with WT or non-265P (p = 0.046).

Conclusions

We revealed that patients with TP53 mutation are more likely to have primary refractory to standard R-CHOP. This study also showed the prognostic potential of MYD88 L265P in those with WT TP53 and indicated that distinct subgroups could be identified by TP53 and MYD88 L265P mutations.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

161P - Differential expression of various miRNAs in pediatric cytogenetically normal acute myeloid leukemia (CN-AML) (ID 3809)

Presentation Number
161P
Lecture Time
12:00 - 12:00
Speakers
  • Vikas Gaur (Noida, India)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Dysregulation of various miRNAs has been linked to the initiation and progression of several cancers including acute myeloid leukemia (AML). However, their role in pediatric cytogenetically normal AML (CN-AML) is still unclear. The objective of the present study was to identify deregulated miRNA expression patterns and their correlation with survival outcome in pediatric CN-AML.

Methods

The study was approved by Institutional Ethical Committee. Informed written consent was taken from all the subjects. Bone marrow (BM) samples from 36 pediatric CN-AML patients and 20 pediatric controls (with solid tumors without BM involvement) were collected and used for isolation of mononuclear cells, genomic DNA and total RNA. Various clinical parameters were accessed and mutation status (NPM1 and FLT3-ITD) determined by PCR. Total RNA from 10 samples (5 CN-AML and 5 controls) was used for global miRNA profiling on Illumina HiSeq2500 platform and data were analysed using bioinformatic pipeline. For all 36 CN-AML patients, cDNA was prepared using TaqMan advanced miRNA cDNA synthesis kit followed by qPCR using TaqMan advanced miRNA assay for selected miRNAs.

Results

Global miRNA profiling revealed differential expression of 168 miRNAs of which 66 were upregulated and 102 were downregulated (fold change>1.5, p ≤ 0.05) in pediatric CN-AML patients. Interestingly, 40 miRNAs belonging to human 14q32 miRNA cluster were significantly downregulated in CN-AML patients. The expression of 11 miRNAs selected for qPCR-based validation based on their involvement in signalling pathways in AML (and other cancers), were found to be dysregulated in 36 patients. Most of these miRNAs were found to target genes involved in the initiation and progression of AML. Importantly, there was a significant correlation between expression levels of miR-75, miR-589, miR-4446, miR-889, and miR-654 and survival outcomes like Event-free, Disease-free, and Overall survival. Clinical parameters like TLC, ANC, LDH, Blast percentage were also significantly correlated with survival outcomes.

Conclusions

Along with various genetic abnormalities, deregulation in the expression of miRNAs might be an important contributor to the development of pediatric CN-AML.

Legal entity responsible for the study

The authors.

Funding

Department of Biotechnology, Government of India.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

162P - Circulating tumour cells in head and neck and non-small cell lung cancer (ID 4750)

Presentation Number
162P
Lecture Time
12:00 - 12:00
Speakers
  • Kenneth J. O'Byrne (Woolloongabba, QLD, Australia)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Metastasis in cancer patients is reflected by measurable levels of circulating tumour cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumour burden of an individual patient.

Methods

Our study was designed to use microfluidic devices for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (HNC) and non-small cell lung cancer (NSCLC) patients were recruited to investigate the prognostic role of CTCs (n = 400).

Results

We demonstrated a higher CTC capture efficiency using microfluidic CTC platforms. Molecular alterations present in the primary tissue were confirmed in the CTCs by DNA FISH (EGFR-amplification, ALK-translocations). The presence of CTC clusters was associated with the development of distant metastatic disease (P = 0.0313). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Likewise CTC cultures were established from 6/40 NSCLC samples. Exome sequencing of CTC and white blood cells (as germline control) confirmed the presence of somatic mutations in the CTC culture with mutational signatures consistent with NSCLC. Additionally our preliminary data indicate that PD-L1 is frequently expressed on CTCs in HNC and lung cancer and an immunoscore may be able to identify patients likely to benefit from immunotherapy.

Conclusions

Expanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumour, understanding of the disease progression and testing of therapies.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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Poster Display session 3 Poster Display session

163P - OX40/OX40L protein expression in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers (ID 3704)

Presentation Number
163P
Lecture Time
12:00 - 12:00
Speakers
  • Xiaoshen Zhang (Shanghai, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Anti-tumoral immunotherapy of anti- programmed cell death protein-1 (PD-1)/programmed cell death protein-ligand 1 (PD-L1) immune checkpoint therapy demonstrated the efficacy and tolerability in patients with lung cancer. Apart from inhibitory checkpoints, OX40, the co-stimulatory receptor related to T cell priming and proliferation, was valued identically. In this study, the relationship between OX40/OX40L among PD-1/PD-L1 and other immunological factors, as well as its role serving as the potential prognostic biomarker were analyzed in NSCLC.

Methods

We investigated the relationship between OX40/OX40L, PD-1/PD-L1 and TILs in surgical samples from 139 patients with NSCLC by immunohistochemistry (IHC). Factors related to OX40/OX40L expression were analyzed by logistic regression and multi-linear regression. Cox analysis was also performed to find the influencing factors. Survival analysis was conducted in order to testify its role in predicting patients’ prognosis.

Results

The TILs OX40/OX40L expression was negatively correlated with the PD-1/PD-L1 expression. PD-1expression was negatively correlated with the TILs OX40 expression (R = 0.250, [p = 0.003]), it was also negatively correlated with the TILs OX40L expression (R = 0.386, [p = 0.0001]). PD-1expression was positively correlated with TILs grades and negatively correlated with the TILs OX40L expression (R = 0.531, [X1, 95%CI 3.552-8.176, p = 0.0001; X2, 95%CI 0.216-0.683], [p = 0.0001]). The expression of TILs OX40 varied significantly among tumor OX40, OX40L, PD-1, PD-L1, TILs and pathology types. Tumor OX40L expression, TILs OX40L expression, PD-1 expression, PD-L1 expression and TILs were considered as risk factors for TILs OX40 expression. The staging and TILs OX40L were considered as risk factors for overall survival (OS) while stage and gender were risk factors for recurrence-free survival (RFS). The low-expression of OX40 was related to longer RFS, OS and better prognosis.

Conclusions

OX40 plays a pivotal role in NSCLC, which was closely correlated with immunological factors, RFS and prognosis.

Legal entity responsible for the study

The authors.

Funding

This study was supported in part by a grant from National Natural Science Foundation of China (81802255), Shanghai Pujiang Program (17PJD036) and a grant from Shanghai Municipal Commission of Health and Family Planning Program (20174Y0131). National key research & development project (2016YFC0902300). Major disease clinical skills enhancement program of three year action plan for promoting clinical skills and clinical innovation in municipal hospitals, Shanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC (16CR1001A). The fundamental research funds for the central universities.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

164P - Effect of serum survivin on survival among non-small cell lung cancer patients: NCI experience (ID 2235)

Presentation Number
164P
Lecture Time
12:00 - 12:00
Speakers
  • Reham A. Rashed (Cairo, Egypt)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Survivin is a protein that inhibits apoptosis and has been shown its role in cancer progression, tumor angiogenesis, tumor cell resistance to chemotherapeutics and ionizing radiation. We aimed to evaluate the importance of survivin in lung cancer patients and identify its role in disease progression and outcome.

Methods

We prospectively enrolled advanced non-small cell lung cancer (NSCLC) patients (2015-2017). Serum survivin expression levels were detected in the peripheral blood using real-time RT-PCR. The primary outcomes were to identify overall survival (OS), progression free survival (PFS) and time to progression (TTP) while the secondary outcomes were to identify the associations between different variables and survivin cut-off determined by receiver operating characteristic (ROC) curve. Chi(X2) and Mann Whitney-U tests were used. Kaplan-Meier survival curves were used and compared using Log-rank. Cox regression was used to identify if survivin was a predictor of survival.

Results

66 patients were recruited with median age of 55 years (Inter-quartile range: 47- 63.3), 74.2% were males. Adenocarcinoma represented 59.1%. 12 cases developed progressive disease (PD) with 8 cases had bone metastasis after PD. Median OS, TTP and PFS was 17.1 months (95%CI 13.1-20.9), 11.0 (95%CI 7.3-14.8) and 8.9 (95%CI 8.1-9.8) respectively. Chosen cut-off for survivin was 3.80 (Area under ROC curve=0.644 (95%CI=0.51-0.78), P = 0.044) that was associated with better median TTP and PFS of 12.0 vs 4.9 months and 9.0 vs 4.9 months in low survivin (≤ 3.8 vs high (>3.8) groups (P = 0.001 and 0.006) respectively. Survivin >3.80 was associated with worse TTP (Hazard ratio (HR) 5.66 (95%CI 1.8-17.7; P = 0.003). Higher survivin was associated with bone metastasis after PD (100% vs 26.3 in low survivin (P = 0.014).

Conclusions

Survivin is a significant predictors of time to progression and progression free survival in advanced NSCLC. Bone metastasis is common in high survivin group.

Kaplan Meier survival curves estimated median survival (in months) for survivin subgroups (≤3.80 vs > 3.80): A) overall survival (OS), B) time to progression (TP) and C) progression free survival (PFS)
Median survival (months)Lower CIUpper CIP-value
OS (overall)17.06313.14020.986
- Survivin ≤3.8017.0630.156
- Survivin >3.80NR
TTP (overall)11.0477.32714.766------
- Survivin ≤3.8012.0000.001
- Survivin >3.804.964
PFS (overall)8.9758.1499.802------
- Survivin ≤3.809.0410.006
- Survivin >3.804.964

CI: 95% confidence interval, NR: not reached, OS: overall survival, PFS: progression free survival, TTP: time to progression

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

165P - Enhanced performance of prognostic estimation from TCGA RNAseq data using transfer learning (ID 2788)

Presentation Number
165P
Lecture Time
12:00 - 12:00
Speakers
  • Helene Vanacker (Lyon, CEDEX, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Deep learning (DL) is one of the best approaches to predict nonlinear behaviors from high dimensional data. Nevertheless predicting the outcome of patients affected by cancers from transcriptomic data has shown limited performance, even with DL (C-index usually <0.65). Transfer learning is a DL two-step method where a model is pre-trained for a basic task on large amount of data, and then fine-tuned on the aimed task. We hypothesized that using TL with RNAseq may improve the performances of cancer patients’ outcome estimation.

Methods

The model was a Multi-Mayer Perceptron (MLP) with 22913 inputs corresponding to genes bulk tumor whole genome RNAseq expression analysis. An important restriction was applied to the number of units at second layer (N = 100), with further linear decrease across subsequent layers. Architecture of the model (number of layers, skip connections), L1 normalization value and learning rate were optimized by grid search on 30 parallel models. Training was performed using Keras package in R. Data were split into 70% training, 15% cross validation, 15% validation for each step, without contamination between the 2 transfer learning steps. The pre-training step consisted in predicting the organs of sample origin using 17.487 public RNAseq data of normal & cancer tissues (GTEX from gtexportal.org & TCGA from cBioportal.org). Fine-tuning on patients survival used 6401 training tumors. The model’s performance on survival prediction was evaluated by C-index and the area under the survival receiver-operating characteristic curve (AUROC).

Results

The pre-training using GTEx and TCGA reached very high performance with validation accuracy of 0.96 to predict organ of origins for the best model (all models had validation accuracy > 0.9). Fine-tuning on survival, the prognostic performance of the best model on the validation cohort was C-index=0.74 and AUROC= 0.81 (80% of models had a C-index > 0.6). The best model had 8 hidden layers and a small penalization value.

Conclusions

Thanks to this original transfer learning method, we achieved a high performance to estimate cancer patients’ prognostic from whole genome expression, a classically challenging task. Learning on public databases is a valuable method of DL for personalized cancer care.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

E. Angevin: Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: DebioPharma; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Lilly; Advisory / Consultancy: MedImmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Orion. A. Hollebecque: Advisory / Consultancy: Amgen; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Lilly; Advisory / Consultancy: Debiopharm; Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Incyte; Travel / Accommodation / Expenses: Debiopharm. E. Deutsch: Advisory / Consultancy: Boehringer; Advisory / Consultancy: Medimune; Advisory / Consultancy: Amgen; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): biotrachea; Research grant / Funding (institution): BristolMyersSquidd; Research grant / Funding (self): Clevelex; Research grant / Funding (self): EDF; Research grant / Funding (self): Lilly; Research grant / Funding (self): GlaxoSmisthKline; Research grant / Funding (self): Merk; Research grant / Funding (self): Nanobiotix; Research grant / Funding (self): Oseo; Research grant / Funding (self): Ray Search Laboratory; Research grant / Funding (self): Roche; Research grant / Funding (self): Ipsen; Research grant / Funding (self): Servier; Research grant / Funding (self): Takeda. C. Massard: Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: DebioPharma; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Lilly; Advisory / Consultancy: MedImmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Orion. L. Verlingue: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Adaptherapy. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

166P - Analysis of circulating tumour DNA for early relapse detection in stage III colorectal cancer after adjuvant chemotherapy (ID 4689)

Presentation Number
166P
Lecture Time
12:00 - 12:00
Speakers
  • Samuel A. Jacobs (Pittsburgh, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for early prediction of relapse across different tumor types. In patients with colorectal cancer (CRC), multiple studies have analyzed ctDNA to monitor tumor burden using fixed gene panels and droplet digital PCR. Here, we use a highly sensitive and specific, bespoke, whole exome-based NGS approach (Signatera™) for ctDNA monitoring.

Methods

A cohort of 33 patients with stage III CRC who underwent surgery and were treated with at least 4 months of adjuvant chemotherapy was analyzed. Mutational profiles derived from primary tumor tissue and germline DNA whole exome were used to design assays targeting tumor-specific somatic variants. The bespoke assays were used for ctDNA detection in plasma samples. Relapse-free survival (RFS) was calculated for patients stratified by ctDNA status.

Results

Plasma samples (n = 44; average volume=1.8mL) from patients (N = 33) were analysed for the presence of ctDNA. Of the five ctDNA-positive patients, clinical follow-up was available for three patients, all of whom relapsed (100%; 3/3); three of 27 ctDNA-negative patients (11%) also clinically relapsed. Molecular relapse through ctDNA analysis was detected up to 668 days ahead of radiological imaging with an average lead time of 305 days. The majority of relapses in ctDNA-positive patients (67%; 2/3) occurred within a year of follow-up, while no relapses were observed in ctDNA-negative patients during the one-year time frame. All plasma samples (n = 34) from 24 non-relapsing patients were ctDNA negative, corresponding to a specificity of 100%. The presence of ctDNA was associated with a markedly reduced RFS compared to ctDNA-negative patients (HR: 5.6; 95% CI: 0.6-52.1; p < 0.01).

Conclusions

The study results indicate that ctDNA status is associated with high relapse risk in patients with CRC and can serve as a predictor of patient outcome. Despite low plasma volumes (<5mL) and lack of longitudinal samples for analysis, ctDNA was detected in 50% of relapse cases.

Legal entity responsible for the study

Natera, Inc. and NSABP Foundation.

Funding

Natera, Inc., Bayer, NSABP Foundation.

Disclosure

H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. T.J. George: Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Pharmacyclics. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. A.S. Tin: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. A. Olson: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. D. Renner: Full / Part-time employment: Natera, Inc. E. Kalashnikova: Full / Part-time employment: Natera, Inc. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. R. Salari: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. B. Zimmermann: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

167P - Ascites-derived circulating microRNAs as potential diagnostic biomarkers of gastric cancer-associated malignant ascites (ID 1454)

Presentation Number
167P
Lecture Time
12:00 - 12:00
Speakers
  • Hye Sook Han (Cheongju, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Peritoneal carcinomatosis with malignant ascites is associated with dismal prognosis in gastric cancer. Malignant ascites is the most relevant body fluid in which to seek diagnostic biomarkers for peritoneal carcinomatosis. We aimed to identify and validate ascites-derived circulating microRNAs (miRNAs) that are differentially expressed between liver cirrhosis-associated benign ascites (LC-ascites) and gastric cancer-associated malignant ascites (GC-ascites).

Methods

MiRNA expression levels were investigated in three independent cohorts. Overall, 165 ascites samples (73 LC-ascites and 92 GC-ascites) were obtained from the National Biobank of Korea. Initially, microarrays were used to screen the expression levels of 2,006 miRNAs in the discovery cohort (n = 22). Subsequently, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses were used to validate the expression levels of selected miRNAs in the training (n = 70) and validation (n = 73) cohorts. In addition, the levels of carcinoembryonic antigen (CEA) were determined in the ascites samples.

Results

A total of 36 miRNAs were identified as having the potential to discriminate GC-ascites from LC-ascites via microarray analyses. Expression levels of miR-574-3p, miR-181b-5p, miR-4481, and miR-181d were significantly lower in the GC-ascites samples than in the LC-ascites samples via qRT-PCR analyses, and miR-181b-5p showed the best diagnostic performance for GC-ascites (area under the curve [AUC] = 0.798 and 0.846 for the training and validation cohorts, respectively). The diagnostic performance of CEA for GC-ascites was improved if miR-181b-5p and CEA were analyzed together (AUC = 0.981 and 0.946 for the training and validation cohorts, respectively).

Conclusions

We identified ascites-derived circulating miRNAs capable of differentiating non-malignant ascites and GC-ascites, and demonstrated that the combined use of miR-181b-5p and CEA produces the optimal diagnostic yield.

Legal entity responsible for the study

The authors.

Funding

National Research Foundation of Korea (NRF).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

168P - Results from TRIO030, a pre-surgical tissue-acquisition study to evaluate molecular alterations in human breast cancer tissue following short-term exposure to the androgen receptor antagonist darolutamide (ID 5574)

Presentation Number
168P
Lecture Time
12:00 - 12:00
Speakers
  • Hsiao-Wang Chen (Los Angeles, CA, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The role of the androgen receptor (AR) in breast cancer (BC) is not fully elucidated. TRIO030 was conducted to identify molecular changes in BC tissue following short-term exposure to darolutamide (DAR), a new next-generation AR antagonist.

Methods

TRIO030 was a multicenter, tissue-acquisition trial in women with treatment-naïve early BC, T ≥ 1.0 cm, N0-1. Primary objective: identify molecular alterations in BC tissue following preoperative exposure to DAR (600mg bid for 14-35 days). Formalin-fixed paraffin-embedded (FFPE) blocks and fresh frozen tissue (FFT) were collected before DAR and at surgery (or pre neoadjuvant therapy). AR, ER, PgR, HER2, Ki67, Cytokeratin 5-6 were assessed by IHC. Gene expression microarray (GEx) and Reverse Phase Protein Analysis (RPPA) were done on FFT. Differentially expressed genes (DEGs) were found by ANOVA from an integrated gene expression analysis software (Resolver). A gene enrichment search by Gene Ontology (GO) analysis was done using Database for Annotation, Visualization and Integrated Discovery (DAVID).

Results

36 patients (pt) (median age 61.5) were enrolled (20 HR+, 7 TNBC, and 9 HER2+ per central lab). Median duration of DAR was 14.5 days. 32 pts were evaluable by RPPA, 31 by GEx. Based on AR level changes in both RPPA and GEx in pre vs. post-DAR samples, cases were grouped: AR upregulated (≥1.2 fold increase, n = 14), AR downregulated (≥1.2 fold decrease, n = 11), AR unchanged (n = 6). 233 unique DEGs were detected with 84 identified as forming two GEx profiles among the 3 AR groups. GO analysis revealed that DEGs profiles were enriched in an immune (IMM) signature or cell proliferation (CP) signature which were anti-correlated (e.g., if CP is upregulated, IMM is down). No correlation between AR groups and BC subtypes was found. One pt had a grade 3-4 adverse event (non-serious ALT-AST increase).

Conclusions

TRIO030 suggests an association between DAR and immune regulation genes. There was no association between pre/post-DAR AR level changes and BC subtype. Future studies will likely be needed to further investigate the role for AR blockade in BC as well as the mechanism of action for DAR at molecular level.

Clinical trial identification

2016-004151-79.

Legal entity responsible for the study

Translational Research in Oncology.

Funding

Bayer (provided the study drug), Translational Research in Oncology (not for profit organization, funded other aspects of the trial).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

169P - JMJD2A is a novel epigenetic factor of chemotherapeutic susceptibility in gastric cancer (ID 1787)

Presentation Number
169P
Lecture Time
12:00 - 12:00
Speakers
  • Yasushi Sato (Tokushima, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Jumonji domain-containing protein 2A (JMJD2A), belonging to the JMJD2 family of histone lysine demethylases, has been implicated in tumorigenesis. However, its expression profile and role in drug resistance of gastric cancer remains unknown. Previous studies show that docetaxel, cisplatin, and S-1 (DCS) therapy has a high response rate in patients with metastatic gastric cancer, but acquired drug resistance is often observed. In this study, we investigated the role of JMJD2A in drug susceptibility of DCS therapy in patients with gastric cancer, and its clinical relevance in gastric cancer.

Methods

siRNA-mediated downregulation of 14 relevant genes from previously identified gene signatures was performed to identify functional factor to modulate drug susceptibility in DCS therapy. In 34 clinical tissues with metastatic gastric cancer, we examined whether JMJD2A expression predicted tumor regression rate in patients. Furthermore, the downstream effects of JMJD2A on drug susceptibility were analyzed by whole-gene expression array and immunoprecipitation.

Results

After specific silencing of 14 candidate genes, inhibition of JMJD2A induced significant drug resistance in three anti-cancer drugs; IC50values for 5-FU, cisplatin, and docetaxel were 15.3-, 2.7-, and 4.0-fold increased, respectively. Overexpressed JMJD2A was universally expressed in 12 gastric cancer cell lines, positively correlated with tumor regression rate in DCS therapy. JMJD2A is physically associated with histone lysine demethylation. By analysis of downstream effect of JMJD2A, cooperation of Coiled-coil domain containing 8 (CCDC8) was identified, using whole-gene expression analysis. Direct interaction of CCDC8 and JMJD2A was verified by immunoprecipitation. Of note, inhibition of CCDC8 also induced significant drug resistance in docetaxel, cisplatin, and S-1.

Conclusions

JMJD2A sensitizes gastric cancer to combination chemotherapy of S-1, cisplatin, and docetaxel by cooperating CCDC8, and JMJD2A/CCDC8 would be a potential biomarker and therapeutic target.

Legal entity responsible for the study

The authors.

Funding

JSPS KAKENHI.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

171TiP - Phase II study of olaparib in previously treated advanced solid tumours with homologous recombination repair mutation (HRRm) or homologous recombination repair deficiency (HRD): LYNK-002 (ID 3140)

Presentation Number
171TiP
Lecture Time
12:00 - 12:00
Speakers
  • David Hyman (New York, NY, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Poly(ADP-ribose) polymerases (PARPs) play a key role in DNA damage repair (DDR). DDR defects due to HRRm (eg BRCA mutation [BRCAm]) or resulting in HRD (eg global loss of heterozygosity) may sensitize tumors to PARP inhibitors, eg olaparib. Olaparib monotherapy has activity in BRCAm ovarian, breast, pancreatic, and prostate cancer, and in prostate cancer with DDR defects beyond BRCAm (TOPARP). Olaparib improved efficacy outcomes vs placebo/chemotherapy as treatment in ≤ 3rd-line (3L) HER2-negative BRCAm breast cancer (OlympiAD) and ≥2L BRCAm ovarian cancer (SOLO3), and maintenance therapy in ≥ 1L ovarian cancer irrespective of BRCAm (SOLO1, Study 19). LYNK-002 (NCT03742895) evaluates HRRm/HRD positivity (HRD+; per Lynparza HRR-HRD assay, Foundation Medicine, Inc., Cambridge, MA) as biomarkers of tumor-agnostic response to olaparib.

Trial design

This open-label, phase 2 study will enroll ∼370 patients (pts) ≥18 y with previously treated, histologically/cytologically confirmed HRRm/HRD + (per Lynparza HRR-HRD assay) advanced solid tumors who failed/are intolerant to/ineligible for available SOC and have no PD during prior platinum-based treatment (any number of prior regimens), measurable disease per RECIST v1.1/Prostate Cancer Working Group (PCWG)-modified RECIST v1.1, no CNS metastases, ECOG PS 0–1, and no persistent toxicity from prior therapy. Newly obtained/archival tumor samples will be centrally evaluated using the Lynparza HRR-HRD assay to confirm eligibility. Pts will be grouped into 2 cohorts: 1) solid tumors with BRCAm (n∼84; excluding breast and ovarian), 2) solid tumors with HRRm (BRCA non-mutated; n∼174)/HRD (n∼112) per Lynparza HRR-HRD assay. Pts will receive olaparib 300 mg BID until documented PD/unacceptable toxicity/study withdrawal. Tumor imaging will occur at baseline, Q8W for 1 y, and then Q12W per RECIST v1.1 by BICR/PCWG-modified RECIST v1.1 (modified for ≤5 target lesions/organ; 10 total). Primary endpoint is ORR. Key secondary endpoints are DOR, PFS, and OS. AEs will be graded using NCI CTCAE v4.0. Enrollment is ongoing at 51 sites in 15 countries. As of Apr 18, 2019, 23 patients have been enrolled.

Clinical trial identification

NCT03742895.

Editorial acknowledgement

Cindy Taylor, PhD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca.

Disclosure

D. Hyman: Travel / Accommodation / Expenses, Personal fees: Atara Biotherapeutics; Travel / Accommodation / Expenses, Personal fees: Chugai Pharma; Travel / Accommodation / Expenses, Personal fees: CytomX Therapeutics; Travel / Accommodation / Expenses, Personal fees: Boehringer Ingelheim; Travel / Accommodation / Expenses, Personal fees: AstraZeneca; Research grant / Funding (institution), Research funding: Puma Biotechnology; Research grant / Funding (institution), Research funding: AstraZeneca; Research grant / Funding (institution), Research funding: Loxo Oncology. A. Hendifar: Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Perthera. H. Cheol Chung: Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GSK; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): BMS/Ono; Research grant / Funding (institution): Taiho; Honoraria (institution): Merck-Sorono; Honoraria (institution): Lilly/Foundation Medicine; Advisory / Consultancy: Taiho; Advisory / Consultancy: Celltrion; Advisory / Consultancy: MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck-Serono. M. Maio: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Incyte; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo SmithKline; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Roche. A. Leary: Advisory / Consultancy, Advisory board: Tesaro; Advisory / Consultancy, Advisory board: AstraZeneca; Advisory / Consultancy, Advisory board: Clovis; Advisory / Consultancy, Advisory board: GamaMabs; Advisory / Consultancy, Advisory board: Gridstone; Advisory / Consultancy, Advisory board: Seattle Genetics; Research grant / Funding (institution), Research funding from the lab: Merus; Research grant / Funding (institution), Research funding from the lab: Inivata; Research grant / Funding (institution), Research funding from the lab: GamaMabs. J. Rhee: Full / Part-time employment: AstraZeneca Pharmaceuticals LP. M. Marton: Full / Part-time employment: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M. Chen: Full / Part-time employment: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S. Krishnan: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. R. Shapira: Speaker Bureau / Expert testimony, Speaker honoraria: MSD; Speaker Bureau / Expert testimony, Speaker honoraria: BMS; Speaker Bureau / Expert testimony, Speaker honoraria: Roche; Speaker Bureau / Expert testimony, Speaker honoraria: Novartis; Speaker Bureau / Expert testimony, Speaker honoraria: AstraZeneca. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

172TiP - The K-BASKET trial: A prospective phase II biomarker-driven multiple basket trial in Korean solid cancer patients (ID 2655)

Presentation Number
172TiP
Lecture Time
12:00 - 12:00
Speakers
  • Seul G. Kim (Seoul, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Previous studies reveal that key oncogenic pathways are shared across various human cancer types, and molecularly targeted therapies show clinical efficacy, influenced by predictive biomarkers rather than by tumor histologic types. These results raised the concept of biomarker-driven therapy that enables personalized cancer treatment regardless of tumor location and origin. We hereby introduce the designs and goals of the K-BASKET trial (Korea-biomarker-driven multi-arm drug-screening, knowledge and evidence-generating targeted trial), enabling to match the right drug to right target like NCI-MATCH trial.

Trial design

This is a proof-of-concept phase II multiple basket trial to test the clinical significance of matched targeted therapies with comprehensive biomarker profiling. The patients with refractory metastatic or unresectable cancer of various origins will be screened for molecular biomarkers by next-generation sequencing, immunohistochemical staining, and in situ hybridization. Those who have cancer with druggable biomarkers will be treated with matched targeted agents. Three treatment arms for the second step are the followings; 1) Patients with MET amplification or exon 14 skipping MET mutation will be assigned to the TAS-115 arm, a novel multikinase inhibitor. 2) Patients with activating PIK3CA or AKT mutations will be assigned to the TAS-117 arm, a novel selective AKT inhibitor. 3) The remaining patients will be screened for PD-L1/MSI/EBV status and those with positive PD-L1/MSI/EBV results or PolD/PolE mutations will be treated with PD-L1 monoclonal antibody. The clinical efficacy and safety of the targeted therapy, as well as the feasibility of molecular profiling and drug matching, will be tested. This study is particularly relevant because: 1) it will identify new indications and predictive biomarkers of targeted therapies in common cancer types in Asian; 2) it is one of the earliest basket trials in tumor immunotherapy and molecular profiling. We anticipate that this trial will provide valuable information on biomarker-driven therapy in clinical practices of personalized treatment.

Legal entity responsible for the study

Yonsei University.

Funding

National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HA16C0018).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

173TiP - Cambridge liquid biopsy “CALIBRATION” study: Can changes in circulating tumour DNA (ctDNA) predict durable tumour responses in patients with advanced oesophageal cancer receiving MEDI4736? (ID 5938)

Presentation Number
173TiP
Lecture Time
12:00 - 12:00
Speakers
  • Constanza Linossi (Cambridge, United Kingdom)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Oesophageal cancer is the 6th most common cause of cancer death with incidence of adenocarcinomas (EAC) increasing in western countries. Long term survival is poor (<5%) (ESMO guidelines 2016) and mutational signatures of EAC suggest patients with "mutagenic" or "DDR" signatures can benefit from immune-checkpoint blockers (ICB) (Secriert et al. Nat gen 2016). However, there is uncertainty around the population to benefit from ICBs. Circulating tumour DNA (ctDNA) can be used to predict responses to immuno-oncology (IO) agents (Howell J, Trans res 2017). TP53 mutations is frequent in EAC 6 and ctDNA-TP53 mutations can be measured/followed in plasma to track tumour behaviour (response, clonal changes) during treatment (Zill O. Clin Can Res 2018, Fisher O. Gut 2017). Next-generation sequencing (NGS) provides high sensitivity, coverage and the possibility to interrogate tumour treatment-response and heterogeneity.

Trial design

CALIBRATION is a single-centre, open-label, pilot trial of durvalumab (1500mg/4w) for patients with EAC progressing to standard chemotherapy. Pts with measurable disease undergo biopsies at screening/C3/progression alongside weekly blood sampling. Primary objective: asses if early changes in TP53 ctDNA variant allele fraction (VAF) levels, by weeks 4 and/ or 7 can predict durable (6 month) RECIST V 1.1 responses (Complete or Partial Response, Stable Disease). We plan to recruit 19 pts with a 5 % significance (one-sided) and 80 % power to detect if ctDNA changes correctly predict radiological response in ≥ 70 % pts. The trial opened to recruitment in October 2018, 13 pts have been pre-screened and 4 pts included. An interim analysis is planned for September 2019. Secondary endpoints include characterization of paired blood/biopsy samples from pts pre/post durvalumab of: • genomic heterogeneity (evolution of mutational signatures under IO) and changes in the tumour microenvironment (dynamics of T-cell populations). • changes in ctDNA and PBMC markers to identify biomarkers of resistance/response. • predictive value of the mutagenic and DDR signatures to predict response to IO compounds.

Clinical trial identification

NCT03653052.

Legal entity responsible for the study

Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge.

Funding

AstraZeneca.

Disclosure

S. Dovedi: Leadership role: AstraZeneca.

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Poster Display session 3 Poster Display session

New diagnostic tools (ID 6618)

Lecture Time
12:00 - 12:00
Speakers
  • Sabine C. Linn (Amsterdam, Netherlands)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00
Poster Display session 3 Poster Display session

1405P - Validation of a tumour mutational burden workflow on routine histological samples of colorectal cancer and assessment of a cohort with synchronous hepatic metastases (ID 3799)

Presentation Number
1405P
Lecture Time
12:00 - 12:00
Speakers
  • Andrea Mafficini (Verona, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Colorectal carcinoma 5-year survival ranges from 90% in patients with localized disease to 15% for those with distant metastasis. Recent research has suggested that hypermutation may predict response to immunotherapy in these tumors, but routine tests for microsatellite (MS) instability miss tumours which acquire hypermutation through other mechanisms. Tumour mutational burden (TMB) measured by next-generation sequencing has been proposed to overcome this limitation.

Methods

A commercially available next-generation sequencing panel targeting 409 cancer-relevant genes was validated for TMB measurement using 12 MS stable and 14 MS instable metastatic colorectal carcinomas, defined by routine testing of MS loci. The same panel was applied to 53 untested colorectal carcinomas with matched synchronous metastases, collected across 10 years to determine both their TMB and presence of KRAS/BRAF mutations.

Results

All samples could be sequenced at a mean coverage depth of 766x and uniformity of 97%. Mean TMB (mutations/megabase) was 8.84 for MS stable vs. 33.36 for MS instable cases in the assay validation cohort. A cut-off value of 15.56 reached 100% sensitivity (95% CI 77-100%) and 100% specificity (95% CI 73-100%). Analysis of the 10 years cohort showed KRAS mutation in 25 cases and BRAF mutation in 4; automated TMB analysis was feasible for samples collected within 7 years (n = 16), while in older specimens DNA deamination caused artefactual calls. 14 cases showed a low TMB in both primary and metastasis, one MS instable case showed high TMB in both primary and metastasis, and one MS stable case showed low TMB (11.61) in the primary and a higher TMB (21.37) in the metastasis. The mutational signature of the metastatic sample showed C>A transversions (11%), missing in the primary tumour, suggesting an additional mutational mechanism.

Conclusions

Gene panel-based TMB analysis can be performed on routine histology samples to detect both hypermutation and cancer relevant somatic mutations. Analysis of older samples may lead to deamination artifacts, which can however be revealed by mutational signature analysis.

Legal entity responsible for the study

Aldo Scarpa (ARC-NET Cancer Research Centre).

Funding

Associazione Italiana Ricerca Cancro [AIRC grant n. 12182].

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1406P - Microsatellite instability testing and lynch syndrome screening for colorectal cancer patients through tumour sequencing (ID 4647)

Presentation Number
1406P
Lecture Time
12:00 - 12:00
Speakers
  • Li Liu (San Diego, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Universal tumor screening for Lynch Syndrome (LS), which involves up to 6 sequential tests, is recommended by NCCN guidelines for all patients with colorectal cancer (CRC) at diagnosis. Microsatellite instability (MSI) testing is the first step in the genetic diagnosis for LS. Additionally, MSI status has been approved by FDA to select patients for immunotherapy treatments. Here we evaluate the performance of a single tumor sequencing test using Illumina TruSight™ Oncology 500 (TSO500) for MSI status determination and LS screening.

Methods

A total of 233 CRC subjects were screened through a commercial MSI-PCR assay run on tumor-normal DNA. Tumor DNA from 63 selected subjects was sequenced with TSO500. The MSI score was calculated using 130 homopolymer microsatellite loci targeted by the TSO500 panel. Subsequently, BRAF p.V600E status and potential mutations in MMR genes or EPCAM were analyzed from TSO500 results. For LS screening, a method with three filtering criteria was used: 1) MSI-high (MSI-H) status, 2) without BRAF p.V600E mutations, and 3) at least 1 MMR gene variant or EPCAM deletion inferred as germline small variant mutation by TSO500 germline classifier or copy number change. Finally, matched normal samples were sequenced with TSO500 to confirm any germline mutations linked to LS.

Results

Using MSI-PCR, 45 of the 233 (19.3%) subjects were identified as MSI-H and 188 (80.7%) as microsatellite stable (MSS). TSO500 achieved an overall percent agreement (OPA) of 100.0% (95% CI: 94.3% - 100.0%) with MSI-PCR for the 63 subjects analyzed by both methods. Eight subjects were identified as LS positive through tumor sequencing by TSO500. Matched normal sequencing confirmed all 8 positive cases of identified potential LS mutations as germline. Overall, TSO500 tumor sequencing achieved an OPA of 100.0% (95% CI: 94.3% - 100.0%) with matched normal sequencing.

Conclusions

Collectively, our results demonstrated that MSI status can be accurately determined with tumor sequencing. Moreover, LS screening by TSO500 with secondary filtering algorithms can be used as a single upfront test to identify BRAF p.V600E status and potential pathogenic germline mutations linked to LS.

Legal entity responsible for the study

Illumina.

Funding

Illumina.

Disclosure

L. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ilumina. C. Garbutt: Full / Part-time employment: Illumina. M. Golkaram: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. S. Kaplan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. L. Costa: Research grant / Funding (institution), PIC/IC/82821/2007: Faculdade de Medicina da Universidade de Lisboa. A. So: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. S. Zhang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. T. Pawlowski: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1407P - "Liquid withdraw" technique in CT-guided cutting needle lung biopsy: Decreased incidence of complications and increased tissue amount for lung cancer molecular testing (ID 3231)

Presentation Number
1407P
Lecture Time
12:00 - 12:00
Speakers
  • Xue Wang (Nanjing, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

CT-guided percutaneous biopsy is a minimally invasive technique used for obtaining enough tissue samples in the diagnosis of pulmonary lesions. The common complications of CT-guided percutaneous lung biopsy include pneumothorax, hemoptysis. Coaxial technique makes it much easier to repeat sampling and obtain adequate specimens, still it makes no change to the high incidence of pneumothorax. Basic on the research De Filippoet al. had done about complications, we hypothesis that when the inner chuck of coaxial guiding needle was removed and the cutting needle was placed inside the guiding needle, the injection of a small amount of liquid (a mixture of lidocaine and hemocoagulase) through the syringe while withdraw of the guiding needle may help to prevent the incidence of pneumothorax for which close the needle track with liquid.

Methods

From August 24th, 2018 to April 1th ,2019, a total of 32 CT-guided percutaneous transthoracic biopsy procedures performed in 32 patients were retrospectively evaluated. The patients were divided into groups regarding the lesion from pleural surface: <30 mm or ≥ 30 mm. The rates of complications such as pneumothorax and pneumorrhagia were analyzed. And the complications were graded as mild/very mild, moderate, and severe. Different complications between the two groups were analyzed using Pearson’s Chi-squared test for categorical values.

Results

Pathology results were malignant in 28 patients (17 cases were adenocarcinoma), benign in 4 patients.7 cases (21.9%) happened pneumothorax (4 very mild pneumothorax, 2 mild pneumothorax, 1 moderate pneumothorax),13 cases (40.6%) happened pneumorrhagia (12 mild pneumorrhagia, 1 very mild pneumorrhagia). And there was no statistically significant between pneumothorax and the depth of lesion to pleural surface (P > 0.05).

Conclusions

Compared to co-axial technique only, CT-guided percutaneous lung biopsy using co-axial combined with "liquid withdraw" significantly reduced the incidence of pneumothorax, which has been confirmed what we found in earlier retrospective study. The new technique provided an more accurate, secure and reliable way to obtain adequate tissue samples in the diagnosis.

Legal entity responsible for the study

Comprehensive Cancer Center of Drum-Tower Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1408P - WGS implementation in standard cancer diagnostics for every cancer patient (WIDE) (ID 3282)

Presentation Number
1408P
Lecture Time
12:00 - 12:00
Speakers
  • Paul Roepman (Amsterdam, Netherlands)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Advances in DNA sequencing technology have strongly reduced costs of Whole Genome Sequencing (WGS) and have made it possible to perform WGS on tumor biopsies within 2 to 3 weeks. Despite its great potential, the value of WGS has so far only been addressed in retrospective or small prospective studies. We have retrospectively shown in > 2,400 metastatic cancer patients that in 31% an approved biomarker for a targeted treatment could be identified. Of these biomarkers, 58% were not targets for standard-of-care (SoC) treatment but suggested off-label use or clinical study eligibility. The potential of WGS in a routine diagnostic setting is explored in the WIDE study and will address feasibility, clinical validity and added value of WGS.

Methods

WGS will be performed on a prospective cohort of 1200 patients with (suspicion of) stage IV metastatic cancer including all solid tumor types. WGS is conducted at the Hartwig Medical Foundation independently of, and in parallel with, SoC diagnostics at the Netherland Cancer Institute. Results are discussed in a tumor board to assess the value of WGS findings for treatment decision and clinical study eligibility. In addition, cost-effectiveness will be evaluated and all participating treating physicians will be asked to what extent WGS has aided their decisions making.

Results

With an accrual rate of 50-75 patients/month starting end of Q2 2019, results of the first 200 patients will be presented. Data from 25 retrospective cases (all with WGS, and 13 with parallel SoC MDx) indicated targets for standard targeted treatment in 5 patients (EGFR, ERBB2 and ROS1 inhibitors) and were identified both WGS and SoC MDx. In 19 patients, WGS found potential clinical study eligibility targets (including PI3K/mTOR, CDK4/6, MEK, FGFR1, MDM2, PARP and checkpoint inhibitors), whereas SoC MDx identified only 6 of these patients as potentially eligible. No relevant DNA aberration was identified for 5 patients.

Conclusions

The WIDE study will provide quantifiable data regarding the feasibility, clinical validity and added value of WGS analysis for patients with metastatic cancer in a routine clinical diagnostic setting.

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

Illumina.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1409P - Known and unknown gene fusion detection capabilities of solid tumour laboratories conducting next generation sequencing in 6 countries (ID 5905)

Presentation Number
1409P
Lecture Time
12:00 - 12:00
Speakers
  • Steph Finucane (Belfast, United Kingdom)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Developments in next generation sequencing (NGS) have revolutionized oncogenic biomarker detection, removing the limitations of single-nucleotide polymorphisms (SNPs) to allow for massive parallel sequencing to detect multiple oncogenic gene fusions. We believe NGS testing platforms are not uniform within the current solid tumor lab landscape, with NGS analysis capabilities ranging from SNPs only to SNPs and known gene fusions, potentially missing crucial biomarkers. The objective of this study was to determine the current NGS capability of solid tumor labs to detect unknown fusions.

Methods

This study used real-world clinical pathology solid tumor labs data from the United States, United Kingdom, France, Spain, Italy, and Germany that conduct NGS. The Diaceutics proprietary global database of more than 2500 labs was analysed across these markets in Q4 2018 to understand NGS testing capabilities currently available within the routine clinical lab setting.

Results

The results of the study are presented in the table. Of the 131 labs in the US performing NGS, only 50 were able to detect fusions. Of those 50 labs, 42 were restricted to using panels designed to detect specific known fusions. Only 8 labs in the US were able to detect unknown fusions. This pattern was reflected in labs surveyed in 5 other countries.

Solid tumor labs: NGS panel use and gene fusion detection

CountryNumber of solid tumor labs performing NGSNumber of labs that can detect fusionsNumber of labs that can detect known fusionsNumber of labs that can detect known and unknown fusions
US13150428
France391174
Germany21541
Spain23440
Italy30761
UK24716

Conclusions

Labs are not well equipped to handle the pace of advancement in biomarker testing. While targeted treatments and companion diagnostics usher in a new age of precision medicine in cancer and extend survival times, many labs lack the technology needed to accurately identify emerging gene fusion biomarkers, especially unknown fusions. This results in both confusion among physicians regarding testing adequacy and missed opportunities for improved outcomes among patients.

Legal entity responsible for the study

Diaceutics.

Funding

Diaceutics.

Disclosure

S. Finucane: Full / Part-time employment: Diaceutics. S. Haridas: Shareholder / Stockholder / Stock options, Full / Part-time employment: Diaceutics. L. Handley: Full / Part-time employment: Diaceutics. J. Clark: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Diaceutics. A. Jack: Shareholder / Stockholder / Stock options, Full / Part-time employment: Diaceutics. S. Munksted: Shareholder / Stockholder / Stock options, Full / Part-time employment: Diaceutics.

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Poster Display session 3 Poster Display session

1410P - Clinical and analytical accuracy of a 523 gene panel next-generation sequencing (NGS) assay on formalin-fixed paraffin-embedded (FFPE) solid tumour samples (ID 4238)

Presentation Number
1410P
Lecture Time
12:00 - 12:00
Speakers
  • Ina Deras (San Diego, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

We developed a tumor-only NGS assay (TruSight assay), a 523 gene panel covering 1.94 megabases (Mb), that detects small DNA variants, provides a microsatellite instability (MSI) score, and estimates tumor mutational burden (TMB) from FFPE tissue DNA. We demonstrate the assay’s ability to detect a variety of biomarkers compared to various orthogonal methods across a range of solid tumor tissues. We also demonstrate accuracy in determining TMB status, using a clinically based cutoff, in non-small cell lung cancer (NSCLC) FFPE samples compared to tumor-normal whole exome sequencing (WES).

Methods

The study used ∼400 paired tumor-normal FFPE samples from 7 tumor types, including 240 NSCLC. Tumor samples were tested using the verified assay workflow including software analysis. All tumor and normal FFPE were tested with internal WES (with an independent analysis pipeline) and most with a commercial MSI PCR kit (Promega). The TMB score threshold, in mutations (mut)/Mb, was established for the TruSight assay and WES using 119 independent NSCLC FFPE samples and correlated with an external published cutoff.

Results

Across different tumor types, there was high concordance in small DNA variant calling (>95% positive percent agreement [PPA], >99% negative percent agreement [NPA]) between the TruSight assay and WES. For MSI, >95% PPA and 100% NPA were achieved between the TruSight assay and MSI-PCR. TMB scores from the TruSight assay showed good correlation with WES TMB scores (R2 >0.95 on linear regression). Among the NSCLC samples, TMB scores (range 0 – 184.6 mut/Mb) determined by the TruSight assay correlated well with WES (R2 0.94). Using cutoffs of 12.3 and 8.3 mut/Mb (TruSight assay and WES, respectively) to assign TMB High and Low statuses, overall percent agreement (OPA) was 85%.

Conclusions

The tumor-only TruSight assay showed high accuracy in detecting biomarkers across a range of solid tumors. The assay showed a good correlation in TMB score and agreement in TMB status with tumor-normal WES in a collection of NSCLC samples.

Legal entity responsible for the study

The authors.

Funding

Illumina.

Disclosure

I. Deras: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina; Shareholder / Stockholder / Stock options: Bristol-Myers Squibb. T. Du: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. C. Zhao: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. N. Haseley: Full / Part-time employment: Illumina. A. Yazdanparast: Full / Part-time employment: Illumina. T. Jiang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina; Shareholder / Stockholder / Stock options: Bristol-Myers Squibb. A. Mentzer: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. A. Purdy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina; Shareholder / Stockholder / Stock options: Bristol-Myers Squibb. B. Crain: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. C. Echegaray: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. D. Lee: Full / Part-time employment: Illumina. J. Lee: Full / Part-time employment: Illumina. J. Silhavy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. K. O’Brien: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. R. Vijayaraghavan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. R. Garcia: Full / Part-time employment: Illumina. R. Haigis: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. T. Pawlowski: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina. J. Dockter: Shareholder / Stockholder / Stock options, Full / Part-time employment: Illumina.

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Poster Display session 3 Poster Display session

1411P - Methylation analysis of MLH1 using droplet digital PCR and methylation sensitive restriction enzyme (ID 2493)

Presentation Number
1411P
Lecture Time
12:00 - 12:00
Speakers
  • Celine De Rop (Gosselies, Belgium)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes being MLH1 and MSH2 the most commonly mutated. By contrast MLH1 inactivation as the result of promoter methylation is strongly indicative of a sporadic cancer, providing LS exclusion criteria for 85% of high microsatellite instability (MSI-H) tumours. Here we present a cost effective strategy enabling to test methylation of MLH1 promoter without bisulfite conversion and with minimal DNA quantity requirement.

Methods

After macrodissection from HE stained slides, DNA was extracted from FFPE tissue sections of colorectal carcinomas. A droplet digital PCR (ddPCR) was performed using two reactions mix. A 270-bp region of the MLH1 promoter (chr3:36993151-36993420) is amplified in the presence/absence of HinP1I, a methylation sensitive restriction enzyme, targeting 3 CpG islands. Analysis was made by the QuantaSoft™ (Bio-Rad) software which calculates amplicon concentrations between the 2 reactions to obtain a percentage of MLH1 methylation. Sensitivity of the technique was assigned to 5% of methylation with a minimal DNA concentration of 5 ng.

Results

Methylation analysis by ddPCR was compared to pyrosequencing combined with bisulfite conversion for 65 samples and a 100% concordance was obtained. Moreover 10 samples were analysed by ddPCR and MethylLight RealTime-PCR with the same concordance. After validation, the technique was implemented in the clinical diagnosis and, in one year, out the 79 MMR-deficient colorectal carcinomas analysed, 60 (76 %) were MLH1-methylated tumours.

Conclusions

This ddPCR sequencing combining methylation sensitive restriction enzyme is a cost-effective strategy, requiring less technical turn around time and minimal DNA quantity as compared to standard analysis. Moreover, this technique could be further used for other promoter methylation analysis (such as MGMT) and on circulating tumoral DNA.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1412P - Analytical performance of the resolution-HRD plasma assay used to identify mCRPC patients with biallelic disruption of DNA repair genes for treatment with niraparib (ID 2963)

Presentation Number
1412P
Lecture Time
12:00 - 12:00
Speakers
  • Ira Pekker (Kirkland, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Metastatic castration-resistant prostate cancer (mCRPC) patients with DNA repair gene defects (DRD) have a shorter life expectancy than patients without DRD and may benefit from treatment with PARP inhibitors. Niraparib is a highly selective PARP inhibitor, with activity against PARP-1/2 DNA-repair polymerases. Detection of DRD in cell free DNA (cfDNA) isolated from blood is minimally invasive and of special benefit to mCRPC patients, including patients without accessible lesions. The assay would also have the advantage of a shorter turnaround time (TAT) than genotyping of tissue. However, using cfDNA to identify biallelic disruption of DNA-repair genes is technically challenging.

Methods

Resolution-HRD identifies patients with biallelic pathogenic alterations of the ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, HDAC2, or PALB2 genes, by targeted NGS sequencing of cfDNA. Analytical performance of Resolution-HRD was validated using cfDNA from mCRPC patient plasma, cfDNA from healthy donor plasma, and contrived samples with a wide spectrum of technically challenging genetic aberrations.

Results

The LOD95 at a cfDNA input level of 40 ng ranged from 0.2 to 1.37 for SNVs and indels, and 6-12 for CNL. APA for intra-run and inter-run studies at the 1X LOD was 95% and 95% respectively. No false-positives were detected in any samples from healthy donors (N = 60). Resolution-HRD has been validated to give consistent results across the 10-75 ng input range. Resolution-HRD is used to identify patients for enrollment in the GALAHAD Phase II Efficacy and Safety Study (64091742PCR2001) of Niraparib in Men with mCRPC and DNA-Repair Anomalies. As of April 2019, over 2000 patients are tested successfully (0.88% failure rate) with a median TAT of 8.6 days (range 5-12 days).

Conclusions

The analytical performance of the Resolution-HRD assay offers highly sensitive, specific and robust test results, and meets analytical requirements for clinical applications. This test is currently being evaluated in several clinical trials for prospective identification of mCRPC patients with DRD for treatment with niraparib.

Legal entity responsible for the study

Resolution Bioscience.

Funding

Janssen Research and Development.

Disclosure

I. Pekker: Shareholder / Stockholder / Stock options, Full / Part-time employment: resolution bioscience. L. Lim: Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment, Officer / Board of Directors: Resolution Bioscience. J.S. Simon: Leadership role, Shareholder / Stockholder / Stock options: Janssen. M. Gormley: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. Z. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. J. Pollak: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. K. Potts: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. S. Watford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. J. Posey: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. P. Chan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. K. Urtishak: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. K. Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. A. Hosseini: Shareholder / Stockholder / Stock options, Full / Part-time employment: Resolution Bioscience. M. Li: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Resolution Bioscience.

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Poster Display session 3 Poster Display session

1413P - Results of a global external quality assessment scheme for EGFR testing on liquid biopsy (ID 3523)

Presentation Number
1413P
Lecture Time
12:00 - 12:00
Speakers
  • Nicola Normanno (Napoli, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Cell free DNA (cfDNA) testing of EGFR mutations is widely employed in lung cancer patients. Liquid biopsy testing is highly challenging due to the low level of mutant DNA present with normal DNA. Therefore, cfDNA testing requires quality assessment to ensure patient safety. The international external quality assessment (EQA) provider consortium, IQNPath has delivered a second successful EQA run to determine the standard of cfDNA testing for EGFR mutations.

Methods

Five European EQA providers (AIOM, EMQN, ESP, Gen&Tiss, UKNEQAS), under the umbrella of IQNPath, collaborated to deliver the assessment during 2018-19 to a total of 310 laboratories from 44 countries. A panel of bespoke manufactured plasma samples with varying EGFR mutations at a range of allelic frequencies were validated by a range of methodologies prior to distribution to ensure stability and reproducibility. The EQA samples were supplied for testing and reporting according to laboratory routine protocols. Peer reviewed criteria was applied to assess the standard of genotyping and reporting.

Results

Of the 310 laboratories that had joined the program, 270 submitted the results within the established deadline. Preliminary analysis of the data submitted by participating laboratories showed that low allelic frequency samples were the most challenging and some methods did not detect these mutations. Reporting of such cases often did not address the risk that tumour DNA may have not been tested and limitations of the testing performed was not addressed when reporting the result. The final results of the EQA scheme will be presented at the meeting.

Conclusions

The variability in the standard of genotyping and reporting highlights the need for EQA in this field and educational guidance to ensure the delivery of high-quality clinical service where testing of cfDNA is the only option for clinical management.

Legal entity responsible for the study

IQNPath.

Funding

IQNPath.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1414P - Clinical impact of plasma next-generation sequencing (NGS) in advanced non-small cell lung cancer (aNSCLC) (ID 3295)

Presentation Number
1414P
Lecture Time
12:00 - 12:00
Speakers
  • Laura Bonanno (Padova, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

NGS provides genetic information with potential impact on clinical practice. Plasma NGS has the advantage to reduce the need to repeat biopsy and provide information about tumor heterogeneity.

Methods

Since March 2018 we prospectively screened aNSCLCs consecutively referring to our institution for potential eligibility to VISION trial (NCT02864992). All the patients (pts) were previously screened for EGFR/ALK/ROS1 sensitizing alterations according to standard methods and positive cases were excluded. NGS was performed with METex14 Guardant360® covering 73 genes including all somatic alterations recognized as potential targets by NCCN. A parallel cohort of pts was also analysed with NGS in tissue by using METex14 Oncomine™ Focus Assay (MolecularMD) covering 59 genes. All identified druggable genetic alterations were tested for confirmation with a different method.

Results

We included 159 pts, 91 (57%) male, 37 (23,3%) smokers and 81 (50,9%) former smokers. Histology was: 144 adenocarcinoma, 7 squamous cell carcinoma, two sarcomatoid and 6 large cell/undifferentiated. 129 (81%) cases were analyzed in plasma and 63 (49%) had tissue NGS results for comparison. Median number of detected genetic alterations was 2 and maximum number was 17. No alterations were found in 14 cases (11%). Two of them were then retested and became positive. We found 34 (26%) potentially druggable genetic alterations and three of them showed discordant results between tissue and plasma. Among all druggable genetic alterations, till now we have treated 12 pts with targeted agents and six had already radiological response evaluable: five of them obtained control of disease. 18 pts with druggable alterations had already received immunotherapy (IT) and only two of them obtained objective response: METex14 mutation and RET rearrangement. We also found 5 cases of KRAS-STK11 co-mutations, three were treated with IT and no response was recorded. In parallel, 89 (56%) cases were analyzed in tissue and 44 (49%) were evaluable for NGS. Ten (23%) potentially druggable genetic alterations were found.

Conclusions

Plasma NGS was feasible and provided additional information: new druggable genetic alterations were found and potential impact of NGS on response to IT emerged.

Legal entity responsible for the study

Istituto Oncologico Veneto, IOV IRCCS.

Funding

Merck KGaA.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1415P - Feasibility study of a ctEGFR prototype assay on the fully automated Idylla™ platform (ID 5632)

Presentation Number
1415P
Lecture Time
12:00 - 12:00
Speakers
  • Martin Reijans (Mechelen, Belgium)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

To predict the response to EGFR tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients, formalin-fixed paraffin-embedded (FFPE) tumor tissue is routinely tested for the presence of somatic mutations in the epidermal growth factor receptor (EGFR) gene. Sufficient tumor tissue is not always available and ctEGFR testing from plasma is an alternative approach for the detection of EGFR mutations. Therefore, a fast and fully automated ctEGFR assay with minimal hands-on time should allow laboratories to quickly generate EGFR testing results.

Methods

IdyllaTM (Biocartis) is a fully integrated molecular diagnostics platform that combines speed and ease of use with high sensitivity and high multiplexing capabilities. In terms of ctDNA testing, it overcomes the time-consuming step of ctDNA extraction from plasma. After insertion of 2 ml of plasma into the cartridge, the complete process of ctDNA extraction, real-time PCR, data analysis and reporting is fully automated. The ctEGFR prototype assay allows the detection of 49 mutations including insertions and deletions in exons 18, 19, 20 and 21. The results obtained by the ctEGFR prototype assay were compared with NGS (sensitivity 2-5%).

Results

Sixty-four NSCLC samples were tested with both assays. Overall, 34 mutations were detected by NGS and confirmed by the ctEGFR prototype assay. In 33 samples, NGS detected no mutation. The ctEGFR prototype assay detected 7 additional mutations in this cohort. Retesting with the cobas EGFR Mutation Test v2 confirmed the presence of these mutations. Analytical sensitivity was assessed for 20 mutations using plasma spiked with synthetic targets. Analytical sensitivities ranging from 1 to 4% were obtained for the tested mutations. Inclusivity was demonstrated for 49 mutations in total. The average turnaround time of a run was <2h 40 min and the hands-on time for the assay was <2 min.

Conclusions

This study shows that the Idylla™ platform enables the development of a prototype ctEGFR assay with high sensitivity and ease of use combined with a fast turnaround time for the testing of 49 relevant EGFR mutations in 2 ml of plasma from NSCLC patients.

Legal entity responsible for the study

Biocartis.

Funding

Biocartis.

Disclosure

M. Reijans: Full / Part-time employment: Biocartis. S.V. Gestel: Full / Part-time employment: Biocartis. E.D. Haes: Full / Part-time employment: Biocartis. C. Vandesteene: Full / Part-time employment: Biocartis. J.M. Castro Gomez: Full / Part-time employment: Biocartis. C. Gouedard: Full / Part-time employment: BioPath Innovations SA. S. Patera: Full / Part-time employment: BioPath Innovations SA. S. Murray: Full / Part-time employment: BioMarker Solutions Ltd. G.G. Maertens: Full / Part-time employment: Biocartis.

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Poster Display session 3 Poster Display session

1416P - Enhanced access to EGFR molecular testing in NSCLC using a cell-free DNA tube for liquid biopsy (ID 3614)

Presentation Number
1416P
Lecture Time
12:00 - 12:00
Speakers
  • Theresa E. May (Pleasanton, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The clinical utility of non-invasive liquid biopsy and ability to accurately detect EGFR mutations in circulating-tumor DNA of patients with NSCLC has been well demonstrated. This expands the pool of patients eligible for molecular testing. The cobas® EGFR Mutation Test v2 (cobas test) is a real-time PCR test for qualitative and semi-quantitative detection of 42 EGFR mutations in DNA from tissue and circulating free DNA (cfDNA) from K2 EDTA plasma. Blood collected in K2 EDTA requires plasma be separated within 8 hours, which can be a barrier to molecular testing and thus impact treatment decisions. The Roche Cell-Free DNA Collection Tube (Roche cfDNA) stabilizes blood up to 8 days, allowing greater flexibility in transportation and time to plasma separation. Here the suitability of plasma from Roche cfDNA tubes for use with the cobas test is demonstrated.

Methods

Test performance with Roche cfDNA plasma was verified with NSCLC patient specimens or surrogate samples (sheared cell line DNA in healthy donor plasma). Correlation was tested using paired draws in K2 EDTA and Roche cfDNA tubes for 51 NSCLC patients and 20 healthy donor surrogate samples. Limit of detection (LoD) and linearity established with K2 EDTA plasma were verified with Roche cfDNA plasma. Reproducibility was assessed using surrogate samples at two levels with multiple operators, Roche cfDNA tube lots, instruments, days and sites. Blood storage conditions were established at an external laboratory with 6 NSCLC patient specimens.

Results

Compared to K2 EDTA plasma, Roche cfDNA plasma had a PPA, NPA and OPA of 100.0% with the cobas test. LoD for EGFR mutation detection in Roche cfDNA plasma was verified as ≤ 100 cp/mL. Linearity for EGFR mutations in Roche cfDNA plasma was verified. The reproducibility study had a call agreement of ≥ 98.6%. Blood in Roche cfDNA tubes was stable for up to 8 days at 18-25ºC with one excursion of up to 24 hours at 15-30ºC prior to separation.

Conclusions

Use of the Roche cfDNA tube with the cobas® EGFR Mutation Test v2 provides the flexibility to store blood for up to 8 days prior to separation, with equivalent performance to K2 EDTA plasma, and facilitates use of liquid biopsy for NSCLC patients needing molecular testing.

Legal entity responsible for the study

Roche Molecular Systems Inc.

Funding

AstraZeneca PLC.

Disclosure

T.E. May: Full / Part-time employment: Roche Molecular Solutions. S.A. Scudder: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche Molecular Solutions. S.J. Joshi: Full / Part-time employment: Roche Molecular Solutions. M. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca, PLC. N. Shrestha: Full / Part-time employment: Roche Molecular Solutions. N. Lee: Full / Part-time employment: Roche Molecular Solutions. J. Lai: Full / Part-time employment: Roche Molecular Systems Inc. M. Tsourounis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca PLC. A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca PLC. P. O’Donnell: Full / Part-time employment, Spouse / Financial dependant: Roche Molecular Systems. H. Halait: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche Molecular Systems. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1417P - Analysis of circulating tumour DNA in paired plasma and sputum samples of EGFR-mutated NSCLC patients (ID 5664)

Presentation Number
1417P
Lecture Time
12:00 - 12:00
Speakers
  • Christina Grech (Vienna, Austria)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Liquid biopsy is a minimally invasive strategy to detect genetic alterations in non-small cell lung cancer (NSCLC) patients. In particular, it is clinically useful for the detection of the EGFR T790M resistance mutation in advanced EGFR-mutated NSCLC patients who had progressed under treatment with an EGFR-TKI. While plasma analysis is commonly performed, sputum could be another potential source for circulating tumor DNA (ctDNA) in NSCLC, which has not yet been entirely evaluated.

Methods

Paired plasma and sputum samples from 23 patients with EGFR-mutated lung adenocarcinoma were analyzed for EGFR exon 19 deletions (del19), L858R, and T790M mutations by droplet digital PCR (ddPCR). All patients had histologically confirmed lung adenocarcinoma with EGFR mutations in their initial tissue biopsy at diagnosis.

Results

Tissue genotyping at diagnosis revealed 18 patients with EGFR del19 and 5 patients with L858R mutations. Among the 18 EGFR del19-positive patients, 8 showed concordant test results in plasma and sputum (2 positive, 6 negative), 6 had del19-positive plasma samples but del19-negative sputum samples, 4 were del19 negative in plasma and del19 positive in sputum. Among 5 L8585R-positive patients, 4 had concordant test results in plasma and sputum (3 positive, 1 negative), one patient was L858R positive in the plasma sample but L858R negative in sputum. In 10 out of 23 patients the T790M mutation was assessed in paired samples, 9 showed concordant test results in plasma and sputum (3 positive, 6 negative), one patient was T790M positive only in the sputum sample.

Conclusions

Our results show a high concordance between plasma and sputum for EGFR L858R and T790M mutation testing. A lower concordance was observed for EGFR del19. Thus liquid biopsy from sputum is a promising strategy that should be further evaluated.

Clinical trial identification

GS1-EK4/479-2017, 20.07.2017 EK-18-172-0918, 08.11.2018.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1418P - Liquid biopsy and array comparative genomic hybridization (aCGH) (ID 4945)

Presentation Number
1418P
Lecture Time
12:00 - 12:00
Speakers
  • Panagiotis Apostolou (Filotas, Greece)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Cancer of unknown primary origin (CUP) represents a metastatic cancer with unidentified primary origin. An efficient cancer treatment algorithm is based on detection and characterization of the tumor’s origin. CUP is characterized by chromosomal instability; therefore the detection of chromosomal aberrations might contribute in tumor characterization. aCGH combines DNA microarray with CGH providing better detection rates than conventional cytogenetic methods. The present study aimed to evaluate aCGH as a technique for detection the origin of tumor, based on liquid biopsy and particular in circulating tumor cells.

Methods

Blood samples were collected from five patients suffering from prostate (2), lung (2) and breast (1) cancer and five healthy individuals. CTCs isolated using enrichment protocols while CD45 (-ve) cells isolated from healthy individuals. In addition to patients’ samples, six commercial cancer cell lines provided by ECACC were used, representing prostate and lung cancer (DU145, 22Rv1, LNcaP, COLO699N, COR0L 105 and MOR). Genomic DNA extracted and aCGH experiments followed with Sureprint G3 platform (Agilent). The genes located in chromosomal aberrations were literately analyzed and potential cancer type suggested by another researcher. The researcher performed the analysis based only on aCGH raw data, ignoring the identity and medical history of all samples. Samples firstly analyzed based on normal vs cancer prediction and secondly whether the predicted type of cancer was correct.

Results

The sensitivity was around 90% while the specificity was 80%. Among eleven cancer samples only one predicted as normal, as well as one normal sample predicted as cancer. As far as the cancer type prediction the positive predictive value was 90.1%. Only one sample categorized wrongly in total cancer samples.

Conclusions

aCGH is a powerful technique with potential of discrimination of cancer and healthy samples, but most important with ability to distinguish the type of cancer. The identification of primary origin of cancer is very important in CUP, since it is correlated with more efficient treatment algorithm. The above encouraging data from the combination of aCGH and liquid biopsy need to be validated in more samples and types of cancer so to be used at clinical level.

Legal entity responsible for the study

Research Genetic Cancer Centre S.A.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1419P - Next-generation sequencing panel verification to detect low frequency single nucleotide and copy number variants from mixing cell line studies (ID 5746)

Presentation Number
1419P
Lecture Time
12:00 - 12:00
Speakers
  • Rocio Rosas-Alonso (Madrid, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The next-generation sequencing (NGS) technology has increased the number of genes and types of genomic alterations detectable by a high-throughput assay and has become an essential part of clinical decision-making. We aimed to verify the analytical specifications of TruSight™ Tumor 170 (TST170, Illumina Inc.) panel for detecting 5% variant allele frequency (VAF) and reliable amplifications (copy number variants, CNVs) for ensuring high quality of sequencing results.

Methods

We use well-characterized human cancer cell lines mixtures with known specific gene mutations to evaluate the specifications given by TST170 and defined thresholds for each type of genomic alterations intended to detect. We performed the following mixing studies by using the lung adenocarcinoma cell lines H1975 and H1299 to acquired proportions: 100%, 33%, 10% and 2% H1975. H1975 harbors EGFR p.Thr790Met (c.2369C>T), p.Leu858Arg (c.2573T>G), TP53 p.Arg273His (c.818G>A), CDKN2A p.Glu69Ter (c.205G>T) and PIK3CA p.Gly118Asp (c.353G>A). H1299 harbors an EGFR, CDKN2A, PIK3CA wild type and a homozygous partial deletion of the TP53 gene. We extracted DNA and performed NGS TST170 analysis with each diluted sample.

Results

When we calculated the correlation between the expected and observed VAFs by linear regression analysis, the coefficient of determination was 0.99 in hotspot NSCLC genes. This result further supports the reliability of this system for variant identification. Mutations with a low VAF (<5%) were identified in half of the mutations and all mutations with >5% VAF were detected without exception. In the CNV analysis, the number of copies seen in the undiluted cell line (100% H1975) were found in all 33% dilution cases, in one third of the 10% dilution cases and in no case in the 2% dilution, independently of undiluted cell line fold changes.

Conclusions

Our analytical verification determines the ability of TST170 pipeline to detect 5% VAF with high confidence and CNVs in samples of tumor purity at 33% or more.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1420P - Automated rarefaction analysis for precision B and T cell receptor repertoire profiling from peripheral blood and FFPE-preserved tumour (ID 5901)

Presentation Number
1420P
Lecture Time
12:00 - 12:00
Speakers
  • Luca Quagliata (Basel, Switzerland)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Identifying the optimal input amount and sequencing depth for B and T cell receptor repertoire profiling is challenging owing to variation in material quality and lymphocyte diversity in blood and FFPE preserved tumor specimens. Rarefaction analysis has emerged as a potential approach for assessing whether immune repertoire libraries have been sequenced to saturation. Here we present a novel automated method for saturation analysis of IGH and TCRB chain libraries derived from sequencing of peripheral blood leukocytes (PBL) and FFPE-preserved tumor RNA and DNA.

Methods

Human TCRB and IGH repertoire libraries were generated using the Oncomine TCRB and IGH assays from: (1) 25ng PBL total RNA (2) 500ng PBL gDNA (3) 150ng RNA from FFPE preserved NSCLC and (4) 200ng gDNA from FFPE preserved brain tissue. Libraries were sequenced on the Ion Torrent Gene Studio S5 then analyzed with Ion Reporter to identify clonotypes, quantify clonal expansion and diversity, and for IGH chain libraries, identify B cell clonal lineages and assess isotype usage. We then repeated clonotyping and analysis of secondary repertoire features using data that had been downsampled to fixed read depths.

Results

We observed an asymptotic relationship between the sequencing depth and the number of B and T cell clones detected, clone Shannon diversity, and B cell clonal lineage richness and diversity, indicating that libraries had been sequenced to saturation. By contrast, T and B cell normalized Shannon entropy appeared robust to sequencing depth.

Conclusions

Automated downsampling analysis may serve as a convenient tool for optimizing sequencing depth and input amount for B and T cell repertoire sequencing studies. We expect this approach to become a routine component of immune repertoire analysis.

Legal entity responsible for the study

Thermo Fisher Scientific.

Funding

Thermo Fisher Scientific.

Disclosure

L. Quagliata: Full / Part-time employment: Thermo Fisher Scientific. T. Looney: Full / Part-time employment: Thermo Fisher Scientific. D. Topacio-Hall: Full / Part-time employment: Thermo Fisher Scientific. G. Lowman: Full / Part-time employment: Thermo Fisher Scientific.

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Poster Display session 3 Poster Display session

1421P - A heptamethine cyanine dye is a potential diagnostic marker for myeloid-derived suppressor cells (ID 2027)

Presentation Number
1421P
Lecture Time
12:00 - 12:00
Speakers
  • Chaeyong Jung (Gwangju, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with inhibitory effects on T cell proliferation. MDSC are over-amplified in most cancer patients so that cancer cells avoid anticancer immunity. Unlike mouse MDSCs, however, specific surface markers to define human MDSCs is still controversial due its complexity of subsets. Heptamethine cyanine dyes are fluorescent dyes, particularly used for noninvasive in vivo imaging and detection of cancer. MHI-148 is known to be specifically retained by tumor cells but not by normal cells. In this study, we investigated the potential application of MHI-148 as a specific MDSC detection probe.

Methods

Mice bearing 4T1 breast cancer cells were created in female BALB/c mice. Splenocytes were isolated at 21 days after injection. Cells were stained with anti-Gr-1-FITC, anti-CD11b-PE antibodies for MDSCs or with MHI-148 dye followed by isolating positive cells with cell sorter. To determine whether MHI148-positive cells possess inhibitory effect on T-cell proliferation, EdU-based T cell proliferation assay was performed. Arginase assay and measurement of Nitrite production were also performed for assessing T cell activity inhibition.

Results

Compared to normal mice, tumor-bearing mice showed tremendous increase of MDSCs (CD11b+/Gr-1+). Over 81% of these MDSCs in tumor bearing mice were reactive to MHI-148 dye. Most sorted cell for MHI-148 fluorescence was also CD11b+/Gr-1+ MDSCs (97.7 %). Notably, lymphocytes and monocytes were not reactive to MHI-148. In addition, MHI-148 dye-positive cells significantly reduced T cell proliferation with increased arginase activity and nitrites concentration, suggesting that MHI-148 reacts to the cells possessing similar function of MDSCs.

Conclusions

This study demonstrates that MHI-148 reacts to mouse CD11b+/Gr-1+ PBMCs with the function of MDSC characteristics. Further studies have be focused on MHI148 affinity to human MDSC and outcome of which will result in a novel tool to detect MDSC to be utilized to predict cancer patient prognosis.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1422P - Molecular fingerprinting in breast cancer (BC) screening using Quantum Optics (QO) technology combined with an artificial intelligence (AI) approach applying the concept of “molecular profiles at n variables (MPnV)”: A prospective pilot study (ID 5517)

Presentation Number
1422P
Lecture Time
12:00 - 12:00
Speakers
  • Jean-Marc A. Nabholtz (Riyadh, Saudi Arabia)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

BC screening by mammography is associated with a significant reduction in mortality (19 % overall reduction of the relative risk), however with significant limitations and debatable cost-effectiveness. Screening individuals for cancer using liquid biopsies (LB) represents an unmet need. We report the first prospective “proof of concept” study using the QO technology combined with an AI approach using the concept of “MPnV” applied to BC detection.

Methods

QO (femto/atto-second infrared laser spectroscopy) on LB is a simple, non-invasive and reproducible method allowing to identify individualized molecular spectra (MS). These highly detailed MS can be correlated to physiological or pathological changes allowing detection and translation of differences. Integrated into a super-computational approach using a non-hierarchical deep data mining strategy (MPnV concept), MS could discriminate individuals with and without BC. The plasma of 68 controls and 27 BC patients, accrued at the King Saud University BC screening program, Riyadh, Saudi Arabia (KSA), were studied by QO (Max Planck Institute of Quantum Optics /Ludwig Maximillian University Munich, Garching, Germany). The MS were analysed on the Shaheen II supercomputer at King Abdallah University for Science and Technology (KAUST), KSA, in order to generate comparative algorithms.

Results

The use of special feature selection, followed by class analysis allowed to differentiate profiles between the two groups with a sensitivity of 97% and a specificity of 72% (variables n = 1,100). A more in-depth analysis led to 99% sensitivity, but with a lower specificity of 64%. Further analysis of the series, using an age-matched approach led to 97% sensitivity with 98% specificity in differentiating women with or without BC.

Conclusions

These results warrant a large scale prospective validation BC screening trial (ongoing) and “proof of concept trials” in other frequent cancers, in particular those without existing screening programs.

Editorial acknowledgement

Prof. Ferenc Krausz, Director, and Dr. Mihaela Zigman, Leader of the Broadband Infrared Diagnostics, Max Planck Institute of Quantum Optics (MPQ), Faculty of Physics at Ludwig-Maximilians Universität München (LMU), Garching, Germany.

Legal entity responsible for the study

Jean Marc Nabholtz, Oncology Centre, King Saud University, Riyadh, Saudi Arabia.

Funding

1. Oncology Centre, King Saud University Medical City, King Saud University, Saudi Arabia. 2. Max-Planck-Institut für Quantenoptik and Faculty of Physics at Ludwig-Maximilians Universität München, Garching, Germany. 3. Computational Bioscience Research Centre, King Abdallah University for Science and Technology (KAUST), Thuwal, Saudi Arabia.

Disclosure

M.R.K. Bahadoor: Travel / Accommodation / Expenses, ASCO Participation Funded: Pfizer; Advisory / Consultancy, Pancreas Expert Opinion Advisory: Baxter. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1423P - Inferring the correlation between incidence rates of melanoma and the average tumour-specific epitope binding ability of HLA class I molecules in different populations (ID 2152)

Presentation Number
1423P
Lecture Time
12:00 - 12:00
Speakers
  • Istvan Miklos (Budapest, Hungary)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Human Leucocyte Antigen (HLA) molecules are encoded by the most polymorphic genes in the human genome. The genetic variation of these genes are considerable across different geographic subpopulations. We hypothesised that this genetic variation might contribute to the risk of melanoma both at population and subject level.

Methods

We developed a cancer risk predictor based on the complete HLA class I genotype of individuals. The HLA-score, used in the predictor describes the ability of the HLA class I alleles of an individual to bind epitopes derived from 48 selected tumor antigens as an indicator of the breadth of the tumor-specific T-cell responses. We collected HLA data for subjects from 20 different geographic regions (ethnic populations) (n = 3278) as well as the corresponding melanoma incidence rates. The average HLA-scores were compared to the incidence rates. We also classified a mixed US population consisting of melanoma and healthy subjects based on their HLA-score.

Results

On population level, we found significant correlation between the incidence rates of melanoma and average HLA-scores in different geographic regions (R2 = 0.5005; p < 0.001; n = 20; df = 18). The highest average HLA-scores (range 75-140) were obtained for the Far East Asian and Pacific regions, where the incidence rates are low (0.4-3.4 per 100,000 per year). The lowest average HLA-scores (range 50-90) were obtained in the European and US regions, where the rates are high (12.6-13.8 per 100,000 per year). On subject level, the risk ratio between the riskiest (HLA-score <34) and the most protected groups (HLA-score ≥96) was 5.69 comparing the top and bottom 20% of the HLA-score distribution (p < 0.05). These HLA-score ranges are consistent with the threshold values separating populations with low and high incidence rates of melanoma.

Conclusions

By developing a novel HLA-score determined by autologous HLA allele binding epitopes of tumor antigens, we showed that individuals with HLA allele sets supporting broader tumor-specific T-cell responses have lower risk of developing melanoma. These results imply that the HLA genotype and HLA-score could be used to determine the immunogenetic risk of melanoma.

Legal entity responsible for the study

Treos Bio Zrt.

Funding

Treos Bio Zrt.

Disclosure

L. Molnar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. J. Toth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. O. Lorincz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. Z. Csiszovszki: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. P. Pales: Full / Part-time employment: Treos Bio Ltd. K. Pántya: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. M. Megyesi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. E. Somogyi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. E.R. Tőke: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Treos Bio Ltd. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1424P - Thermal liquid biopsy as a valuable tool in lung cancer screening programs (ID 4382)

Presentation Number
1424P
Lecture Time
12:00 - 12:00
Speakers
  • Alberto Rodrigo (Lleida, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Implementing screening programs for risk populations can reduce lung cancer mortality by detecting the disease at early stages, when surgical intervention or chemotherapy treatment can be conducted with best prognosis. Screening protocols based on Low-Dose CT presents a series of drawbacks and needs complementary methods for improving sensitivity and specificity in the screening procedure. Thermal Liquid Biopsy (TLB) is as a complementary technique that, combined with imaging techniques, may improve the efficacy of the screening method.

Methods

Blood samples from Healthy Controls (HC) and Lung Cancer Patients (LCP) were analyzed with a high sensitivity microcalorimeter VP-DSC (MicroCal – Malvern Panalytical). The data were processed in Origin 7.0 software. The plasma thermograms were analyzed through a multiparametric method developed by our research group. Statistical models allowed classifying the subjects according their serum thermograms.

Results

115 LCP subjects (average age 64.6±8.7, 83.0% men) with broad stage distribution (II: 5%, III: 26%; IV: 69%), smoking status (64% smoking, 7% non-smoking), histology distribution (37% adenocarcinoma, 29% squamous, 30% small cell) were compared to 119 HC subjects homogeneously distributed from a blood bank. TLB parameters obtained showed statistical differences between HC and LCP groups. Different statistical models were applied in order to establish the optimal TLB output, which is able to classify subjects according to their TLB thermogram: 92% success rate, 90% specificity, and 94% sensitivity (i.e., diagnostic odds ratio of 140).

Conclusions

High positive association between clinical groups and TLB multiparametric model offers advantages over current diagnosis techniques (LDCT imaging), providing a powerful diagnostic approach with a minimally-invasive, low-risk, low-cost clinical test for LCP. Future promising applications, such as screening programs, could be developed from TLB.

Legal entity responsible for the study

The authors.

Funding

Instituto Carlos III (Spain).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1425P - Towards a screening test for cancer by circulating DNA analysis (ID 2465)

Presentation Number
1425P
Lecture Time
12:00 - 12:00
Speakers
  • Rita Tanos (Montpellier, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Circulating DNA (cfDNA) has emerged as a potential biomarker in cancer, and is the subject of extensive studies in translational and clinical research. Our group has been interested in its implication and clinical significance in the field of oncology for many years, and is now focused on evaluating its potential for early cancer detection.

Methods

We recently developed a screening test (MNR: Multi Normalized Ratio), based on various cfDNA parameters determined by a specific q-PCR based method, targeting both nuclear and mitochondrial sequences.

Results

When applied to the supernatant of cell culture, the MNR had a discriminative potential of 100% between normal and cancer cell lines. An extensive evaluation of this test was carried out in plasma samples of 289 healthy subjects and 987 cancer patients (CRC, breast, liver, pancreatic, ovarian) of all stages. Preliminary results revealed a high potential with an AUC of 0.81 (0.78-0.84, 95% CI), a 70% sensitivity (Se) and 77% specificity (Sp). In breast cancer (N = 169), an AUC of 0.82 (0.78-0.86, 95% CI) with 72% Se and 80% Sp were observed. In all stages CRC patients (N = 795), the results showed an AUC of 0.80 (0.78-0.84, 95%, CI), 75% Se and 70% Sp; for CRC stages 0/I/II (N = 426), an AUC of 0.79 (0.75-0.82, 95% CI), 70% Se and 72% Sp; and for CRC stage IV (N = 186), a 0.86 AUC (0.82-0.89, 95% CI) with 75% Se and 80% Sp. When combining the MNR to a total cfDNA concentration threshold value (AUC = 0.81 (0.79-0.83, 95% CI), 72% Se and 76% Sp for all stage cancers (N = 987)), in a test cohort of 173 stages 0/I/II CRC patients and 132 healthy individuals, we increased the sensitivity and specificity to 74% and 95% respectively. Furthermore we recently discovered that cfDNA fragmentation, as determined by Whole Genome Sequencing using either double or single strand library, is also a parameter enabling discrimination between healthy and cancer individuals.

Conclusions

The implementation of a multi-parametric test combining total cfDNA quantification, MNR and fragmentation biomarkers, with help of a decision tree in machine learning, is currently on-going. Our data suggest that our strategy in targeting cfDNA structural features might be powerful for early cancer detection, and appears as an alternative or a synergistic combination to the detection of mutations.

Legal entity responsible for the study

Alain R. Thierry - INSERM (Institut national de la santé et de la recherche médicale).

Funding

MSDAvenir - Mitest / Alain R. Thierry is supported by INSERM (Institut national de la santé et de la recherche médicale).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1426P - Evaluation of a successful launch of the MammaPrint and BluePrint NGS kit (ID 3788)

Presentation Number
1426P
Lecture Time
12:00 - 12:00
Speakers
  • Leonie Delahaye (Amsterdam, Netherlands)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Centralized MammaPrint (MP) and BluePrint (BP) microarray-based genomic tests on FFPE RNA were succesfully translated to a targeted RNA NGS kit that can be performed locally in decentralized sites. Since the launch of the CE-marked MP and BP NGS test, more data has been generated on this platform as well as on the established FDA-cleared microarray platform. Furthermore, decentralized sites worldwide have been onboarded and are certified to locally run the MP and BP NGS test.

Methods

Paired MP and BP results were generated from FFPE RNA samples using the standard microarray as well as the MP and BP NGS test. The results from both platforms were compared to assess the concordance. Since the launch of the MP and BP NGS kit several decentralized sites underwent the onboarding process. As part of the onboarding, these sites processed a set of RNA and FFPE tissue samples previously processed at Agendia using the MP and BP NGS test. A site could only be certified if NGS results showed a 100% concordance with the Agendia results.

Results

To date, over 150 RNA FFPE samples were processed with both microarray and NGS tests and MP/BP results showed concordance above 97%. Onboarding results were available for the decentralized sites. The FASTQ files generated at the sites were uploaded into the cloud-based Agendia Data Analysis Pipeline Tool (ADAPT) to generate MP and BP results. Results showed 100% concordance between Agendia’s central laboratory and the decentralized laboratories.

Conclusions

MP and BP NGS test delivers equivalent results to the standard microarray test. Additionally, NGS results generated at decentralized sites also show extremely high concordance. These results confirm the high quality and robustness of the MP and BP NGS test.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Delahaye: Full / Part-time employment: Agendia. A.T. Witteveen: Full / Part-time employment: Agendia. M. Snel: Full / Part-time employment: Agendia. T. Cavness: Full / Part-time employment: Agendia. B. Chan: Full / Part-time employment: Agendia. L. Mittempergher: Full / Part-time employment: Agendia. A.M. Glas: Full / Part-time employment: Agendia.

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Poster Display session 3 Poster Display session

1427P - Analysis of prognostic factors on overall survival in elderly women treated for early breast cancer using data mining and machine learning (ID 3863)

Presentation Number
1427P
Lecture Time
12:00 - 12:00
Speakers
  • Pierre Heudel (Lyon, CEDEX, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

One third of early breast cancers (EBC) in women are diagnosed over 70 years (y) old. In this population, clinicians look not only at EBC characteristics but also antecedents and comorbidities to determine the best treatment.

Methods

ConSoRe is a new generation data analytics solution using natural language processing and perform advanced data mining. It was used for data extraction from electronic patient record of 2048 patients (pts) of more than 70 years, operated for EBC in Centre Leon Berard since 1997. Patient and tumor characteristics, treatment and survival were extracted.

Results

Mean age was 75.5 y (range 70-100 y). Main comorbidities described were coronary heart disease: 340 pts (16,6%) and diabetes: 321 pts (15,7%). Distribution of body mass index (BMI) was under 18.5: 56 pts (3,3%), 18.5-25: 677 pts (39,6%); 25-30: 620 (36,3%) and over 30: 356 (20,8%). Mean tumor size was 23,5 mm (range 6 to 150), SBR grading was distributed as well: grade 1: 317 (17%) ; grade 2: 1007 (55%) ; grade 3: 476 (26%) while estrogen receptor were positive (>10%) in 1553 pts (86%), progesteron receptor positive (>10%) in 1299 pts (71%) and HER2 positive in 101 pts (6,3%). Histological nodes staging was N0 in 1497 pts (72%); N1 in 414 pts (20%); N2 in 95 pts (5%); N3 in 52 pts (2%). 295 pts (14%) were treated by chemotherapy, 80 pts (3,9%) by trastuzumab, 1544 pts (75%) by radiotherapy and 1543 (75%) by hormonotherapy. Despite a limited mean follow-up of 5,1 y (range 0.3-20,7y), we observe 83 local relapse (4%), 144 metastatic relapse (7%) and 261 deaths (12.7%) with a mean overall survival (OS) of 4,6 y (10 days to 21,4 y). In the multivariate analysis, BMI under 19 and HER 2 positive were independent predictors of OS (HR: 0,85; p = 2.49e-09). Using Multiple Correspondence Analysis, percentage of explained variances is very low with less than 10%. These results show the limit of classical approach by descriptive data analysis, that is why, we propose new method by machine learning and operational research to determine the best adjuvant treatment.

Conclusions

This elderly population has a poor prognosis for which taking BMI into account is important when defining the therapeutic strategy. Classical approaches by data analysis reach their limits.

Legal entity responsible for the study

Heudel Pierre.

Funding

Has not received any funding.

Disclosure

P. Heudel: Research grant / Funding (institution): AstraZeneca; Honoraria (institution): novartis; Honoraria (self): Pfizer. O. Tredan: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): novartis; Honoraria (self): AstraZeneca; Honoraria (self): lilly; Honoraria (self): BMS; Honoraria (self): MSD. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1428P - Circulating tumour cell detection in epithelial ovarian cancer using dual-component antibodies targeting EpCAM and FRα (ID 1993)

Presentation Number
1428P
Lecture Time
12:00 - 12:00
Speakers
  • Na Li (Wuhan, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Circulating tumor cell (CTC) detection methods based on epithelial cell adhesion molecule (EpCAM) have low detection rates in epithelial ovarian cancer (EOC). Meanwhile, folate receptor alpha (FRα) has high expression in EOC cells. We explored the feasibility of combining FRα and EpCAM as CTC capture targets in EOC.

Methods

EpCAM and FRα antibodies were linked to magnetic nanospheres (MNs) using the principle of carbodiimide chemistry. Blood samples from healthy donor spiked with A2780 ovarian cancer cells were used for detecting the capture rate. Ninety-five blood samples from 30 patients with EOC were used for comparing the positive rate of detection when using anti-EpCAM-MNs alone with that when using combination of anti-EpCAM-MNs and anti-FRα-MNs. Samples from 28 patients initially diagnosed with EOC and who did not undergo any treatment and 20 patients with ovarian benign disease were used for evaluating the sensitivity and specificity of combination of anti-EpCAM-MNs and anti-FRα-MNs.

Results

Regression analysis between the number of recovered and that of spiked A2780 cells revealed yEpCAM = 0.535x (R2 = 0.99), yFRα = 0.901x (R2 = 0.99) and yEpCAM+FRα = 0.928x (R2 = 0.99). In mixtures of A2780 and MCF7 cells, the capture rate was 92% using the combination of anti-EpCAM-MNs and anti-FRα-MNs, exceeding the rate when using anti-EpCAM-MNs or anti-FRα-MNs alone by approximately 20% (P < 0.01). The combination of anti-EpCAM-MNs and anti-FRα-MNs showed significantly increased positive rate compared with anti-EpCAM-MNs alone (χ2 = 14.45, P < 0.001). Sensitivity values were 0.536 and 0.75 when using anti-EpCAM-MNs alone and when using the combination of anti-EpCAM-MNs and anti-FRα-MNs, respectively. Specificity values were 0.9 and 0.85, respectively. The combination of anti-EpCAM-MNs and anti-FRα-MNs improved the sensitivity of CTC detection in patients with newly diagnosed EOC (χ2 = 4.17; P = 0.041).

Conclusions

The combination of FRα and EpCAM is feasible as a CTC capture target of CTC detection in patients with EOC.

Legal entity responsible for the study

The authors.

Funding

The NNSFC (National Natural Science Foundation of China) (81802980, 81770169, 81670144) and the Health Committee Research Project Fund of Hubei Province (WJ2019M179).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1429P - CEUS of the breast: Is it feasible in improved performance of BI-RADS evaluation of critical breast lesions? A multi-center prospective study in China (ID 4281)

Presentation Number
1429P
Lecture Time
12:00 - 12:00
Speakers
  • Jun Luo (Chengdu, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Ultrasound is the first and primary breast screening for thoes women with small and dense breast and is superior to mammography. BI-RADS using ultrasound causes approxinately over 40%-60% false-positive results, unnecessary biopsy and relatively low cancer-to biosy rate. This multi-center study in China is to determine whether contrast-enhanced ultrasound (CEUS) of the breast can improve the precision of BI-RADS.

Methods

1721 patients were enrolled at 8 sites in China. CEUS was performed before core needle biopsy or surgical resection and a revised BI-RADS classification was assigned based on CEUS performance. Using pathological results as golden standerd to evaluate the diagnostic performance of CEUS-based BI-RADS.

Results

1738 solid breast lesions (5.0-39.8mm, 17.89± 8.65mm) classified as BI-RADS 4 or 5 on conventional ultrasound or mammography. 771/1738(44.36%) are malignant and 967/1738(55.64%) are benign. The CEUS-based BI-RADS evaluation classified 402/1738 (23.13%) lesions into category 3 and its accuracy, sensitivity, specificity, positive and negative predictive values of 65.0%, 97.0%, 40.0%, 56.0% and 94.0%. The cancer-to-biopsy yield was 57.71% with CEUS-based BI-RADS 3 selected as the biopsy threshold compared with 44.36% otherwise, while the total biopsy rate was only 76.87% compared with 100% otherwiseand will reduce 39.5% (382/967) unnecessary biopsy rate in those benign nodules. Overall, only 2.59% of invasive cancers were misdiagnosed similar as BI-RADS 3 we use nowadays.

Conclusions

This study suggests that evaluation of BI-RADS 4 or 5 breast lesions with CEUS result in reduced biopsy rates and increased cancer-to-biopsy yields.

Legal entity responsible for the study

Jun Luo.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1430P - Classification of abnormal findings on ring-type dedicated breast PET for detecting breast cancer (ID 2268)

Presentation Number
1430P
Lecture Time
12:00 - 12:00
Speakers
  • Shinsuke Sasada (Hiroshima, Hiroshima, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Ring-type dedicated breast positron emission tomography (DbPET) can detect small breast cancers; however, there are no category classifications of abnormal findings on DbPET such as BI-RADs (mammography, ultrasonography, and magnetic resonance imaging). We investigated whether the classification of DbPET findings was useful for detecting breast cancer.

Methods

A total of 674 patients with breast cancers underwent ring-type DbPET using FDG before treatment between January 2016 and March 2019. Findings were morphologically categorized as a focus (uptake size ≤5 mm), mass (>6 mm), or non-mass (multiple uptakes). Non-mass uptakes were additionally classified based on the distribution: focal, linear, regional, segmental, and diffuse. Maximum standardized uptake value (SUVmax) and tumor-to-normal tissue ratio (TNR) were calculated. The final diagnosis was pathologically evaluated based on biopsy or surgical specimens, and lesions of category 2 or lower by conventional examinations were determined benign.

Results

Among 867 abnormal findings, 668 (77%) were malignant and 199 (23%) were benign. Morphologically, 187 (21.6%) lesions were foci, 413 (47.6%) were masses, and 267 (30.8%) were non-masses. Among non-mass lesions, 131 focal, 1 linear, 15 regional, 115 segmental, and 5 diffuse distributions were presented. The median SUVmax was 5.0 and TNR was 2.8. The area under the curve values of SUVmax and TNR for predicting malignancy were 0.824 and 0.855, respectively. In a multivariate analysis, mass, focal and segmental distributions of non-mass lesions, high TNR were significantly related with breast cancer (all P < 0.001). Pathologically confirmed benign lesions included 45 mastopathies, 29 papillomas, 10 fibroadenomas, 7 ductal adenomas, and 3 others.

Conclusions

Classification using morphological findings and TNRs on DbPET are useful to detect breast cancer. The DbPET classification should be considered for breast cancer screening.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1431P - Prediction of benign and malignant breast masses using digital mammograms texture features (ID 4035)

Presentation Number
1431P
Lecture Time
12:00 - 12:00
Speakers
  • Cui Yanhua (Jinan, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Breast cancer is one of the most common malignant disease for women. Mammography is the preferred method for breast cancer detection. The purpose is to investigate the feasibility and accuracy of texture features extracted from digital mammograms at predicting benign and malignant breast mass using Radiomics.

Methods

494 digital mammograms data who diagnosed as breast masses (Benign: 251 Malignant: 243) by mammography were enrolled. Enrol criteria: breast masses classified as BI-RADS 3, 4, and 5 and at last confirmed by histopathology. Lesion area was marked with a rectangular frame on the Cranio-Caudal (CC) and MedioLateral Oblique (MLO) images at the 5M workstation. The rectangular regions of interest (ROI) was segmented and 456 radiomics features were extracted from every ROI. Extracted features were dimensioned by Maximum Relevance Minimum Redundancy (MRMR) and Lasso algorithm. Post-dimension features were classified using Support Vector Machine (SVM). 70% of the data as a training set and the other 30% as a testing set. The reliability of the Classifier was evaluated by the 10-fold cross-validation. The classification accuracy was evaluated by the accuracy and sensitivity and AUC.

Results

Both the MRMR and Lasso screened 30 radiomics features respectively. 10-fold cross-validation showed that their accuracy were 88.70% and 86.71%, respectively. In testing sets, Through the MRMR algorithm, the classifier achieves an accuracy of 92.00% and a sensitivity of 91.10% and AUC of 95.10%. Through the lasso dimension reduction algorithm, the classifier achieves an accuracy of 83.26% and a sensitivity of 75.90% and AUC of 89.38%.

Conclusions

Radiomics texture features from digital mammograms may be used for benign and malignant prediction. This method offer better accuracy and sensitivity. It is expected to provide an auxiliary diagnosis for the imaging doctors.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1432P - Nanomaterials augmented LDI-TOF-MS for hepatocellular carcinoma diagnosis and classification (ID 5678)

Presentation Number
1432P
Lecture Time
12:00 - 12:00
Speakers
  • Jian Zhou (Shanghai, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Hepatocellular carcinoma (HCC) has relatively sensitive and specific serum tumor antigen markers (AFP), which is also the most common serological marker for cancer screening. However, there are unignorable limitations, including possible false-negatives/positives owing to confounding conditions. Reliable non-invasive diagnostics is still in urgent need. This work proposes a novel LDI-TOF-MS technique for HCC screening and diagnosis. By taking advantage of 3D nanostructures and machine learning, our technique enables high fidelity and reproducibility.

Methods

An LDI-TOF-MS platform was established for HCC screening and was applied to 139 patients with liver cancer, as well as 203 healthy controls (Table). All mass spectrum was collected within a mass range of 100 to 1,100 Da for metabolites. Based on the data acquired by LDI-TOF-MS, SVM algorithm was developed and applied for automated cancer classification across six cancer types, which was further validated by single blinded samples with randomly selected cancer patients and controls.

Summary of patient and healthy control characteristics

Patient TypeNGenderGenderAgeAJCC StageAJCC StageAJCC StageAJCC Stage
M(%)F(%)IIIIIIIV
HCC139120 (86.33%)19 (13.67%)55.63± 11.22(25-80)514840-
HC203117 (57.64%)86 (42.36%)47.68± 10.78(23-76)----

Results

This assay demonstrated an average sensitivity of 96% and a specificity over 98% in detecting HCC. In our cohort, 47 of 137 HCC patients (35.77%) were AFP negative (AFP<20ng/ml, stage I n = 18, stage II n = 17 and stage III n = 12). Here, we showed that the LDI-TOF-MS recognized almost all AFP-negative HCC. The sensitivity and specificity were obviously superior to AFP in HCC: only 2 of 137 HCCs (1.46%) were misclassified as healthy controls. In contrast, AFP positive and AFP negative HCCs were not readily distinguished by this method. Therefore, this method was independent of tumor markers.

Conclusions

This work established a low-cost, high-throughput procedure based on trace amount of serum to identify HCC as well as healthy controls with superior precision, making it a promising technique for clinical cancer research and translation.

Legal entity responsible for the study

Zhongshan Hospital, Fudan University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1433P - Development and validation of an RNA-Seq Assay for gene fusions detection in formalin-fixed paraffin-embedded samples (ID 2436)

Presentation Number
1433P
Lecture Time
12:00 - 12:00
Speakers
  • Hua Dong (Shanghai, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

RNA sequencing (RNA-Seq) assay has been widely used for transcript level gene quantification and fusion detection for research use in fresh frozen samples. Clinical use of RNA is complicated by the common use of formalin-fixed paraffin-embedded (FFPE) tissue storage, which can cause low yield and RNA degradation. We evaluate the feasibility, quality, and analytical performance of RNA-Seq on clinical FFPE tumor samples for gene fusion detection.

Methods

Total RNA was extracted from FFPE tumor samples and/or adjacent normal samples. Ribosomal RNA depletion, cDNA synthesis, and library preparation were used to prepare next-generation sequencing (NGS) libraries that were sequenced on Illumina HiSeq X instrument. Sequencing data were analyzed and annotated with an in-house developed pipeline. A set of experimental and data quality control parameters were set up.

Results

The assay identified all the positive fusions from RNA reference material with 15 NTRK fusions spiked-in and ALK, RET, NTRK1 and FGFR3 fusions from 5 positive cell lines. The assay Limit of Detection was tested by diluting RNA from ALK fusion positive cell H2228C to fusion-negative cell line. Gene fusions were generally detectable down to 10% dilutions for all fusion types and as little as 5% for some fusion types. RNA-Seq assay detected 10 of 12 gene fusions detected by DNA based NGS assay, for a sensitivity of 83%. No false-positive gene fusions were identified in 28 tumor specimens that were negative for fusions, for a specificity of 100%. The assay also identified 6 novel fusions in 3 tumor specimens, which had been confirmed by RT-PCR and Sanger sequencing. Good intra-assay and inter assay reproducibility was observed with complete concordance for the presence or absence of gene fusions in 3 samples and 6 replicates. We observed 81% success rate on whole transcriptome RNA-Seq process for more than 100 FFPE samples.

Conclusions

RNA-Seq assay can help identify gene fusions in patients with cancer, which is a good supplement for DNA based NGS assay, especially for novel fusion detection or fusion breakpoints which are hard to design probes for DNA samples. These patients may in turn benefit from approved and investigational fusion related targeted therapies.

Legal entity responsible for the study

3DMed Inc.

Funding

3DMed Inc.

Disclosure

H. Dong: Full / Part-time employment: 3DMed Inc. C. Wang: Full / Part-time employment: 3DMed Inc. Q. Xu: Full / Part-time employment: 3DMed Inc. Y. Guo: Full / Part-time employment: 3DMed Inc. Y. Chen: Full / Part-time employment: 3DMed Inc. B. Li: Full / Part-time employment: 3DMed Inc. S. Liu: Full / Part-time employment: 3DMed Inc. C. Chen: Full / Part-time employment: 3DMed Inc. L. Xiong: Full / Part-time employment: 3DMed Inc. F. Li: Full / Part-time employment: 3DMed Inc. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1434P - A pilot study to implement an artificial intelligence (AI) system for gastrointestinal cancer clinical trial matching (ID 5271)

Presentation Number
1434P
Lecture Time
12:00 - 12:00
Speakers
  • Zhaohui Jin (Rochester, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Clinical trials improve our knowledge of diseases and treatments while providing patients access to investigational agents. However, approximately 3% of newly diagnosed cancer patients are enrolled in clinical trials in the United States. Identifying an appropriate trial for a patient is time-consuming and cumbersome in the busy clinical practice. The Watson for Clinical Trial Matching (CTM) cognitive system uses AI to derive patient and cancer-related attributes from structured and unstructured text found in the electronic health record. These attributes are matched to complex eligibility criteria in clinical trial protocols.

Methods

In April 2019, a pilot study was launched to test the feasibility of implementing CTM in Gastrointestinal (GI) oncology at Mayo Clinic in Rochester, MN. Two clinical research coordinators (CRCs) screened patients for potential clinical trials prior to their clinic visits using both CTM and the traditional manual screening method. To avoid bias, each CRC screened a separate set of patients by both methods alternating which methodology was used first. The clinical trial match results were blinded to both CRCs. For each method, time to complete the screen and number of potential clinical trial matches were recorded.

Results

A total of 35 GI cancer patients with new diagnosis, recent resection or restaging scans were analyzed. Patients were evaluated against 50 GI-specific drug therapy and multi-disease phase I clinical trials. Clinical trial matching using CTM took an average of 10.1 minutes (Range: 4 to 20 min) per patient compared to an average of 30.5 minutes (Range: 5 to 75 min) per patient (p < 0.0001) using the manual method. CTM identified an average of 7.66 clinical trials (Range: 0-16) while the manual screening method identified an average of 1.97 clinical trials (Range: 0 to 6) per patient (p < 0.0001).

Conclusions

Implementation of Watson for CTM system with a CRC team may enable high volume patient screening for a large number of clinical trials in an efficient manner and promote awareness of clinical trial opportunities within the GI oncology practice. Further analysis to evaluate CTM accuracy and impact on enrollment is warranted and currently underway.

Legal entity responsible for the study

The authors.

Funding

Mayo Clinic.

Disclosure

T. Haddad: Advisory / Consultancy: TerSera Therapeautics; Research grant / Funding (self): Takeda. S. Coverdill: Full / Part-time employment: IBM Watson Health; Shareholder / Stockholder / Stock options: IBM. M. Rammage: Full / Part-time employment: IBM Watson Health; Licensing / Royalties: IBM. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1435P - A blinded comparison of patient treatments to therapeutic options presented by an artificial intelligence-based clinical decision-support system (ID 4787)

Presentation Number
1435P
Lecture Time
12:00 - 12:00
Speakers
  • Suthida Suwanvecho (Bangkok, Thailand)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Comparison of options from clinical decision-support (CDS) systems and decisions made in practice may be biased towards the treating institution. In this retrospective study, bias was minimized by blinding evaluators to the source of treatment recommendations, either Watson for Oncology® (WFO®) or treatments patients received at Bumrungrad International Hospital (BIH), a user of WFO®.

Methods

Treatments given were compared to therapeutic options provided by WFO®. Treatments that were identical to WFO® “recommended” (green, acceptable) were not evaluated further. Paired treatments were evaluated independently in a blinded fashion by each oncologist before consensus ranking of each pair as either acceptable, acceptable alternatives, or unacceptable treatment. The consensus for each treatment was compared to WFO®, with WFO® “for consideration” (yellow, acceptable alternative), and “not recommended” (red, unacceptable). Chi-squared tests analyzed the association between risk factors and discordant recommendations.

Results

Of 228 treatments given to patients with lung, colon, breast and rectal cancers, 174 were identical to WFO® acceptable (green) and not evaluated further; 54 non-identical pairs were evaluated (Table). Overall, 88.6% of decisions were either the same or viewed as equally acceptable by oncologists; oncologists preferred 3.9% of BIH treatments and 4.4% of WFO treatments. In cases where reasons for discordance were provided, 70% were due to BIH oncologist preference, 20% to patient preference and 10% to WFO treatment availability. We found no association between discordant recommendations and patient age or stage of cancer.

TreatmentsN (%) 228 Total
Treatments are identical174 (76.3%)
Oncologists’ Evaluations
Acceptable alternatives28 (12.3%)
BIH Preferred9 (3.9%)
WFO Preferred10 (4.4%)
Both WFO and BIH-Rx unacceptable7 (3.1%)

Conclusions

This blinded study suggests WFO®’s therapeutic options are at as least as good as (or are an acceptable alternative to) treatments in practice. Blinding evaluators to source of treatment may minimize bias in comparisons of CDS systems and decisions made in practice.

Legal entity responsible for the study

Bumrungrad International Hospital.

Funding

Bumrungrad International Hospital.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1436P - OncOS: Scalable and accurate next-generation sequencing analytics for precision oncology and personalized patient care (ID 5744)

Presentation Number
1436P
Lecture Time
12:00 - 12:00
Speakers
  • Joe S. Thompson (Cambridge, United Kingdom)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The advent of high-throughput next-generation sequencing (NGS) technologies has resulted in a deluge of data for a wide variety of clinical uses, with millions of samples sequenced to date. Data generated at an “-omics” level (genomics, transcriptomics, epigenomics, proteomics, etc) in cancer research and for clinical decision making is ushering in a new era of personalized cancer care. However this requires fast, accurate, and easily automatable bioinformatics pipelines capable of large scale analytics on big datasets without sacrificing accuracy. Here we present OncOS, a cloud-based auto-scaling architecture capable of performing highly accurate molecular profiling for personalized clinical insights.

Methods

A flexible cloud architecture implements bioinformatics pipelines dynamically depending on the input data, including a range of possible sample types (FFPE, fresh frozen, plasma/cfDNA), and clinical insights (clinical trial matching, drug matching, and genomic insights such as mutation calls, copy number variant calls, and MSI/TMB). This is powered by a pipeline scheduler and an elastic container service cluster that is capable of initializing a large number of elastic compute cloud instances for scalable and parallelized processing. Data is stored on HIPAA compliant and securely encrypted databases and simple storage services, with key information relayed to a web app for use in a clinical setting.

Results

OncOS has also been optimized for Positive Predictive Value (PPV), with testing on samples from the Multi-Center Mutation Calling in Multiple Cancers (MC3) project, a collaborative effort to provide a high confidence set of variants for patients in The Cancer Genome Atlas (TCGA). Benchmarking shows OncOS performs with a PPV of 87.4%, outperforming similar variant calling pipelines (BROAD institute 75.4%; MD Anderson 80.1%).

Conclusions

OncOS is a precision oncology platform with a cloud architecture capable of processing a variety of sample types at scale, optimized for variant calling PPV and drawing of key clinical insights.

Legal entity responsible for the study

The authors.

Funding

Cambridge Cancer Genomics.

Disclosure

J.S. Thompson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. J.H.R. Farmery: Shareholder / Stockholder / Stock options: Cambridge Cancer Genomics. H. Dobson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. S. Frost: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. J.W. Cassidy: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Cambridge Cancer Genomics. N. Patel: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. H. Thompson: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. H.W. Clifford: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics.

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Poster Display session 3 Poster Display session

1437P - The association between wearable device physical activity metrics and performance status in oncology: A systematic review (ID 3752)

Presentation Number
1437P
Lecture Time
12:00 - 12:00
Speakers
  • Milan Kos (Amsterdam, Netherlands)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The expanding armamentarium of wearable devices offers new opportunities to supplement physician-assessed performance status (PS) with continuously acquired real-life patient data. It is relevant to identify and characterize the level of association between wearable device physical activity (PA) metrics and PS in cancer patients as a first step into evaluating their potential combined utility in evaluating treatment outcomes and clinical decisions. Therefore, we conducted a systematic review to examine the association between wearable device PA metrics and PS in cancer patients.

Methods

We searched PubMed and EMBASE for studies that were conducted among adults with cancer, quantitatively assessed a relation between wearable device PA metrics and PS, and had a full text available in English. We extracted information on study design and population, wearable device type and PA metrics, outcome definitions, and results. Included studies were subjected to methodological quality assessment.

Results

Nine studies with a total of 574 patients were included in this review. Eight studies had a prospective observational study design and all studies reported on a different combination of wearable device PA metrics including: steps per day (n = 5), sedentary behavior (n = 5), and PA volume/intensity (n = 4). Much heterogeneity was observed regarding study population, wearable devices used, and reporting of results. None of the studies could be defined to be of ‘high methodological quality’ (≥ 70%): mean methodological quality was 47% and ranged from 40-60%. We found moderate evidence for a positive association between steps per day and PS, and for a negative association between sedentary behavior and PS.

Conclusions

Much heterogeneity was identified between studies with regards to study population, reported PA metrics, and used devices. Nevertheless, results of this study indicate that higher daily step count is associated with better PS in cancer patients. Whereas sedentary behavior is associated with worse PS. The next step into determining their potential combined utility in evaluating treatment outcomes and clinical decisions is to investigate the association between wearable device PA metrics and cancer outcomes.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

H.W. Wilmink: Advisory / Consultancy: Shire; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Merck. H.W.M. van Laarhoven: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Philips. M. van Oijen: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Amgen. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1438P - SomaticNET: Neural network evaluation of somatic mutations in cancer (ID 5820)

Presentation Number
1438P
Lecture Time
12:00 - 12:00
Speakers
  • Geoffroy Dubourg-Felonneau (Cambridge, United Kingdom)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

DNA sequencing to identify variants is becoming increasingly valuable in clinical settings; including matching patients to approved targeted therapies, immunotherapies, and/or clinical trials. However, accurate calling of genetic variants from sequencing still remains challenging. With little corroboration between the different tools available, patients are at risk of being treated with therapies that are unsuitable for their cancer.

Methods

Here we present a novel machine learning based method for the accurate identification of somatic variants in cancer patient tumour samples, with a neural network architecture from encoded raw sequencing read information of tumour/normal sample pairings into an image, enabling it to classify whether a variant is germline, somatic, or sequencing error. The model was trained and tested on in-silico spike-in data using bam-surgeon, and then validated on a multi-cancer and multi-center dataset and benchmarked against industry standard variant callers.

Results

The approach, called somaticNET, outperforms existing industry standard tools in sensitivity and specificity, achieving an AUROC of ∼1.00 on the bam-surgeon dataset and an AUROC of ∼0.99 on the multi-cancer multicenter dataset. The model also works faster than other variant callers, in minutes compared to hours.

Conclusions

Using the power of machine learning for accurate somatic variant calling can improve patient matching to approved therapies and clinical trials, thus ensuring patients are given the right therapy at the right time to treat their cancer.

Legal entity responsible for the study

The authors.

Funding

Cambridge Cancer Genomics.

Disclosure

G. Dubourg-Felonneau: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. D. Rebergen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. C. Parsons: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. H. Thompson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. J.W. Cassidy: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Cambridge Cancer Genomics. N. Patel: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. H.W. Clifford: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics.

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Poster Display session 3 Poster Display session

Translational research (ID 6619)

Lecture Time
12:00 - 12:00
Speakers
  • Sabine C. Linn (Amsterdam, Netherlands)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00
Poster Display session 3 Poster Display session

1883P - Is there a role for next-generation sequencing (NGS) profiling on metastatic non-colorectal gastrointestinal carcinomas (MNCGIC) in developing countries? A single center experience (ID 4771)

Presentation Number
1883P
Lecture Time
12:00 - 12:00
Speakers
  • Mauricio F. Ribeiro (Sao Paulo, Brazil)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Metastatic non-colorectal cancers have adverse prognosis and no target or immunotherapy is approved until now. NGS platforms are supposed to be useful tailoring systemic treatments and/or screening patients(pts) for early phase clinical trials. Although attractive, NGS-tailored therapies (NGS-TT) can have disappointing results in not approved indications outside clinical trials. In this analysis we evaluated the tumor genetic profiles including potential germline mutations, suggested therapies, available clinical trials, and the results for off-label NGS-TT.

Methods

we performed a retrospective assessment of clinical and molecular characteristics, NGS-TT prescribed and responses in a cohort of MNCGIC evaluated through the 315 genes NGS platform between 2013-2019. We looked for potential germline mutations in mismatch-repair genes and BRCA1/2, as well as the TP53R337H founder mutation.

Results

among 78 pts, the median age was 58.5y (20-79), with 51 (65%) males and 27 (35%) females. The most common sites were pancreas (41%), stomach (15.4%) and biliary tract (15,4%); 83% were ECOG 0/1, with up to 2 lines of therapy (60.25%). Mean number of altered genes was 4.41 (1-19) and tumor mutational burden (TMB) was assessed in 24 pts, with 79% TMB-low (mean 5.22 muts/Mb). Ten pts (12.85%) underwent off-label NGS-TT after discussion at multidisciplinary tumor boards; among 9 available for response evaluation, 7 experienced progression as best response. Clinical trials were suggested for 73 pts (93,6%), but only one patient (pt) was referred to it, since all trials where abroad. We also identified 3 cases for which germline sequencing would be of value (1 pt with TP53 R337H mutation; 2 young gastric cancer pts: one with concurrent MSH6/BRCA2 mutations and another with MLH1truncation exon10 alteration).

Conclusions

in our cohort, the adoption of NGS to tailor systemic treatment did not show an important impact for MNCGIC pts. Increase participation of developing country centers in clinical trials is strongly needed. Potentially germline mutations were present in this series and deserve further investigation.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

D. de Freitas: Honoraria (self): Roche. D.L.F. Jardim: Honoraria (self): Foundation Medicine. B. Gumz: Honoraria (self): Novartis. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1884P - Metastatic cancer whole-exome sequencing in daily practice (ID 1209)

Presentation Number
1884P
Lecture Time
12:00 - 12:00
Speakers
  • Manon Réda (Dijon, France)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Genomically-guided clinical trials began to evaluate the efficacy of molecularly-targeted therapies across different tumor types sharing genetic mutations, but trial organisation remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in a prospective cohort of metastatic cancer patients.

Methods

Exoma trial is a multicenter, prospective clinical trial to test whether exome analysis is feasible and improves access to targeted therapies in routine care. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and constitutive exome analysis was restricted to 342 genes adapted from Foundation Medicine gene list. Variants were classified using Tier models and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was PFS2/PFS1 ratio.

Results

Between May 2016 and October 2018, 506 patients were included. The main tumor type was breast cancer, followed by colorectal and pancreatic cancer. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were performed for 386 patients (76.3%). The most frequently altered gene was TP53 (38.6%), followed by KRAS (18%) and PIK3CA (13.8%). In total, 342 patients (67.5%) received a therapeutic proposal, including change in chemotherapy or addition of an antiangiogenic drug. 79 patients (15.6%) were treated with NGS matched therapy (PIK3/mTOR inhibitors (27.8%), PARP inhibitors (24%), tyrosine kinase inhibitors (21.5%) or immunotherapy (11.4%)). Data for both PFS2 and PFS1 were available for 148 patients (29.2%). PFS2/PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy (n = 51) and 23,7% of patients treated with standard therapy (n = 97).

Conclusions

Study shows that exome analysis is feasible in cancer routine care, improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard.

Clinical trial identification

NCT02840604.

Legal entity responsible for the study

François Ghiringhelli.

Funding

Centre Georges-François Leclerc.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1885P - Genomic-guided individualized precision therapy in refractory metastatic solid tumor patients with extensively poor performance status: A Chinese single institutional prospective observational real-world study (ID 5702)

Presentation Number
1885P
Lecture Time
12:00 - 12:00
Speakers
  • Haitao Wang (Tianjin, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

In recent years, molecular interrogation of tumors and deployment of matched individualized precision therapies has shown remarkable responses in a variety of refractory malignancies. However, to date, few prospective studies have evaluated comprehensive next-generation sequencing (NGS) testing for actionable genomic alterations to guide matched therapy in advanced refractory solid tumors with extensively poor performance status.

Methods

The study was a prospective, observational mono-institutional study. The main eligibility criteria were that patients diagnosed with treatment-refractory disease with poor performance status (ECOG PS ≥ 3) undergoing commercial NGS (Foundation Medicine) testing with the intent of clinical application of available matched targeted agents. Variants were classified in three levels of actionability using a novel scale tool. Treatment recommendations were discussed in a molecular tumor board. Among these treated patients, the primary end point for the analysis was the ORR. Secondary end points included DCR, PFS, OS and safety. The registry is ongoing.

Results

From October 2018 to April 2019, 48 patients were enrolled, which concluded ovarian cancer, stomach cancer, liver cancer, and so on, all underwent NGS of a metastatic site biopsy. About 93.8 percent of patients underwent successful molecular analysis (93.8%) and treatment recommendations were given to 28 patients (62.2 %). These included single-agent targeted therapies (60.7%), checkpoint inhibitors (25%), and combination targeted therapies (14.3%). Treatment recommendations were implemented in 22 of 28 patients (78.6%), of whom 8 (36.4%) showed complete remission (n = 1) or partial response (n = 7), in addition, 16 patients (72.7%) receiving off-label treatments.

Conclusions

Genomic-guided individualized precision therapy is effective for a small proportion of patients in challenging clinical situations. Molecular tumor board and evidenced based actionable gene variation scale tool are effective approach to improve the effectiveness of genomic-guided precision therapy.

Legal entity responsible for the study

Institutional review board of the Second Hospital of Tianjin Medical University.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1886P - Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology (ID 4021)

Presentation Number
1886P
Lecture Time
12:00 - 12:00
Speakers
  • Paolo G. Nuciforo (Barcelona, Spain)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

In the recent years, there has been an increased incorporation of research biopsies in clinical trials and translational research. However, limited information is available on the determinants of sample quality, which could help identifying parameters for successful biopsy ascertainment.

Methods

Data from all consecutive patients who had one or more research biopsies at our institution as part of a phase I-III trials and/or translational research projects approved by Ethics Committee from January 2017 to December 2018 were extracted and analyzed.

Results

A total of 1517 procedures were performed in 979 consenting patients, reaching in total 3811 tissue samples (71% at screening and 29% on-treatment or at progression) with an average of 2.5 samples per procedure. Tumor biopsies were obtained under ultrasound (60%), computed tomography (12%) guidance or non-guided (28%). Samples were formalin-fixed and paraffin embedded (FFPE, 48%), snap frozen (20%) or alternatively stabilized (32%) according to study protocol. Tumor content (TC) was determined in 1514 FFPE samples: 90% of them had tumor cells, 81% showed more than 10% TC and 59% more than 50% TC. No significant difference in TC was found between screening and on-treatment biopsies (p = 0.12). Sample quality was negatively affected by biopsy site (<10% TC rates in non-visceral vs visceral were 26% vs 14%, respectively, p<.0001), method (non-guided vs guided, 37% vs 17%, p<.0001), and operator expertise (<50 vs > 50 biopsies x year, 31% vs 16.5%, p<.0001). In a multivariate logistic model, biopsy site and method were independent determinants of poor sample quality (<10% TC). Within the same biopsy procedure, inter-sample variability was low with 77% of samples showing between 0% to 30% difference in TC. Among 134 intra-trial sequential biopsies with available TC assessment, only 25% pairs were not suitable for performing downstream comparative analyses (<10% TC).

Conclusions

Our experience provides important information to improve research biopsy effectiveness in a biomarker program linked to clinical trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

P.G. Nuciforo: Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): MSD. C. Saura: Advisory / Consultancy: AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Roche, Genomic health, Novartis, Pfizer, Pierre Fabre, Puma, Synthon and Sanofi; Travel / Accommodation / Expenses: AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Roche, Genomic health, Novartis, Pfizer, Pierre Fabre, Puma, Synthon and Sanofi. E. Elez: Honoraria (self): Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Advisory / Consultancy: Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Research grant / Funding (self): Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Honoraria (institution): Array, MSD, Abbvie, Amgen, GSK, AstraZeneca, Bristol Myers Squibb, Novartis, Boehringer, Ingelheim, Hoffman La-Roche.. E. Felip: Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime.; Advisory / Consultancy: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime.; Research grant / Funding (institution): Fundación Merck Salud, Grant for Oncology Innovation EMD Serono. A. Oaknin: Advisory / Consultancy: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen and Genmab; Travel / Accommodation / Expenses: Roche, AstraZeneca, and PharmaMar. E. Muñoz-Couselo: Advisory / Consultancy: Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche; Honoraria (self): Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche ; Leadership role, Clinical trial participation (principal investigator): Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche. T. Macarulla Mercade: Advisory / Consultancy: Shire Pharmaceuticals, Roche, Tesaro, Batxer, Sanofi, Celgene, QED Therapeutics, Genzyme Europe, Baxalta, Bayer, Incyte, Genzyme ; Travel / Accommodation / Expenses: from Merck, H3 Biomedicine, Bayer, Sanofi. M. Alsina Maqueda: Advisory / Consultancy: Servier, Lilly, BMS and MS. Honoraria for speaking issues from Servier, BMS, MSD, Lilly, Roche and Amge; Travel / Accommodation / Expenses: Servier, Roche, Amgen and Lilly. J. Carles: Advisory / Consultancy: Bayer / Johnson & Johnson / Bristol-Myers Squibb / Astellas Pharma / Pfizer / Sanofi / MSD Oncology / Roche/ AstraZéneca; Speaker Bureau / Expert testimony: Bayer / Johnson & Johnson / Asofarma / Astellas Pharma; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol-Myers Squibb Inter. R. Dienstmann: Advisory / Consultancy: Roche; Research grant / Funding (self): Merck. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. E. Garralda: Advisory / Consultancy: F.Hoffmann-La Roche, Ellipses Pharma, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, ; Speaker Bureau / Expert testimony: Bristol-Mayers Squibb ; Travel / Accommodation / Expenses: Merck Sharp & Dohme, Glycotope, Menarini; Research grant / Funding (self), Scitron Project - VHIO Technology : Novartis; Research grant / Funding (institution), Clinical Trial Principal Investigator: Principia Biopharma Inc, Lilly, S.A, Novartis, Genentech, Loxo Oncologi Inc, F.Hoffmann-La Roche Ltd, Symphogen A/S, Merck, Sharp & Dohme de España, S.A, Incyte Biosciences International, Pharma Mar, S.A.U, Kura Oncology Inc, Macrogenics Inc, Glycotope G; Leadership role: ESMO Women for Oncology - W4O. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1887P - Development of a comprehensive next-generation targeted sequencing assay for detection of gene-fusions in solid tumors (ID 5603)

Presentation Number
1887P
Lecture Time
12:00 - 12:00
Speakers
  • Vinay K. Mittal (Ann Arbor, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Gene fusions caused by chromosomal rearrangements play an important role in oncogenesis, the progression of cancer and the selection of targeted therapies. Next-generation sequencing (NGS) using RNA enables sensitive, specific and precise detection of potentially clinically relevant gene fusions, especially when the fusion breakpoint is known. We have developed an NGS solution appropriate for FFPE tissues to detect fusion biomarkers in routine clinical research.

Methods

Fusion content was selected based on prioritization of actionability, verified fusion isoforms reported in the literature and collaborations, as well as prevalence of solid tumor fusion driver genes. The assay was designed to use Ion AmpliSeq multiplex PCR chemistry using manual or automated library preparation, automated templating on the Ion Chef, and sequencing on the Ion Torrent GeneStudioTM S5 sequencing platform. The analysis was supported by fully automated analysis software that performs sample QC, read-filtering, fusion calling and reporting. Streamlined access to decision support software was enabled by Oncomine™ Reporter.

Results

Over 1200 targeted isoforms from over 50 known fusion driver genes were incorporated into the assay that included prominent fusion drivers such as ALK, RET, ROS1, NTRK1/2/3 and FGFR1/2/3, and intragenic fusion events in MET, EGFR, BRAF and AR. The assay also reported non-targeted fusion events in relevant driver genes by using a novel statistically significant expression imbalance algorithm comparing 5’- and 3’- end gene expression. A preliminary development study was performed using commercially available total RNA for a Tri-Fusion control and Seraseq™ Fusion RNA Mix v3 where all of the expected fusions were detected with 100% sensitivity and specificity. Results were also concordant when characterized FFPE tumor samples with known fusion targets were tested using the assay.

Conclusions

A comprehensive NGS assay was developed to support clinical research in oncology for detecting relevant RNA structural alterations from solid tumor FFPEs. An update on assay performance will be presented.

Legal entity responsible for the study

Thermo Fisher Scientific.

Funding

Has not received any funding.

Disclosure

V.K. Mittal: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. S.P. Myrand: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. D. Cyanam: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. P.D. Williams: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. G.G. Bee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. A. Marcovitz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. R. Gottimukkala: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. F. Hyland: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. C. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. E. Wong-Ho: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. S. Sadis: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. C. Van Loy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. J. Kilzer: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. N. Khazanov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific.

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Poster Display session 3 Poster Display session

1888P - Next-generation sequencing for better treatment strategy of cancer of unknown primary (CUP) (ID 4952)

Presentation Number
1888P
Lecture Time
12:00 - 12:00
Speakers
  • Kang Kook Lee (Daegu, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Cancer of unknown primary (CUP) consists of diverse histology types of cancer and have shown poor prognosis. In the era of precision medicine, next-generation sequencing (NGS) may contribute new therapeutic target which could improve treatment outcomes of CUP.

Methods

Patients who were diagnosed with CUP and underwent NGS exam between August 2017 and August 2018 at Samsung medical center were included for the study. NGS data were analyzed, and medical records were reviewed retrospectively to evaluate clinical characteristics and response to various treatments.

Results

A total of 21 patients with CUP who had NGS data were analyzed. The median age was 58 (range, 35-78 years). Male was dominant (57.1%) and most of the patients were ECOG 1 (90.5%). Among the patients, 14 (66.7%) were poorly differentiated carcinoma, 6 (28.6%) patients were adenocarcinoma, and one patient was squamous cell carcinoma. Most common metastatic site was lymph node (57.1%), followed by bone (38.1%), lung (19.0%), pleura (19.0%). Paclitaxel combined with carboplatin was most frequently used regimen for the first-line treatment (57.1%). Cisplatin-based chemotherapy was used second most (28.6%). One patient showed complete remission during the first-line treatment whereas 7 patients and 5 patients achieved the best response of partial response and stable disease, respectively. Median progression-free survival was 4 months (95% CI: 0.316-7.684), and median overall survival was not reached. Except four patients, 17 (81.0%) patients showed 25 gene alterations on the NGS results. TP53 mutation was observed most commonly (n = 6, 25.6%), followed by ERBB2 alterations (n = 3, mutations [n = 2], amplification [n = 1]), KRAS mutation (n = 2), MET amplification (n = 2), CDKN2A deletion (n = 2), and MYC amplification (n = 2). One patient harbored ERBB2 amplification was treated with trastuzumab combined with paclitaxel, and the patient demonstrated sustained partial response at 9 months, until the data cut-off date.

Conclusions

Most of CUP patients had variety actionable gene alterations. Precision medicine based on molecular analysis with NGS will improve the prognosis of the patients with CUP.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1889P - Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease (ID 4590)

Presentation Number
1889P
Lecture Time
12:00 - 12:00
Speakers
  • Michele Ghidini (Milan, (MI), Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Liquid biopsies (LB) allow monitoring of genetically different and co-occurring cancer cell clones. In metastatic colorectal cancer (mCRC), circulating-free DNA (cfDNA) can be relevant for monitoring treatment and identification of molecular alterations resulting in disease relapse often earlier than radiological examinations.

Methods

Patients with mCRC at diagnosis and treated with chemotherapy (CT) in combination with antibodies (bevacizumab, cetuximab or panitumumab) before undergoing surgery for resectable disease were included. LB were collected before therapy start, every four weeks during treatment, within ten days of radiological disease evaluation, at radiological relapse and until two months after progression. Next generation sequencing based on plasma samples was performed (testing for mutations and copy number variations covering 77 genes).

Results

From February 2016 to October 2018, 14 patients having surgery after first line treatment were included herein; median follow-up was 21.5 months. Five of them had RAS wild-type disease and received CT plus anti-EGFR treatment, while nine RAS mutated mCRC patients received bevacizumab. Disease relapse happened in seven cases, with subsequent death in three cases. In six out of seven cases, gene alterations were already detected in the pre-operative cfDNA. In the seven cases without disease relapse, gene variants were detected even after the surgery in two patients despite receiving radical resection. Median number of gene variants was two. Beside the well-established mutations in TP53 gene, both APC and ROS1 gene mutations were frequent, while further evaluations are required for the other variants detected.

Conclusions

Evaluation of cfDNA mutations in LB from mCRC may be a useful tool for monitoring clinical response and predict treatment outcome. Moreover, this molecular analysis can help to subgroup patients with regard to risk of relapse after radical surgery. Indeed, cfDNA mutations present before surgery seem to be an indication for a higher risk of post-surgery disease relapse.

Legal entity responsible for the study

The authors.

Funding

MEDeA Onlus.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1890P - Ultra-sensitive detection of circulating tumor DNA identifies patients in high risk of recurrence in early stages melanoma (ID 3696)

Presentation Number
1890P
Lecture Time
12:00 - 12:00
Speakers
  • Filip Janku (Houston, TX, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Up to 70% of patients with resected high-risk melanoma develop disease recurrence within 5 years. Adjuvant immunotherapy or targeted therapy can reduce the recurrence rate below approximately 60%; however, it is at the cost of possible toxicity including long-term side effects. We hypothesize that detection of plasma-derived circulating tumor DNA (ctDNA) from patients with resected melanoma can identify patients in high-risk of disease recurrence.

Methods

We developed an ultrasensitive and specific droplet digital PCR – based method (Bio-Rad) to detect BRAFV600E-mutated ctDNA in pre-amplified cell-free DNA with sensitivity up to 1 mutant copy in the wild-type background. Plasma samples from patients with surgically resectable melanoma and BRAFV600E mutation in tumor tissue were collected on the day of surgery and during follow-up visits for BRAFV600E ctDNA detection. Results were correlated with clinical outcomes.

Results

Total of 23 patients with resectable melanoma (stage 1, n = 7; stage 2, n = 9; stage 3, n = 6; stage 0, n = 1) with BRAFV600E mutation in tumor tissue were enrolled. BRAFV600E-mutated ctDNA was detected in 11 (48%) patients before surgery and in 8 (35%) patients after surgery. Patients with ctDNA in samples collected after surgery had more disease recurrences (4/8, 50% vs. 0/11, 0%; P = 0.02) and shorter disease-free survival than patients without ctDNA in samples collected after surgery (P = 0.03).

Conclusions

Our early data demonstrate that ultrasensitive droplet digital PCR method can detect ctDNA in patients with resectable melanoma and that patients with detectable ctDNA in blood samples collected after surgery have superior disease-free survival.

Legal entity responsible for the study

The authors.

Funding

The Sabine Family Foundation (Filip Janku), the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy (Filip Janku), the Institution Research Grant MD Anderson (Filip Janku), Rising Tide Foundation for Cancer Research (Filip Janku), the National Institute of Health through MD Anderson Cancer Center (P30 CA016672), MH CZ—DRO (Faculty Hospital Plzen—FNPl, 00669806), by the Charles University Research Fund (Progres Q39), and by the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic.

Disclosure

F. Janku: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): BioMed Valley Discoveries; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Plexxikon; Advisory / Consultancy, Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Piqur; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Asana; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: IFM Therapeutics; Advisory / Consultancy: Synlogic; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Trovagene; Advisory / Consultancy: Immunomet; Non-remunerated activity/ies, instrument loan: BioRad. All other authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1891P - Identification of the founder BRCA1 mutation c.4117G>T (p.Glu1373*) recurring in the Abruzzo and Lazio regions of Central Italy and predisposing to breast/ovarian and BRCA1-related cancers (ID 4295)

Presentation Number
1891P
Lecture Time
12:00 - 12:00
Speakers
  • Daniela Di Giacomo (L'Aquila, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Founder BRCA1/2 cancer predisposing mutations have been reported in Italian population. We reported the founder BRCA1 mutation, c.4117G>T - p.Glu1373*, recurring in unrelated families of Abruzzo and Lazio regions of Central Italy.

Methods

Preliminary analysis of 17 unrelated families carrying BRCA1 c.4117G>T nonsense mutation reported in the Hereditary Breast/Ovarian Cancer Registry of the Oncology Territorial Care Unit, University of L’Aquila and Genetic Unit, Catholic University of Rome was performed by genetic counselling and peripheral blood collection after written informed consent from affected and unaffected probands. BRCA1/2 genetic analysis were performed by direct sequencing; haplotype analysis was carried out using microsatellite markers in the 17q21 region: D17S846, D17S1328, D17S855 (intragenic), D17S902, D17S806. Post-test genetic counselling was performed to address Therapeutic and/or Preventive Clinical strategies. Geographic area of origin, cancer family trees, cancers affecting the probands were collected. To date, overall 23 unrelated families were enrolled.

Results

In the preliminary analysis, BRCA1 c.4117G>T mutation was identified in 17 unrelated families with familial origin in a territory of Central Italy including Abruzzo and Lazio regions: this mutation was always and significantly associated with the Allelic Variant (AV) BRCA1, c.3119G>A (p.Ser1040Asn), in 52 tested carriers, 20 affected and 32 unaffected. Microsatellite markers confirmed a common haplotype shared by the 52 probands, comprising the region between D17S1328 and D17S902 markers. In overall 23 unrelated families, the association of BRCA1 founder mutation and the AV were identified in 66 tested carriers, 28 affected and 38 unaffected.

Conclusions

The BRCA1 c.4117G>T is a founder mutation prevalent in the territory of Central Italy in Abruzzo and southern Lazio regions, cosegregating with AV BRCA1 c.3119G>A, providing faster identification of affected and unaffected carriers to specifically address therapeutic and preventive clinical pathways for breast, ovarian and BRCA1-related cancers.

Legal entity responsible for the study

Enrico Ricevuto.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1892P - Enzalutamide (ENZA) and apalutamide (APA) In vitro chemical reactivity studies and activity in a mouse drug allergy model (MDAM) (ID 2214)

Presentation Number
1892P
Lecture Time
12:00 - 12:00
Speakers
  • Mausumee Guha (San Diego, United States of America)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

ENZA and APA are androgen receptor inhibitors approved for treatment of castration-resistant prostate cancer (CRPC) and nonmetastatic CRPC, respectively. Their chemical structures differ with ENZA having 2-cyanophenyl and dimethyl moieties and APA 2-cyanopyridyl and cyclobutyl moieties. In the SPARTAN clinical trial, APA treatment was reported to be associated with an increased incidence of skin rash compared with the placebo group, which was not observed with ENZA in the PROSPER trial in a similar patient population; therefore, we examined their in vitro chemical reactivity and hypersensitivity potential in an MDAM.

Methods

To assess possible reactivity of cyanopyridine, in vitro studies examining the chemical stability in buffer (+/- glutathione) and covalent binding to proteins (eg, bovine serum albumin [BSA]) were evaluated. For the MDAM, C57BL/6 mice were injected subcutaneously with APA, ENZA, or RD162 (Analogue 1), daily for 3 days at 25, 50, or 100 mg/kg/day. Brachial lymph nodes were harvested on day 6 and lymph node cellularity was analyzed by flow cytometry.

Results

The 2-cyanopyridine moiety of APA was found to be chemically reactive with the thiol nucleophile glutathione, resulting in rearranged thiazoline products. Radiolabeled APA, but not ENZA, was shown to react with mouse and human plasma proteins. Thiol nucleophiles decreased the extent of covalent binding to the model protein BSA while amine and alcohol nucleophiles had no effect, suggesting a reaction with cysteine sulfhydryl groups of proteins. In the MDAM, dose-dependent higher lymph node cellularity was observed for the APA groups (compared with the vehicle control), suggesting immune activation. ENZA and Analogue 1 demonstrated substantially less covalent binding activity and no change in lymph node cellularity (compared with vehicle) in the MDAM.

Conclusions

These data support the hypothesis that the 2-cyanopyridine moiety present in APA, but absent in ENZA or Analogue 1, may react with cysteine residues in proteins to form haptens that may trigger an immune response leading to the increased incidence of skin rash clinically observed in patients treated with APA, but not with ENZA.

Editorial acknowledgement

Medical writing and editorial assistance funded by Pfizer Inc. was provided by Ira Mills, PhD, and Michele Salernitano from Ashfield Healthcare Communications.

Legal entity responsible for the study

Pfizer Inc. and Astellas Pharma, Inc.

Funding

Pfizer Inc. and Astellas Pharma, Inc.

Disclosure

M. Guha: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. C. Ji: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. X. Zhu: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. J. Whritenour: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. M. Hemkens: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. S. Tse: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. G.S. Walker: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. E. Evans: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. N.K. Khan: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. M.B. Finkelstein: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. E. Callegari: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. R..S. Obach: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc..

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Poster Display session 3 Poster Display session

1893P - Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients (ID 5044)

Presentation Number
1893P
Lecture Time
12:00 - 12:00
Speakers
  • Bram C. Agema (Rotterdam, Netherlands)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Cisplatin is a widely used chemotherapeutic agent for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin acute kidney injury (AKI) occurs. A recent case report suggested single nucleotide polymorphisms (SNPs) in the COMT gene might be associated with increased cisplatin-induced nephrotoxicity (de Jong et al., BJCP, 2017). Here, we assessed the association of 3 SNPs in this gene with cisplatin-induced nephrotoxicity in our patient population.

Methods

Whole blood samples and serum creatinine concentrations (Scr) of 556 patients who received cisplatin between 2005-2019 were available. The 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316) and c.616 – 367 C>T (rs9332377) SNPs were associated with AKI (CTCAE v4.03) using Fisher’s exact test and difference in Scr up to 2 weeks prior to and up to 6 weeks after cisplatin treatment was described.

Results

Median Scr at baseline was 70 μmol/l (inter quartile range (IQR) 59-81). Up to six weeks after the start of cisplatin treatment the median increased to 81 μmol/l (IQR 69-96). The presence of a variant of c.615 + 310C>T was associated with an increased occurrence of AKI ≥ grade 3 toxicity in patients carrying a homozygous variant (Var) compared to wildtype (WT) patients. AKI grade ≥ 3 occurred in 4 out of 31 (13%) homozygous variant patients against 6 out of 317 (2%) patients carrying wildtype alleles (p = 0.005) after correction for age in a multivariable model. Dehydration occurred in 14 of the 16 patients with AKI grade 3 (3 of 4 WT, 6 of 6 HT and 5 of 6 Var) and likely is a confounding factor. The remaining SNPs were not significantly associated with AKI or difference in Scr.

Conclusions

This study showed that variation in COMT c.615 + 310 C>T (rs4646316) potentially affects the development of AKI grade ≥3, although these results appear to be confounded by dehydration. Therefore, the value of this finding for daily practice is currently unclear and needs to be explored in a prospective setting.

Legal entity responsible for the study

R.H.J. Mathijssen.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1894P - Cardioprotective and anti-inflammatory effects of empagliflozin during treatment with doxorubicin: A cellular and preclinical study (ID 3293)

Presentation Number
1894P
Lecture Time
12:00 - 12:00
Speakers
  • Vincenzo Quagliariello (Napoli, Italy)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2, reduces the risk of hospitalization for heart failure or cardiovascular death, as seen in the EMPA-REG OUTCOME trial.

Methods

We incubated EMPA alone or in combination with Doxorubicin in HL-1 adult cardiomyocytes evaluating: cell viability, lipid peroxidation, Leukotriene-B4 expression, NF-κB activation and Interleukin 1β, 8 and 6 secretion. To evaluate cardiac function in vivo, Global Longitudinal Strain (GLS) was measured using 2D speckle tracking echocardiography in C57BL6 mice treated with Doxorubicin (2.25 mg/kg/day ip) or EMPA (10 mg/kg/day) or EMPA and Doxorubicin in combination for 7 days. Cardiac lysates were processed for analysis of pro-inflammatory Interleukins.

Results

EMPA, co-incubated with Doxorubicin, enhanced significantly the viability of cardiomyocytes, compared to only Doxorubicin treated cells. EMPA reduces the lipid peroxidation during exposure to Doxorubicin. Moreover, EMPA has shown anti-inflammatory activity reducing both Leukotriene B4 and NF-kB expression. Notably, EMPA also decreased the expression of IL-1β, IL-6 and IL-8 of 40-50 % for all, compared to only Doxorubicin exposed cells. In preclinical models, after treatments only with Doxorubicin, GLS decreased significantly, while associating the pretreatment and subsequent combinatorial treatment with EMPA, we observed a prevention of the GLS’s reduction, indicating cardiprotective effects of the hypoglycemic drug. Moreover, we demonstrated that mice treated with EMPA and Doxorubicin the cardiac IL-1β, IL-6 and IL-8 were reduced of 45-60 % compared to mice treated only with Doxorubicin.

Conclusions

We demonstrated for the first time that EMPA exerts anti-oxidant and anti-inflammatory properties during incubation with Doxorubicin. Preclinical studies demonstrated cardioprotective effects of EMPA, with significant reductions of key mediators of cardiotoxicity. These results lay the biochemical and pathophysiological bases for subsequent preclinical and clinical studies concerning the use of EMPA as a cardioprotective agent during treatment with Doxorubicin.

Legal entity responsible for the study

The authors.

Funding

“Ricerca Corrente” grant from the Italian Ministry of Health.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1895P - Breast cancer organoids model treatment response of HER2 targeted therapy in HER2-mutant breast cancer (ID 3324)

Presentation Number
1895P
Lecture Time
12:00 - 12:00
Speakers
  • Xuelu Li (Dalian, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

To facilitate cancer precision medicine, breast cancer organoids have recently emerged as a useful pre-clinical model for retaining sufficient fidelity regarding histology, the transcriptome and genome. However, their potential to predict clinical treatment responses remains unclear.

Methods

We generated breast cancer organoids from breast cancer tissues and performed drug sensitivity test on these organoids based on genomic analysis data.

Results

A total of 25 fresh breast cancer tissues and biopsies from 22 patients were processed between November 2017 and February 2019. Breast cancer organoids were grown successfully from 10 out of 25 patients (40%). We performed histopathological analysis of H&E stained tissues and organoid sections and confirmed that the phenotypes of organoids matched the original histological breast cancer types. We also performed whole genome DNA sequencing (WGS) and RNA sequencing (RNA-seq) on breast cancer organoids and paired breast cancer tissues. One of these breast cancer organoids had HER2 mutations (previously shown to be an activating mutation) and retained expression of estrogen receptor (ER) and progesterone receptor (PR) (Luminal A subtype). In our previous work, we identified activating HER2 mutations (S310F D769Y V777L 778insGSP) in ER positive/HER2-amplification negative breast cancer, who had developed resistance to multi-line endocrine therapy. Two patients achieved a durable partial response (approximately 1 years) to trastuzumab combined with everolimus. We also showed that HER2 mutations were constitutively active, and T47D and MCF7 overexpressing HER2 mutations were sensitive to HER2 targeted therapies combined with everolimus. Hence, we tested the effects of trastuzumab and everolimus on this HER2-mutant breast cancer organoid in vitro and in vivo. HER2-targeted therapies combined with everolimus produced regression of the HER2-mutated organoid.

Conclusions

The breast cancer organoids may serve as a high-fidelity platform and recapitulate clinical treatment responses in personalized medicine. These data provide a strong preclinical rationale for combining HER2-targeted therapies with everolimus in HER2-mutant/ HER2-amplification negative breast cancer.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1896P - Preclinical in vivo screening to predict responder patients depend on EGFR status (ID 2115)

Presentation Number
1896P
Lecture Time
12:00 - 12:00
Speakers
  • Yejin Kim (Seoul, Korea, Republic of)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

Epithelial Growth Factor Receptor (EGFR), a type of the ERBB receptor tyrosine kinase, associated with cell survival and proliferation has properties to activate tumorigenesis and metastasis in cancer. Normally, EGFR is expressed in normal tissues such like other tyrosine kinase receptors especially in epithelial cell type tissues. In various cancer types, EGFR amplification or overexpression is commonly detected in cancer cells compared with normal epithelial tissues, and so known as a still promising therapeutic biomarker for cancer therapy in colorectal cancer, Lung cancer, gastric cancer and glioblastoma. However, several EGFR targeted therapy failed in clinical trial for cancer patients include glioblastoma and hard to find responder group in cancer patients.

Methods

To figure out clinical criteria for cancer patients, we tested a novel EGFR targeted antibody (GC1118) in glioblastoma patient-derived xenograft (PDX) models and patient-derived cell (PDC) with its genomic data.

Results

Through Xeno Trial, a method using a small scale of mice per treatment to enable the investigation of efficacy in substantially larger panels of PDX models, and it implies that therapeutic response is expected to be evident in EGFR amplification in brain tumors, in addition to efficacy was also observed in patients with EGFR amplification via High Throughput Screening (HTS). Through High Throughput Screening using glioblastoma patient-derived cells shown that cell growth inhibition in EGFR amplify cases by GC1118. In Xeno trail, inhibitory effects of tumor growth observed in EGFR amplification PDX models by GC1118 treatment as well.

Conclusions

Overall, this study results suggest that EGFR amplification status is still one of the important criteria to find responder group in glioblastoma patients.

Legal entity responsible for the study

The authors.

Funding

The Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. (HI14C3418).

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1897P - Interplay between miR-17-5p and MALAT-1 shapes the cytokine storm in triple negative breast cancer (TNBC) tumor microenvironment (ID 3349)

Presentation Number
1897P
Lecture Time
12:00 - 12:00
Speakers
  • Raghda A. Soliman (Cairo, Egypt)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

TNBC is the most immunogenic tumor compared to other BC subtypes. Thus, clinicians shifted the treatment among TNBC patients to immunotherapeutic alternatives such as immune checkpoint inhibitors (ICB). Despite the success of ICB, resistance in some TNBC cases had recently appeared. Thus, adding a new factor in the immunotherpeutic equation which could be the tumor microenvironment (TME); TME includes an array of immune-modulatory cytokines such as Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) that acts as a barrier in eradicating the tumor cells by the cytotoxic immune cells. Recently, our group has reported a novel crosstalk between non-coding RNAs (ncRNAs). MALAT1, an oncogenic long ncRNA, is recently reported to directly bind to microRNA-17-92 cluster. However, miR-17-5p role in TNBC is still controversial. Moreover, the impact of miR-17-5p, MALAT1 and their interplay in the TME has never been investigated. The aim of this study is to investigate the crosstalk between ncRNAs and their impact on cytokines in TME of TNBC cells.

Methods

Twenty BC patients were recruited. Bioinformatic analysis was performed using more than 5 softwares. MDA-MB-231 cells were cultured and transfected with miR-17-5p oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular viability and Colony forming ability were measured using MTT and colony forming assay.

Results

MALAT-1, miR-17-5p and IL-10 were down-regulated while TNF-α was upregulated in BC tissues compared to its counterparts. In-silico analysis showed that miR-17-5p binds to MALAT-1, IL-10 and TNF-α. Experimentally, ectopic expression of miR-17-5p (>5000 folds) resulted in a marked reduction in cellular viability and colony forming ability of TNBC cells. On top of that, miR-17-5p mimics resulted in a significant repression of MALAT1. Consequently, a marked increase in IL-10 and TNF-α levels was shown. While anti-miR-17-5p resulted in a marked repression of IL-10 and TNF-α.

Conclusions

miR-17-5p is an upstream orchestrator of MALAT-1/IL-10/TNF-α shaping the TME in TNBC patients. Therefore, this study provides a novel combination therapeutic approach of Anti-miR-17-5p and ICB with decreased chance of resistance in TNBC patients.

Legal entity responsible for the study

German University in Cairo.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1898P - Clinical verification on the relationship between lipid metabolism and the immune microenvironment of breast cancer (ID 4014)

Presentation Number
1898P
Lecture Time
12:00 - 12:00
Speakers
  • Wataru Goto (Osaka, Japan)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract

Background

The importance of regulating and improving the tumor immune microenvironment is increasingly being recognized. While it has been reported that therapeutic agents for hyperlipidemia, in particular statins, can induce cancer cell growth suppression and anti-metastatic effects in breast cancer, few studies have investigated the correlation between improvement of lipid metabolism and antitumor immune response and cancer prognosis in vivo.

Methods

Except for patients with ductal carcinoma in situ, 938 breast cancer patients treated with curative surgery were examined. The correlation between serum levels of total-cholesterol and triglyceride, and clinicopathological features, including neutrophil-to-lymphocyte ratio (NLR) and tumor-infiltrating lymphocytes (TILs), and prognosis was evaluated retrospectively.

Results

194 patients were receiving treatment for hyperlipidemia. Recurrence-free survival (RFS) and overall survival (OS) did not differ significantly between users of the drug for hyperlipidemia or non-users (p = 0.782, log-rank) (p = 0.304, log-rank). Among postmenopausal patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, who were treated for hyperlipidemia, the group with good serum lipid level had significantly better RFS (p = 0.014, log-rank). Also, good serum lipid control was significantly correlated with low-NLR (p = 0.024) and high-TILs in resected tumors (p = 0.039). In addition, lipophilic statin users had lower recurrence rate than hydrophilic statin users (8.2 % vs 16.0 %).

Conclusions

After curative surgery, almost postmenopausal patients with HR-positive breast cancer are treated with adjuvant endocrine therapy, including aromatase inhibitor (AI). Recently, it is reported that AI treatment increases local aromatase activity and promotes autocrine estrogen signaling in AI-resistant metastatic tumor. Our study suggests that good control of lipid metabolism may have a relationship with improvement in these tumor immune microenvironment and favorable outcome.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Display session 3 Poster Display session

1899P - The clinical and transcriptional signatures of human CD204 reveal an applicable marker for tumor associated macrophage in breast cancer (ID 4158)

Presentation Number
1899P
Lecture Time
12:00 - 12:00
Speakers
  • Yunjie He (Nanjing, China)
Session Name
Poster Display session 3
Location
Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
12:00 - 13:00

Abstract