Displaying One Session

Tarragona Auditorium (Hall 7) Poster Discussion session
Date
30.09.2019
Time
10:30 - 11:30
Location
Tarragona Auditorium (Hall 7)
Chairs
  • Alberto Bardelli (Candiolo, (TO), Italy)
  • Dennis (Yuk-Ming) Lo (Shatin, Hong Kong PRC)
Poster Discussion 2 – Translational research Poster Discussion session

92PD - Comprehensive pan-cancer analysis of KRAS genomic alterations (GA) including potentially targetable subsets (ID 1433)

Presentation Number
92PD
Lecture Time
10:30 - 10:30
Speakers
  • Sai-Hong I. Ou (Orange, CA, United States of America)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

KRAS GA are common oncogenic drivers. Effective systemic treatment of KRAS altered cancers has been largely elusive; however covalent inhibitors of G12C (AMG510, MRTX849) and SHP2 inhibitors (TNO155, RMC-4630) have recently entered the clinic in multiple tumor types.

Methods

Hybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from 213,312 unique patients with solid or hematological malignancies. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. PD-L1 expression was determined by IHC (22C3 or SP142 antibodies) for 17% of cases.

Results

KRAS GA were detected in 22% (n = 46,182) of cases: 88% mutations (m; >99% substitutions and <0.2% indels), 8.3% amplification (a) and 3.8% both. KRASm were most common in pancreatic (83%, 8,063/9,723) gastrointestinal (GI; 39%, 13,507/35,019) and lung adenocarcinoma (LUAD; 35%, 9,159/25,968). KRASa (median 10 copies, range 6-421) was most common in esophageal adenocarcinomas (17%, 673/3,920) and testicular germ cell tumors (25%, 46/185). Co-KRASm+a was most common in pulmonary sarcomatoid carcinoma (PSC; 7.4%, 26/353). Median TMB was 3.5, 6.1, and 4.3 mut/Mb in cases with KRASm, KRASa, or KRASm+a. 124 unique KRASm were identified, most commonly G12D/V/C and G13D (26%, 21%, 14%, 6.9% of KRAS GA). G12D resulted from transitions (primarily G>A), and G12V (primarily G>T) and G12C (exclusively G>T) from transversions. G12C was most frequent in LUAD (14%, 3,613/25,968) and PSC (11%, 40/353) but uncommon in pancreatic (1.7%, 161/9,723) and GI (2.7%, 941/35,019) where G12D/V were most common. Tobacco signature (TS; 20% vs 4.5% vs 3.5%), elevated TMB (median 7.0 vs 3.5 vs 3.5 mut/Mb) and PD-L1 positivity (56% vs 29% vs 31%) were all significantly associated with G12C vs non-G12C KRASm and non-KRASm cancers (all p < 0.0001). In LUAD, TS was present in 25% G12C, 19% non-G12C KRASm and 15% non-KRASm (all p < 0.0001).

Conclusions

Diverse KRAS GA are frequent across cancers and subtypes are associated with different solid malignancies. G12C is most common in LUAD and associated with smoking, elevated TMB and PD-L1 positivity. As multiple trials of novel therapeutic agents are currently enrolling for KRAS GA, CGP to identify these alterations is needed.

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine.

Disclosure

S.I. Ou: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Genentech; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ariad; Research grant/Funding (institution): Ignyta; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Peregrine; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): TP Therapeutics; Research grant/Funding (institution): Blueprint Medicines. E.S. Sokol: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. R. Madison: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. J. Chung: Shareholder/Stockholder/Stock options: Roche; Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. J.S. Ross: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. V.A. Miller: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche; Advisory/Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, 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: Revolution Medicines. A.B. Schrock: Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. S.S. Ramalingam: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Brystol Myers Squib; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Tesaro; Advisory/Consultancy: Takeda; Advisory/Consultancy: Nektar.

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Poster Discussion 2 – Translational research Poster Discussion session

1880PD - Genetic variants in the one-carbon metabolism pathway to predict outcome in patients with metastatic colorectal cancer (mCRC): Data from TRIBE and FIRE-3 phase III trials (ID 4105)

Presentation Number
1880PD
Lecture Time
10:30 - 10:30
Speakers
  • Alberto Puccini (Genova, Italy)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

One-carbon metabolism (1CM) comprises the folate and the methionine cycles and is involved in nucleotide synthesis and methylation. 1CM is known to be crucial in CRC development and progression. However, the impact of its genetic variants on prognosis in mCRC patients has not been clarified yet. We hypothesized that single nucleotide polymorphisms (SNPs) in genes related to the 1CM pathway may predict first-line treatment outcomes in mCRC patients.

Methods

Genomic DNA from blood samples of patients enrolled in two independent randomized phase III trials, TRIBE and FIRE-3, was genotyped through the OncoArray, a custom array manufactured by Illumina, including approximately 530K SNP markers. The impact on outcome of SNPs in six genes of the 1CM pathway (MTHFR, MTR, MTRR, MAT2A, SHMT, TYMS) was analyzed.

Results

A total of 451 patients were included. TRIBE FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N = 215, mPFS/OS: 9.7/26.2 months), FIRE-3 FOLFIRI/bev arm as validation (N = 107, mPFS/OS: 11.5/31.4 months) and FOLFIRI/cetuximab arm as control (N = 129, mPFS/OS: 12.8/49.8 months). In the discovery cohort, the overall population carrying the SHMT rs1979277 A/A variant showed a shorter median PFS (8.1 vs 10.3 months) compared to patients with any G alleles both in univariate (HR 2.13; 95%CI, 1.19-3.79; P = 0.007) and in multivariable analysis (HR 2.03; 95%CI, 1.10-3.73; P = 0.023). Additionally, A/A carrier showed a shorter median OS (18.0 vs 27.9 months) both in univariate (HR 1.74; 95%CI, 1.00-3.01; P = 0.045) and in multivariable analysis (HR 2.14; 95%CI, 1.17-3.90; P = 0.013). These findings were validated in overall patients in FIRE-3 bev cohort in median OS (24.9 vs 36 months) both in univariate (HR 2.18; 95%CI, 0.96-4.96; P = 0.049) and in multivariable analysis (HR 3.61; 95%CI, 1.47-8.86; P = 0.005). No significant association was observed in the control arm.

Conclusions

Our results suggest for the first time that SNPs in the SHMT gene may have a prognostic and predictive value in mCRC patients. These findings may provide novel perspectives on the role of 1CM signaling in CRC and possibly contribute to open novel therapeutic options.

Legal entity responsible for the study

The authors.

Funding

This manuscript was partly supported by the National Cancer Institute (grant number P30CA014089), the Gloria Borges WunderGlo Foundation-The Wunder Project, the Dhont Family Foundation, the San Pedro Peninsula Cancer Guild, the Daniel Butler Research Fund, the Call to Cure Research Fund, and the Fong Research Project.

Disclosure

F. Loupakis: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono. S. Stintzing: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck KGaA; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Travel / Accommodation / Expenses: Sirtex Medical; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda. F. Battaglin: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Bayer. M.D. Berger: Travel / Accommodation / Expenses: Astellas Pharma; Research grant / Funding (institution): Merck KGaA. C. Cremolini: Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly; Research grant / Funding (self), Research grant / Funding (institution): Merck. A. Falcone: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Servier; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Sanofi. V. Heinemann: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Baxalta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Honoraria (self): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: SERVIER; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex Medical; Honoraria (self): Taiho Pharmaceutical; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Halozyme; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution): Shire. H.J. Lenz: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: CARIS. All other authors have declared no conflicts of interest.

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Poster Discussion 2 – Translational research Poster Discussion session

1881PD - Oral intestinal alkaline phosphatase improves efficacy of 5-FU in a colorectal cancer mouse model (ID 2381)

Presentation Number
1881PD
Lecture Time
10:30 - 10:30
Speakers
  • Christian Furlan Freguia (Rockville, United States of America)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Intestinal alkaline phosphatase (IAP) is an endogenous intestinal enzyme that promotes gastrointestinal (GI) homeostasis by detoxifying inflammatory mediators, tightening the gut barrier and promoting a healthy microbiome. In previous reports, oral delivery of IAP ameliorated colitis in animals and in a human pilot study. The commonly used chemotherapy, 5-Fluorouracil (5-FU), can cause severe GI damage potentially resulting in dose limiting toxicities. Given the recent implication of the gut microbiome in modulating the anti-cancer response and the role of IAP in mitigating GI toxicity, we sought to evaluate the role of IAP in ameliorating 5-FU related GI side effects and to assess the impact of IAP therapy on anti-cancer efficacy.

Methods

BALB/c mice were inoculated with CT26 murine colorectal cancer cells into the right flank. 5-FU (30 mg/kg) was given IP QD for 5 consecutive days. IAP (0.5 mg/kg) or vehicle was administered PO BID throughout the study. Mice were evaluated for stool consistency, tumor growth and survival. A cohort of mice was sacrificed at day 5 for histopathology analysis.

Results

5-FU administration caused loose stools/diarrhea in all the treated animals, which peaked at day 6 and recovered by day 9. Interestingly, mice that received IAP showed a significantly faster recovery (p < 0.03). As expected, 5-FU slowed tumor progression compared to controls (no 5-FU). Surprisingly, IAP addition significantly improved anti-cancer efficacy. Mice treated with IAP showed diminished tumor growth compared to vehicle (at day 19, 1066 vs 1968 mm3, p < 0.05). Furthermore, IAP administration significantly prolonged animal survival when compared to vehicle-treated animals (p < 0.02). Mechanistically, 5-FU led to goblet cell loss whereas IAP treatment protected the goblet cells.

Conclusions

Oral administration of IAP in mice not only improved some of the side effects associated with 5-FU, such as diarrhea and potentially mucositis, but also enhanced the anti-tumor efficacy of 5-FU leading to significantly prolonged survival. Overall, IAP has the potential to become a new therapeutic agent intended to mitigate cancer-treatment side effects and to enhance the overall anti-tumor response.

Legal entity responsible for the study

The authors.

Funding

Synthetic Biologics.

Disclosure

C. Furlan Freguia: Full / Part-time employment: Synthetic Biologics. M. Kaleko: Full / Part-time employment: Synthetic Biologics.

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Poster Discussion 2 – Translational research Poster Discussion session

Invited Discussant 92PD, 1880PD and 1881PD (ID 6953)

Lecture Time
10:30 - 10:45
Speakers
  • Alberto Bardelli (Candiolo, (TO), Italy)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion 2 – Translational research Poster Discussion session

Q&A led by Discussant (ID 6956)

Lecture Time
10:45 - 11:00
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion 2 – Translational research Poster Discussion session

1878PD - Pan-cancer analysis of clinical acquired resistance (AR) in BRAF-driven real-world cases (ID 1699)

Presentation Number
1878PD
Lecture Time
11:00 - 11:00
Speakers
  • Filippo Pietrantonio (Milan, Italy)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

BRAF genomic alterations (GA) occur in multiple tumor types and BRAF/MEK targeted therapies are approved in melanoma and NSCLC. Diverse mechanisms of AR to these therapies have been proposed but have not been comprehensively assessed.

Methods

Hybrid-capture based comprehensive genomic profiling (CGP) was performed on FFPE (n = 228,629) or blood-based cell free DNA (cfDNA, n = 15,069) samples for 222,952 patients (pts). Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. Samples without evidence of tumor DNA or known to have not received RAF/MEK inhibitors were excluded. Paired samples were collected >60 days apart (median 523, range 71-5571).

Results

Paired samples with BRAF V600E (64%) or other activating BRAF GA (36%) were available for 154 pts with NSCLC (20%), melanoma (19%), CRC (15%) myeloma (8.4%) glioma (7.1%) or other (30%) cancers. Acquired GA previously described preclinically or clinically including in BRAF, KRAS, NRAS, MEK1, PIK3CA, PTEN, MET, and CCND1 occurred in 34 cases (Table). 56 additional cases had reportable acquired GA in other genes (eg. STK11, NF1). Median TMB was 4.0 vs 5.2 mut/Mb in the first vs second sample (p = 0.23). In 12% of cases (9 tissue, 9 cfDNA) a BRAF GA was not detected in the second sample. Most AR mechanisms (MET amp, KRAS mut, secondary BRAF GA) were tumor agnostic, but PIK3CA and PTEN GA were enriched in brain samples and absent in CRC, and NRAS mut were exclusive to melanoma (Table). Treatment status was available for a subset of cases. Notably V600E CRC, NSCLC and melanoma each had acquired MET amp post-dabrafenib + trametinib, and a V600E myeloma had acquired MEK C121S post-trametinib + vemurafenib. Additional clinical data will be presented.

Potential AR mechanismNo. cases#AR subtypesDisease HistologiesAssociated Primary BRAF GABiopsy location*
KRAS mut7G12D (2), G12R, G12V, G13D, Q61H, K117NCRC (2), NSCLC (2), cholangiocarcinoma, multiple myeloma, CLLV600E (6), G466Aomentum (2), liver
NRAS mut4G12C, G13R, G13R/Q61H, Q61H/Kmelanoma (4)V600E (2), V600R, G469Abrain (1), lymph node (1), soft tissue (1)
NRAS amp1amp estimated copies: 41NSCLCV600Epericardial fluid
Secondary BRAF GA10N-terminal deletion exons 2-8 (6), duplications exons 10-18, L505H, N581I/D594G, amp estimated copies: 6NSCLC (4), CRC (2), melanoma (2), multiple myeloma, pancreaticV600E (9), G466Aliver (3), lymph node (2), lung, abdominal wall, brain
MEK1 mut1C121Smultiple myelomaV600ENA
PIK3CA mut5H1047R (2), G1049R, R88Q, S405Fglioma (3), NSCLC, thyroidV600E (3), N486_T491>K, R506_K507insVLRbrain (4), lung
PTEN GA5E7fs*, R130*, G129R, splice site 165-1G>A, lossmelanoma (2), glioma, NSCLC, UP neuroendocrineV600E, V600K, R506_K507insVLR, KHDRBS2-BRAF fusionbrain (2), abdomen, soft tissue
CCND1 amp2amp estimated copies: 9, 10NSCLC, thyroidV600E, G464Vbrain, pleural fluid
MET amp4amp estimated copies: 12, 14, 15, 56NSCLC, CRC, melanoma, UP adenocarcinomaV600E (4)lymph node, colon, brain, liver

Indicated for tissue samples only (NA= not applicable); #5 cases had AR alterations in multiple genes included here; NSCLC: non-small cell lung cancer, CRC: colorectal carcinoma; CLL: chronic lymphocytic leukemia; UP: unknown primary; AR: acquired resistance; mut: mutation; amp: amplification.

Conclusions

Novel and previously observed potential AR alterations in paired BRAF altered clinical samples were detected using CGP. Most AR mechanisms appeared independent of tumor type and biopsy site. Additional clinical studies to explore effective treatments for these AR subsets are needed.

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine.

Disclosure

F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eli-Lily; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Merck Serono. J. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. L. Boussemart: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. G. Srkalovic: Speaker Bureau / Expert testimony: Foundation Medicine. R. Madison: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, 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. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest.

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Poster Discussion 2 – Translational research Poster Discussion session

1879PD - Primary ovarian carcinomas arising in BRCA1 mutation carriers contain a small fraction of BRCA1-proficient cells, which rapidly repopulate tumor mass during neoadjuvant chemotherapy but become outgrown by BRCA1-deficient clones during platinum-free intervals (ID 3025)

Presentation Number
1879PD
Lecture Time
11:00 - 11:00
Speakers
  • Evgeny Imyanitov (Saint-Petersburg, Russian Federation)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Somatic loss of the wild-type allele is a key event in the pathogenesis of BRCA1-driven carcinomas. BRCA1 deficiency renders pronounced sensitivity of these tumors to platinum compounds and PARP inhibitors.

Methods

We analyzed BRCA1 loss of heterozygosity (LOH) in serial ovarian cancer (OC) samples, which were obtained from BRCA1 germ-line mutation carriers before neoadjuvant chemotherapy (NACT), at surgery and at disease relapse.

Results

26/36 (72%) OC had BRCA1 LOH before NACT. 15 (58%) of these 26 tumors showed retention of the normal BRCA1 allele after NACT. The analysis of linked SNPs and FISH assay strongly indicated, that the restoration of BRCA1 function is caused not by the second mutation, but by the selection of pre-existing BRCA1-proficient cells. Tumor relapses were available in 7 patients with BRCA1 LOH in the chemonaive tumor and/or BRCA-proficiency in the residual post-NACT neoplasm; 6 (86%) of these relapses had BRCA1 LOH thus resembling the primary tumor. Secondary open reading frame (ORF) restoring BRCA1 mutation was detected in 1 recurrent OC. Serial samples retained same TP53 mutation during the treatment course. Whole exome sequencing revealed that chemonaive, post-NACT and relapsed tumors had both shared and individual mutations.

Conclusions

1) BRCA1 LOH is not the first event in the pathogenesis of BRCA1-driven cancer: gain of TP53 mutation probably precedes BRCA1 inactivation in order to prevent apoptosis; 2) Chemonaïve BRCA1-driven tumors contain a small fraction of BRCA1-proficient cells, which rapidly repopulate the tumor lump during the first weeks of therapy; 3) Change of BRCA1 status during NACT may call to reconsider the existing approaches to adjuvant therapy, as the residual post-NACT tumor masses are likely to be platinum-resistant; 4) The balance between BRCA1-deficient and BRCA1-proficient cells is a subject of fluctuations, depending whether therapy is applied or not; 5) Clinical trials on BRCA1-driven OCs need to address the issue of intratumoral heterogeneity of BRCA1 status.

Legal entity responsible for the study

The authors.

Funding

Russian Science Foundation (grant 19-15-00168).

Disclosure

All authors have declared no conflicts of interest.

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Poster Discussion 2 – Translational research Poster Discussion session

93PD - Analysis of the androgen receptor status in liquid biopsy to predict the outcome to abiraterone and enzalutamide in CRPC patients (ID 4924)

Presentation Number
93PD
Lecture Time
11:00 - 11:00
Speakers
  • Marzia Del Re (Pisa, Italy)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Abiraterone and enzalutamide represent the standard treatment in castration resistance prostate cancer (CRPC) patients, however, some patient displays primary resistance, and several studies investigated the role of the androgen receptor (AR) as a predictive biomarker of response to treatment (Conteduca, et al. Ann Oncol. 2017;28(7):1508-1516; Del Re, et al. BJU Int. 2019 doi: 10.1111/bju.14792). The present study is aimed at evaluating the role the AR in liquid biopsy to predict response to hormone treatment in CRPC patients.

Methods

Six ml of plasma samples were collected from patients affected by castration-resistant prostate cancer before the beginning of first-line hormonal treatment. Circulating free DNA and exosome-RNA were isolated for analysis of AR-gain and AR-V7 by digital droplet PCR.

Results

Eighty-four CRPC were prospectively enrolled in this study. 40 patients received abiraterone and 44 patients received enzalutamide as first-line hormonal therapy. AR-gain was detected in 12 patients (14.3%) and 36% were AR-V7+ at baseline. Median PFS and OS were significantly longer in AR-V7- vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p < 0.0001, respectively). Patients carrying of the AR-gain had a median PFS of 4.8 vs 24.3 months of non-gained AR patients (P < 0.0001). Median OS was significantly longer in AR-no gain vs AR-gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR-gain was observed (r = 0.28; p = 0.01). In the univariate model, known risk factors for progression such as AR-V7, AR-gain, neutrophil/lymphocyte ratio and metastatic spread to either bone or lymph nodes were analysed. In multivariable analysis, only AR-V7 and AR gain were confirmed as independent predictive biomarkers (p < 0.0001 and p = 0.004, respectively).

Conclusions

The present study demonstrates that cfDNA and exosomal RNA are a reliable source of AR-variants and their detection predicts resistance to anti-hormonal therapy. The method is sensitive, fast and represents a convenient alternative to other potentially more expensive and less sensitive approaches.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

V. Conteduca: Travel/Accommodation/Expenses: Janssen; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Bayer. U.F.F. De Giorgi: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Astellas; Advisory/Consultancy: Byer; Advisory/Consultancy: BMS; Honoraria (self): Ipsen; Advisory/Consultancy: Janssen; Advisory/Consultancy: Merk; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: Janssen; Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest.

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Poster Discussion 2 – Translational research Poster Discussion session

1882PD - Comprehensive molecular characterization of brain metastases (BM) from colorectal cancer (CRC) (ID 3707)

Presentation Number
1882PD
Lecture Time
11:00 - 11:00
Speakers
  • Francesca Battaglin (Los Angeles, United States of America)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Although rare, the incidence of BM is increasing due to the improvement in metastatic CRC treatment and longer survival. Genomic analyses of small series revealed that BM can harbor potentially unique driver mutations. We aimed to comprehensively characterize the molecular profile of BM and explore the differences between BM vs other distant metastases (OM) and primary tumors (PT) in CRC.

Methods

Tumor samples from BM (n = 81), PT (n = 6898) and OM (n = 5918) were analyzed using NGS (TruSEQ on 45 genes or NextSEQ on 592 genes), in situ hybridization and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci.

Results

The most frequently mutated genes in BM were TP53 (80%), APC (73%), KRAS (68%), ARID1A (18%), PIK3CA (13%) and FBXW7 (9%). The most prevalent copy number increase was seen in CDX2 (20%), CCND2 (7%), FLT1 (7%), FLT3 (7%) and FOXO1 (7%). When compared to OM and PT, mutations in KRAS (BM: 68%, OM: 49%, PT: 48%), CDKN2A (5%, 1%, 1%), ERCC2 (2%, 0, 0) and HRAS (1%, 0, 0) were significantly higher in BM (P<.05); BRCA1 was significantly higher in BM vs OM (3 vs 1%, P=.025). Conversely, BRAF mutations trended to be lower in BM vs PT (4 vs 10%, P=.059). Overall, copy number alterations (CNA) were significantly higher in BM vs PT and OM, including CDX2, CCND2, FLT1, FOXO1, ERC1, FGF23, KDM5A, NSD3, FGFR1 (P<.05). HER2 overexpression showed a non-statistically significant trend to be higher in BM compared to PT and OM (7%, 2%, 3%, P=.064). Significantly lower rates of TMB-high (>17mut/MB) and MSI-high were seen in BM vs PT (2 vs 9% and 1 vs 8%, P=.049 and .031, respectively) but not compared to OM. No RSPO3 nor NTRK1 fusions were seen in BM (n = 5). Female gender was associated with younger age in BM (53.5 vs 62 yr, P=.0014) and OM (58.8 vs 60.2 yr, P<.0001), not seen in PT.

Conclusions

This is the largest and most extensive profiling study to investigate the molecular makeup of BM and the differences with PT and OM in CRC. Our data show distinct mutations and CNA characterizing BM and lower expression of immune related markers, supporting the rationale to develop tailored approaches to the treatment of this metastatic site.

Legal entity responsible for the study

The authors.

Funding

National Cancer Institute grant number P30CA014089, Gloria Borges WunderGlo Foundation-The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Call to Cure Research Fund and Fong Research Project.

Disclosure

J. Xiu: Full / Part-time employment: Caris Life Sciences. Y. Baca: Full / Part-time employment: Caris Life Sciences. R.M. Goldberg: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. A. Grothey: Travel / Accommodation / Expenses: Caris Life Sciences. A.F. Shields: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. A. Seeber: Advisory / Consultancy: Caris Life Sciences. M.E. Salem: Travel / Accommodation / Expenses: Caris Life Sciences. P.A. Philip: Travel / Accommodation / Expenses: Caris Life Sciences. J.L. Marshall: Advisory / Consultancy: Caris Life Sciences. W..M. Korn: Full / Part-time employment: Caris Life Sciences. H.J. Lenz: Travel / Accommodation / Expenses: Caris Life Sciences. All other authors have declared no conflicts of interest.

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Poster Discussion 2 – Translational research Poster Discussion session

Invited Discussant 1878PD, 1879PD, 93PD and 1882PD (ID 6954)

Lecture Time
11:00 - 11:15
Speakers
  • Dennis (Yuk-Ming) Lo (Shatin, Hong Kong PRC)
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion 2 – Translational research Poster Discussion session

Q&A led by Discussant (ID 6955)

Lecture Time
11:15 - 11:30
Location
Tarragona Auditorium (Hall 7), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30