Browsing Over 164 Presentations
PDX (ID 52)
- Samuel Aparicio (Vancouver, CA)
Mutational processes (ID 59)
- Serena Nik-Zainal (Cambridge, GB)
Clonal evolution in lung cancers (ID 7)
- Nicholas McGranahan (London, GB)
APOBEC (ID 8)
- Reuben Harris (Minneapolis, US)
59O - Preliminary results on mechanisms of resistance to ALK inhibitors: A prospective cohort from the MATCH-R study (ID 217)
- Gonzalo Recondo (Villejuif, FR)
Abstract
Background
ALK tyrosine kinase inhibitors (TKIs) have shown to be effective in the treatment of patients with ALK rearranged NSCLC. The clinical benefit is eventually limited by the acquisition of resistance to ALK TKIs by tumor cells. The study of the biological mechanisms implied in tumor progression can provide the rational for therapeutic strategies to overcome resistance.
Methods
In the MATCH-R prospective study, patients with unresectable or metastatic cancer were included upon acquired resistance to targeted therapies or immunotherapy, defined as progressive disease after partial or complete response or stable disease for 6 months. Upon progression tumor biopsy is performed and serial blood samples are collected. Targeted NGS, CGH, WES and RNAseq were performed on the tissue, and PDX models and patient derived cell lines were established to fully profile the underlying mechanisms of resistance.
Results
From June 29th 2015 and as of June 15th 2018, 309 patients were included of which 139 (45%) had advanced lung adenocarcinoma and n = 10 (7.2%) had tumors with ALK rearrangements. In 2 patients, multiple biopsies were taken upon progression to sequential treatments with ALK TKI. Evaluable tumor biopsies were taken upon progression to treatment with crizotinib (n = 3), ceritinib (n = 1), brigatinib (n = 2), lorlatinib (n = 5). PDX models/patient derived cell lines (n = 4) were developed from 2 patients. Mechanisms of resistance: Secondary mutations (n = 5), pathway bypass (n = 3), other non-genetic (n = 3). Novel compound mutations implied in resistance to lorlatinib were characterized by infecting BA/F3 cells with EML4-ALK V3 mutated lentiviral vectors, together with the characterization and reversion of a novel bypass mechanism. We also studied therapeutic strategies aiming at reverting resistance driven by EMT in patient derived cell lines treated with lorlatinib.
Conclusions
Mechanisms of resistance were identified in 9 out of 11 tumors from patients with ALK rearranged NSCLC. The development of patient derived cell lines provides further information on how to overcome the resistance to ALK inhibitors.
Clinical trial identification
NCT02517892.
Legal entity responsible for the study
Gustave Roussy Cancer Campus.
Funding
Natixis, European Research Council (ERC), Foundation Nelia et Amadeo Barletta.
Disclosure
F. André: Research grants from Novartis. J-C. Soria: Full-time employee of MedImmune. B. Besse: Institutional grants for clinical and translational research from AstraZeneca, BMS, Boehringer-Ingelheim, Inivata, Lilly, Loxo, OncoMed, Onxeo, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, and OSE Pharma. All other authors have declared no conflicts of interest.
Single cell/PDX (ID 9)
- Sohrab Shah (Vancouver, CA)
43P - ‘Real world data’ of genomic sequencing for personalised therapy (ID 207)
- Milana S. Bergamino (Barcelona, ES)
Abstract
Background
AMPLICON deep sequencing to determine gene mutations (mut) and copy number alterations (CNA) helps to understand tumors' molecular biology and to personalize therapy. At Institut Català d’Oncologia l’Hospitalet it is used to find the best treatment options. We aim to analyze its efficiency.
Methods
We use AMPLICON sequencing to analyze genomic profile and CNA of unresectable or metastatic breast cancer tumors from selected patients (pts) with eligible criteria for clinical trials: 18-75 years, Performance Status (PS) ≤1, non-relevant comorbidity, organ preserved function and not heavily pretreated. We obtained the informed consent from all pts. An observational prospective analysis was carried out to evaluate pts and tumor characteristics, mut and CNA, target therapy (TT) and survival.
Results
Since December 2017, 45 pts were tested. Median age at diagnosis of metastatic disease was 51 years (29-70) and at molecular screening 55 (29-72). Most patients had PS 0. In the metastatic setting, 32 pts (71%) had luminal breast tumors, 8 (18%) triple-negative and 5 (11%) HER2+. Median number of hormonotherapy lines at screening was 1 (0-5) and 1 chemotherapy line (0-5). Median follow up was 4.5 months. Only 2 pts died during this analysis. Overall, 30 mut were found. 23 pts (51%) had at least one mut. Almost 60% pts had 1 mut. Median number of mut was 1 (1-3). 49% pts had Wild Type (WT) tumors. The most prevalent mut were: 30% in PI3K, followed by 23% in ESR1, 13% in TP53, 7% in PTEN, 7% in FGRF4, and 3% in APC and in NOTCH. CNA was reported in 16 pts (35%). Pts with mut or CNA that could potentially benefit from TT were estimated in 13 pts (28%). 2 pts are currently under TT with PI3K inhibitors (inh) and 5 will be consider at progression for personalized treatment (PI3K inh and TAS 120).
Conclusions
Personalized therapy by sequencing tumors is an option for pts who could benefit from TT in clinical trials. In our analysis we found less mut or CNA than those described in literature, may be due to the different population. Potential benefit from TT was only considered in less than half of pts with any genomic alteration maybe because some mut are not targetable as ESR1 or p53 and lack of follow-up. Genomic sequencing can be a useful tool to achieve personalized therapy if used in selected pts but further evidence is needed.
Legal entity responsible for the study
Institut Català d\'Oncologia L\'Hospitalet.
Funding
Institut Català d\'Oncologia i Vall d\'Hebron Institut d\'Oncologia.
Disclosure
All authors have declared no conflicts of interest.
110TiP - PREvalence of BRCA mutations and correlations with Demographic and clinical characteristICs in paTients with ovarian, fallopian tube or primary peritoneal cancer in Romania (PREDICT) (ID 191)
- Cristina L. Cebotaru (Cluj-Napoca, RO)
Abstract
Background
The epidemiology of ovarian cancer in Romania is not well characterized and only few limited regional data are available. Moreover, the BRCA status in patients with homologous recombination-deficient tumorsis not known and no data about dominant founder mutations exist. BRCA1/2 are tumor suppression genes critical to DNA repair through homologous recombination in response to DNA damage. Around 13% of high-grade serous ovarian cancers is attributable to germline BRCA mutations.
Trial Design
This is an observational, retrospective, national, multicentre study aiming to describe the prevalence of BRCA mutations in patients with platinum-sensitive high-grade serous ovarian, fallopian tube or primary peritoneal cancer. As the link between BRCA1/2 mutation and ovarian cancer is well known, the primary objective of this study is to describe the prevalence of germline BRCA mutations in Romania. Secondary objectives will explore the correlations between mutational status and demographic and clinical characteristics and identify any dominant founder mutations. Data from 234 patients tested between April 2016 –April 2017 in 47 oncology centers, will be analyzed. Data collection was made from the patient’s files, by investigators, as no databases exists in Romania. It is estimated that clinical study report will be finalized by September 2018. Variables explored: BRCA status, age, weight and/or BS, parity,personal history of breast cancer, family history of cancer, stage at diagnosis, ECOG performance status, number of platinum-based chemotherapy lines, progression free interval, smoking.
Clinical trial identification
D133FR00135 Observational Study.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
C.L. Cebotaru: Advisory board: Boehringer Ingelheim, Novartis, Pfizer; Lecture fees: AstraZeneca, BMS, Bayer, Ipsen, Astellas; Travel grants: Alvogen, Merck Serono, Boehringer Ingelheim; Educational grants: AstraZeneca. D.L. Stanculeanu: Grant/Research Support: Sandoz, Roche; Speaker’s Bureau: AstraZeneca, Astellas, Roche, BMS, Jonson and Jonson, Pfizer, Boehringer Ingelheim, Sandoz; consultant: AstraZeneca, Astellas, Roche, BMS, Pfizer, Boehringer Ingelheim, Sandoz. D.M. Median: Advisory role: Roche, Pfizer; Lecture fees: AstraZeneca, Teva, Roche, Sandoz; Travel grants: Alvogene, A&D Pharma; Educational grants: Pfizer, AstraZeneca, Roche; Institutional grants: Novartis, Lilly, Samsung Bioepis, Tesaro, Roche, Boehringer Ingelheim.
10P - EGFR T790M mutation in treatment-naïve tumor samples: Low frequency, evidence for interaction with EGFR TKI-sensitizing mutations and lack of clear predictive value (ID 118)
- Evgeny Imyanitov (Saint-Petersburg, RU)
Abstract
Background
EGFR T790M mutation is associated with acquired resistance of lung cancer (LC) to first-generation TKIs. Several studies suggest that LCs often contain a small fraction of T790M-mutated cells even before the treatment, and the persistence of these mosaic clones renders poor tumor response to gefitinib or erlotinib.
Methods
We utilized a spectrum of methods to detect EGFR T790M allele in tumor and normal human tissues.
Results
Allele-specific PCR (AS-PCR) analysis of treatment-naïve tumor samples revealed somatic T790M mutation in 3/394 (1%) LCs carrying TKI-sensitizing EGFR mutation, but in none of 334 LCs lacking EGFR exon 19 deletions (ex19del) or L858R substitutions and in none of 235 non-lung carcinomas. Cis-/trans- analysis of the ex19del and the T790M was performed on samples from two treatment-naïve LCs and revealed the location of both mutations in the same allele. In one of these tumors, T790M mutation was present only in a fraction of ex19del-containing cells, suggesting that the T790M was acquired later than the ex19del during natural tumor evolution. None of 920 LCs analyzed carried EGFR T790M in germ-line. Use of highly-sensitive and quantitative assays, such as ddPCR and NGS, produced high number of T790M-specific signals even in presumably T790M-negative DNA specimens. This background noise was evidently higher in degraded DNA isolated from formalin-fixed paraffin-embedded tissues as compared to high molecular weight DNA. Combination of AS-PCR, ddPCR and NGS revealed mosaic EGFR T790M allele only in 2 (3%) out of 68 LCs treated by the first-generation TKI. Both these tumors produced evident and durable response to gefitinib.
Conclusions
The occurrence of EGFR T790M mutation in treatment-naïve LC samples is significantly lower than reported in some previous studies. Interestingly, the emergence of EGFR T790M allele is linked to the presence of TKI-sensitizing mutations even in the absence of drug exposure, thus suggesting a biological interaction between these two genetic events. The detection of mosaic EGFR T790M mutations may be compromised by yet unresolved technical issues and may have limited clinical value.
Legal entity responsible for the study
N.N. Petrov Institute of Oncology.
Funding
AstraZeneca (Research Agreement with the N.N. Petrov Institute of Oncology); Russian Science Foundation (grant 17-75-30027).
Disclosure
All authors have declared no conflicts of interest.
75P - Synthetic lethal effects of BMN 673 loaded solid lipid nanoparticles on triple-negative breast cancer (ID 72)
- Gamze Guney Eskiler (Sakayra, TR)
Abstract
Background
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) indicate the synthetically lethal effect in BRCA-defective breast cancers. BMN 673 has attracted considerable attention as the most potent PARPi with the highest PARP trapping efficiency. However, several mechanisms of PARPi resistance have been described in the literature. Solid lipid nanoparticles (SLNs) represent a promising new strategy to overcome resistance mechanisms due to unique features including their unique size and stability etc. In the present study, we aimed to determine a potential therapeutic effect of BMN 673 loaded SLNs formulation on homologous recombination (HR) in triple-negative breast cancer (TNBC).
Methods
Firstly, we produced BMN 673-SLNs by hot homogenization method. After characterization, the cytotoxic effect of BMN 673-SLNs (0.01-10 nM) on HCC1937BRCA1-/- and HCC1937-R (BMN 673 resistant) TNBC cell line was determined by WST-1 assay. Then, DNA damage, gene expression (PARP1, RAD51, H2AX) and western blot analysis were carried out to detect the effects of BMN 673-SLNs on HR mechanism.
Results
The WST-1 results demonstrated that the viability of HCC1937 and HCC1937-R cells treated with 10 nM of BMN 673-SLNs for 12 days decreased to 29.5% and 34.9%, respectively (p < 0.05). The percentage of p-ATM, p-H2AX and double strand breaks-DNA (dsDNA) in HCC1937 cells was 2.5%, 16.5% and 59.9% at 10 nM of BMN 673-SLNs for 12 days, respectively. Additionally, the percentage of p-ATM, p-H2AX and dsDNA was found to be 2.2%, 9.0% and 71.2% in HCC1937-R cells, respectively. The expression level of H2AX (2.7-fold) and RAD51 (2.9-fold) were up-regulated whereas, PARP1 (-1.22-fold) mRNA expression was down-regulated in HCC1937 cells treated with 10 nM of BMN 673-SLNs for 12 days. Besides, we found that the H2AX, RAD51 and PARP1 expression levels were up-regulated 2.2-, 1.4- and 3.0-fold in HCC1937-R cells, respectively. These findings were supported by the results of western blot analysis.
Conclusions
SLNs could potentially provide therapeutic impact on HR mechanism and overcome drug-resistance for the treatment of TNBC. Thus, SLNs could provide suitable alternatives to existing treatment strategies after preclinical validation.
Legal entity responsible for the study
The Scientific Research Projects Foundation of the Uludag University of Turkey.
Funding
This study was supported by a grant from the Scientific Research Projects Foundation (BAP) of the Uludag University of Turkey [Project No: BUAP(T)-2015/1].
Disclosure
All authors have declared no conflicts of interest.
44P - Correlation between an automated functional assay that predicts targeted agent (TA) sensitivity and the tumor response of the sorafenib treatment evaluated within the MOST clinical trial (ID 225)
- Olivier Tredan (Lyon, FR)
Abstract
Background
MOST (My Own Specific Therapy) is a prospective, randomized, open-label, adaptive phase II trial conducted in patients (pts) with progressive solid tumors (any subtype) after at least one prior therapy in advanced setting. This trial aims to evaluate the clinical benefit of therapies targeting molecular alterations identified in the patient’s tumor. NovellusDx’ technology measures the functional impact of alterations including Variants of Uncertain Significance (VUS), and TA efficacy based on NGS findings.
Methods
Pts were treated with sorafenib 400 mg BID based on KRAS/KDR, HRAS and BRAF (non-V600) oncogenic mutations/amplification. After 12 weeks of treatment (induction period), pts with stable disease were randomly assigned to continuation or interruption of sorafenib. NGS data from the treated pts were blindly analyzed by the functional assay: synthesized mutated genes and florescent reporter genes were transfected into live cells and scanned in a microscopy system. The specific pathways activation was evaluated by quantifying the subcellular localization of the reporter proteins. Sorafenib response prediction based on the assay was compared with the best change tumor size assessed in the MOST trial, and the maintenance treatment duration.
Results
17 patients treated for at least 12 weeks with sorafenib were analyzed. Tumor genomic alterations that indicated the sorafenib treatment consisted in KRAS mutations (n = 9), KRAS amplifications (n = 3), HRAS mutation (n = 3), KDR amplification/mutation (n = 2). However, NGS data showed additional molecular aberrations. Of which, the functional impact and response to TA of 18 unique variants in 10 different genes was measured. The correlation between the assay-based response prediction and the variation in the tumor volume of the patients will be presented.
Conclusions
Multidisciplinary molecular tumor board recommends TA based on single actionable oncogenic mutations. Taking into account significant other genomic variants is crucial to accurately predict targeted agent efficacy.
Clinical trial identification
NCT02029001.
Legal entity responsible for the study
Centre Léon Bérard.
Funding
Fundation ARC, INCa.
Disclosure
O. Zelichov, Z. Barbash, Y. Daitsh, L. Birnbaum, G. Tarcic: Full time employee of NovellusDx. All other authors have declared no conflicts of interest.