Molecular subtypes of metastatic (met) gastric cancer (GC) (MoTriGastric): New biomarkers closer to the clinics

Abstract

Background Clinical and molecular heterogeneity of GC is broadly recognized. Three molecular classifications based on sample profiling from resected early-stage tumours have been proposed. Apart from microsatellite instability (MSI) subgroup, they provide conflicting results and are difficult to implement in the met population. We aimed to develop and adapt a molecular classification for stratifying met patients(pt). Methods Fifty surgical samples from GC pt (Dec 2006 – Jan 2017) who relapsed were selected. We performed 1) exon-capture next generation sequencing for mutation(mut) (430 genes, including TP53, PIK3CA, CDH1, RHOA, BRCA1/2, ATM); 2) immunohistochemistry of HER2, MET, MLH1, MSH2, MSH6, PMS2, CDH1, MUC6, MUC5AC, PDL1; and 3) in situ hybridization of HER2, EBV, FGFR2, MET. Tumour mut burden (TMB) defined as number of non-synonymous mut per megabase (Mb) of coding region. Grant PI17/00117. Results Forty-nine pt had evaluable molecular data, 26 (53%) diffuse subtype, 11 (22%) intestinal, 12 (24%) mixed. Eight tumours were HER2-positive (-pos) (16%), 3 MSI-pos (6%), and 2 EBV-pos (4%). Gene mut and copy number variations (CNVs) involving receptor kinases, cell cycle, epigenetic and DNA damage repair pathways were detected in more than 50%. TP53 mut were found in 21 (43%), whereas CDH1 in 10 (20%), ARID1A in 9 (18%), and LRP1B in 8 (16%). Diffuse subtype had an enrichment for CDH1 mut (31%), and intestinal for TP53 mut (82%). We found no enrichment for CNVs in histopathology subtypes, but 6 out of 8 HER2 amplified cases were TP53 mut intestinal. TP53 wild type (wt) tumours had higher expression of MUC6, MUC5A and lower PDL1 combined score (p<0.05). Outlier high PDL1 expression and high TMB (> 10 mut/Mb) were not limited to MSI and EBV-pos. TMB was higher in samples with alterations in DNA damage repair genes (median 6 mut/Mb) or TP53 mut (median 5.4 mut/Mb) as compared to wt (median 3.1 mut/Mb, p<0.05). The overall survival in the met setting was longer in pt with DNA damage repair mut (36.7m) than wt (11.5m; HR 0.51; p=0.06). All pt had received a platinum-based chemo, none immunotherapy. Conclusions The molecular landscape of met GC is unique and may guide development of matched therapies. Our findings will be validated in a larger cohort of 135 samples. Legal entity responsible for the study Vall d’Hebron Institute of Oncology (VHIO). Funding Instituto Carlos III - Proyectos de Investigación en Salud PI17/00117. Disclosure M. Alsina Maqueda: Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Honoraria for speaking issues: Servier; Honoraria (self), Advisory / Consultancy, Honoraria for speaking issues: BMS; Honoraria (self), Advisory / Consultancy, Honoraria for speaking issues: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Honoraria for speaking issues: Lilly; Honoraria (self), Travel / Accommodation / Expenses, Honoraria for speaking issues: Roche; Honoraria (self), Travel / Accommodation / Expenses, Honoraria for speaking issues: Amgen. M. Diez: Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Servier. J. Tabernero: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genentech; Advisory / Consultancy: Genmab A/S; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Imugene Limited; Advisory / Consultancy: Inflection Biosciences Limited; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Kura Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Menarini; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners. P.G. Nuciforo: Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD. A. Vivancos: Advisory / Consultancy, Research grant / Funding (institution): Sysmex; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Guardant Health; Licensing / Royalties, Technology Transfer DX Field: Ferrer; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Cellestia Biothech; Research grant / Funding (institution): Chittern. R. Dienstmann: Advisory / Consultancy, Honoraria for speaking: Roche; Honoraria (self), Honoraria for speaking: Symphogen; Honoraria (self), Honoraria for speaking: Ipsen; Honoraria (self), Honoraria for speaking: Amgen; Honoraria (self), Honoraria for speaking: Sanofi; Honoraria (self), Honoraria for speaking: MSD; Honoraria (self), Honoraria for speaking: Servier; Research grant / Funding (self): Merck. All other authors have declared no conflicts of interest.