1552P - Clinical multi-omics analysis of gastric cancer (GC) in Europe (EU) and Latin America (LatAm): The LEGACy project

Background

Gastric cancer is heterogenous with poor prognosis. The LEGACy project aimed to deepen GC molecular understanding through multi-omics analysis of tumours from EU and LatAm. We present partial results including histopathology, immunohistochemistry (IHC) + in-situ hybridization (ISH) markers, immune cell infiltration pattern, broad multi-gene sequencing panel and targeted transcriptomics of stage IV GC paraffin-embedded tissues.

Methods

After the central pathological confirmation of GC, standard IHC/ISH was performed, nucleic acids were extracted for DNA sequencing of 435 genes (covering mutations, copy number, fusions, MSI + TMB), and mRNA was profiled with custom Nanostring gene expression assay. The primary aim was to explore a clinically feasible diagnostic classification of GC: a. MSI; b. EBV+; c. HER2+; d. other intestinal-type (IT); and e. other poorly cohesive-type (PCT) f. and mixed. Only significant associations (P values <0.05) in non-parametric tests adjusted for multiple testing are reported.

Results

Out of 334 GC patients were enrolled in the project, 148 were eligible for molecular analysis Prevalence of GC subtypes: MSI 11%, EBV+ 4%; HER2+ 9%, IT 41%, PCT 31% and mixed 4%. We found higher HER2+ and IT tumors in EU vs. LatAm (14% vs. 6% and 46% vs. 30%, respectively). MSI tumors had highest TMB (median 38 mut/Mb) enriched for KMT2D, KRAS, PIK3CA and RNF43 mut, but no differences in immune cell infiltration/activation. EBV+ tumors had intermediate TMB (median 14 mut/Mb), highest PIK3CA mut, highest CD3/CD8 infiltration, cytotoxic and apoptotic signatures. HER2+ tumors were enriched for TP53 mut. While both IT and PCT samples had low TMB (median < 7 mut/Mb) and higher dendritic cell/mast cell infiltration, IT tumors had high cell cycle activation + TP53 mut, and PCT tumors had low Ki67, highest Hedgehog + Notch + Wnt activation scores. Interestingly, PCT tumors from LatAm had higher median TMB (7 mut/Mb) when compared to EU (4 mut/Mb). Overall, PDL1 expression was similar across the groups.

Conclusions

Our pathological-molecular classification of GC is comparable with TCGA and others, with potential differences in prevalence and mutational signatures for EU and LatAm populations that will be further explored.

Clinical trial identification

NCT04015466.

Editorial acknowledgement

Legal entity responsible for the study

INCLIVA Biomedical Research Institute, Valencia, Spain.

Funding

This work was funded by the European Union’s Horizon 2020 research and innovation program (Grant agreement No GA825832).

Disclosure

T.C. Fleitas: Financial Interests, Personal, Invited Speaker, Update on the ongoing treatment strategies for GEA: Servier; Financial Interests, Personal, Invited Speaker, The clinical impact of NRTK strategies in GI tumors: Bayer; Financial Interests, Personal, Invited Speaker, Invited as a speaker in an educational session: Bristol Myers Squibb, Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in an educational session: Bristol Myers Squibb, MSD, Lilly, Roche; Non-Financial Interests, Principal Investigator, PI of SURPASS-2 study: Adapt Immune; Non-Financial Interests, Principal Investigator, PI of a clinical trial in GEA tumors: Daiichi Sanyo; Non-Financial Interests, Principal Investigator, PI of a clinical trial: BeiGene. M. Alsina Maqueda: Financial Interests, Personal, Advisory Board: MSD, BMS, Lilly, Servier, AstraZeneca; Non-Financial Interests, Principal Investigator, Investigator Initiated trial: Merck. E. Ruiz: Financial Interests, Personal, Advisory Board: Roche, Amgen, BMS, BAYER; Financial Interests, Personal, Invited Speaker: Roche, Merck; Financial Interests, Institutional, Invited Speaker, gastric cancer talk: Astellas. F. Esteso: Financial Interests, Personal, Invited Speaker: BMS, Roche, Bayer, Amgen, Merck, Pfizer, Nutricia Bago, Raffo, Biotoscana, Servier; Financial Interests, Personal, Advisory Board: Varifarma; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, Roche, Mirati. S. Derks: Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Invited Speaker: BMS, Servier; Financial Interests, Institutional, Funding, sponsoring investigator initiated study: Incyte. R. Dienstmann: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, Ipsen, Libbs, Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, GSK, Takeda, Janssen, Foundation Medicine; Financial Interests, Personal, Advisory Board: Bayer, Roche; Financial Interests, Personal, Full or part-time Employment, Oncoclínicas is a private healthcare provider in Brazil. I work part time as Medical Director of the Precision Medicine and Big Data Initiative. We develop molecular tests (pathology and genomics) that are offered to patients treated in the organisation as part of support programs sponsored by pharmaceutical companies and I coordinate research activities with real-world clinic-genomics cohorts.: Oncoclínicas; Financial Interests, Personal, Stocks/Shares: Trialing; Financial Interests, Personal, Research Grant: Merck. A. Cervantes: Financial Interests, Institutional, Advisory Board: Merck, Amgen, Roche, Transgene, AnHeart Therapeutics, AbbVie, GSK; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor in Chief: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, BeiGene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda, Affimed, Roche, Seamless, Gilead, Janssen, F. STAR Therapeutics, Ribon Therapeutics; Non-Financial Interests, Other, Scientific Director: INCLIVA Biomedical Research Institute. All other authors have declared no conflicts of interest.