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Poster Display session 2

2670 - Molecular subtypes of metastatic(met) gastric cancer(GC) (MoTriGastric): new biomarkers closer to the clinics

Date

29 Sep 2019

Session

Poster Display session 2

Presenters

Maria Alsina Maqueda

Citation

Annals of Oncology (2019) 30 (suppl_5): v253-v324. 10.1093/annonc/mdz247

Authors

M. Alsina Maqueda1, F. Ruiz2, S. Landolfi3, C. VIAPLANA2, J.M. Miquel4, J. Jimenez5, M. Diez1, I. Gullo6, O. Mirallas7, J. Tabernero8, F. Carneiro9, P.G. Nuciforo5, A. Vivancos10, R. Dienstmann2

Author affiliations

  • 1 Medical Oncology, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 2 Oncology Data Science (odyssey) Group, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 3 Pathology, Vall Hebron University Hospital, Barcelona/ES
  • 4 Research Support Unit, Vall d'Hebron Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 5 Molecular Oncology Dept., Vall d'Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 6 Pathology, Centro Hospitalar Universitário São João Faculty of Medicine of the University of Porto Institute of Molecular Pathology and Immunology of the University of Porto Institute for Research and Innovation in Health, 4200 - Porto/PT
  • 7 Medical Oncology, Vall Hebron University Hospital, 08035 - Barcelona/ES
  • 8 Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 9 Genetic Dynamics Of Cancer Cells Lab  , IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-135 - Porto/PT
  • 10 Genomics, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
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Resources

Abstract 2670

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.

Clinical trial identification

Editorial acknowledgement

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.

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