Abstract 472P
Background
Targeting homologous recombination has proven efficacious in several tumor types but it is not fully elucidated in GEA. We aim to describe molecular and clinical features in GEA patients (pts) with HRD alterations.
Methods
We included pts seen at Vall d´Hebron Hospital with a diagnosis of GEA with somatic and/or germline (GL) mutations in HRD genes and other alterations. Clinical and molecular data was collected retrospectively from the electronic medical history. Survival was analyzed by the Kaplan-Meier method. A patient-derived xenograft (PDX) model from a GL mutated BRCA1 gastric tumor was established and drug sensitivity with Olaparib was assessed.
Results
Twenty-nine pts with HRD alterations were identified. Clinical and molecular characteristics are outlined in the table. Median overall survival (OS) among metastatic (25) pts was 25,6 months (m) (95% CI 19,6 – NA). Progression-free survival (PFS) to first-line platinum-based chemotherapy (21 pts) was 10,9m (95% CI 9,23 – 18,1). Overall response rate was 52%. Comparing BRCA mutated pts (somatic or GL) vs other HRD alterations, PFS was 12,2m vs 8,5m (HR 1,308 (95% CI 0,529-3,23)) and OS 28,6m vs 24,6m (HR 1,479 (95% CI 0,46-4,69)) respectively. The PDX model showed high levels of DNA damage and absence of nuclear RAD51 protein and BRCA1 foci, which is indicative of HRD. Olaparib treatment elicited anti-tumor activity. Table: 472P
| N = 29 (100%) | ||
| Sex | Male | 15 (51,7) |
| Female | 14 (48,3) | |
| Age | Mean (years) | 62 (30 - 83) |
| Histology | Tubular | 13 (44,8) |
| Poorly cohesive | 5 (17,2) | |
| Mixed | 3 (10,3) | |
| Others | 7 (27,7) | |
| Stage at diagnosis | Localized | 12 (41,4) |
| Metastatic | 17 (58,6) | |
| Site | Esophagus | 1 (3,4) |
| EGJ | 3 (10,3) | |
| Gastric | 25 (86,2) | |
| HER2 | Positive | 5 (17,2) |
| Negative | 23 (79,3) | |
| ND | 1 (3,4) | |
| MSI Status | MSI | 7 (24,1) |
| MSS | 18 (62,1) | |
| ND | 4 (13,8) | |
| Ebstein-barr virus | Positive | 1 (3,4) |
| Negative | 16 (55,2) | |
| ND | 12 (41,4) | |
| BRCA 1/2 germline mutation | Yes | 10 (34,5) |
| No | 3 (10,3) | |
| ND | 16 (55,2) | |
| HRD somatic mutation | BRCA 1/2 | 11 |
| ATM | 7 | |
| FANCA | 3 | |
| CHEK2 | 2 | |
| BARD1 | 2 | |
| BAP1 | 1 | |
| ND | 5 |
ND: not determined
Conclusions
Although not statistically significant, due to retrospective data and small population, these results denote a subset of GEA pts with HRD alterations that carefully selected may be sensible to platinum-based chemotherapy and potential candidates to target drugs as PARP inhibitors.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
D. Acosta Eyzaguirre: Financial Interests, Personal, Other, Travel and expenses: MSD, BMS. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Meyers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Meyers Squibb, Roche, Incyte. T. Macarulla Mercade: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd., Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp and Dohme, Novocure, QED Therapeutics Inc, Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZeneca, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, FibroGen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, Medimmune, Merimarck, Millenim, Nelum, Novartis, Novocure, Pfizer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” - SEOM, Sociedad Europea de Oncología Médica - ESMO; Other, Editorial Board: GI Annals og¡f Oncology. All other authors have declared no conflicts of interest.