Homologous recombination deficiency as prognostic marker in metastatic gastric cancer.

Abstract

4040 Background: Gastric cancer is the 5th cancer diagnosis and 3rd cause of cancer death worldwide. Metastatic gastric cancer (mGC) has a median survival of 11 months. mGC is an heterogeneous disease and different biologic characteristics may justify differential therapeutic opportunities. Tumors with homologous recombination (HR) deficiency may benefit with treatment with PARP inhibitors or immune checkpoint inhibitors. The purpose of this study was to evaluate the prevalence and prognostic impact of altered expression of HR proteins as surrogates for homologous recombination deficiency (HRD) in mGC. Methods: Multicenter retrospective cohort of mGC treated with platinum-based chemotherapy. HRD defined as absence of at least one of the following proteins: ATM, ATR, CHK2, RAD51, RAD52, BRCA1, BRCA2, MRE11 by immunohistochemistry. Survival time calculated as the difference between first cycle of platinum-based chemotherapy and death or last observation. Association between HRD and survival examined with log-rank test. Results: 440 patients included, of which 70% male, with mean age of 58 years (SD: 11). 75% of patients had mGC at diagnosis, 43% had 2 or more organs involved and 63% were registered as ECOG 0 or 1 at the start of first line chemotherapy. The most common histologic subtype was tubular adenocarcinoma (44%) followed by diffuse carcinoma (32%). HRD was noted in 196 (45%) cases (95%CI: 40%-49%). The most commonly altered proteins were ATM (21%) and BRCA2 (18%). In HRD tumors, 99 (51%) had altered expression of only one HR protein; 47 (24%) had altered expression of two HR proteins; the remaining cases had altered expression of 3 or more proteins. After a median follow up of 11 months, median survival for the cohort was 11 months (95% CI 9-12). HRD was associated with an improved survival, HR = 0.61 (95%CI: 0.48-0.78, p < 0.001), that remained significant after adjustment for sex, age, performance status and disease status (HR = 0.63; 95%CI: 0.48-0.82; p < 0.001). Conclusions: HRD phenotype was present in 45% of mGC cases and is associated with improved prognosis for mGC treated with platinum-based first line chemotherapy.

Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration

“…Here we describe the HRD signature landscape derived from whole-genome sequencing (WGS) of gastrointestinal (GI) and thoracic malignancies sequenced as part of the Personalized OncoGenomics program in British Columbia, Canada and characterize the relationship between HRD and clinical outcomes with platinum-based treatment. Retrospective studies to date have suggested an association between platinum response and selected HRD mutations in pancreatic, colorectal, gastric, and lung cancers, although these studies have largely focused on pre-selected HRD mutations rather than a WGS approach 6 , 8 , 32 , 33 . Gastrointestinal and thoracic malignancies were selected for this analysis due to the relative paucity of data in these tumor sites, particularly when compared to breast and ovarian cancers, as well as their routine use of platinum therapies with the potential for HRD to underlie heterogeneity in clinical response 34 .…”