BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Abstract

Mutations; Gastric cancers; PARP inhibitors

Mutacions; Càncers gàstrics; Inhibidors de PARP

Mutaciones; Cánceres gástricos; Inhibidores de PARP

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as “benign.” However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer.

This work was funded by the Italian Association for Cancer Research (AIRC), IG 20210 and IG 27531 to S. Giordano; IG 23624 to F. Pietrantonio; IG 21770 to S. Corso. FPRC 5×1000 2015 Min. Salute “Strategy” to SG; Fondazione Piemontese per la Ricerca sul Cancro (FPRC) 5×1000 MS2017 PTCRC-intra 2020 to S. Giordano; Ricerca Locale Dept. Oncology 2021 to S. Corso; Italian Ministry of Health-Ricerca Corrente 2022–23. B. Pellegrino was supported by ESMO with a Clinical Translational Fellowship aid supported by Roche and received research grants from GOIRC. Fondazione CR Firenze to M. Benelli.