BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors. in Cancer research / Cancer Res. 2023 May 15;83(10):1699-1710. doi: 10.1158/0008-5472.CAN-22-2620.
2023
ASL Alessandria
AO Ordine Mauriziano
Tipo pubblicazione
Research Support, Non-U.S. Gov't
Autori/Collaboratori (33)Vedi tutti...
Petrelli A
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
Berrino E
Bioinformatics Unit, Oncology Department, Nuovo Ospedale-Santo Stefano, Prato, Italy.
Romagnoli D
Molecular Mechanisms Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
et alii...
Abstract
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. SIGNIFICANCE: PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.
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PMID : 37129948
DOI : 10.1158/0008-5472.CAN-22-2620
Keywords
BRCA2 Protein/genetics; BRCA1 Protein/genetics; Retrospective Studies; Stomach Neoplasms/drug therapy/genetics; Germ-Line Mutation; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use; Female; Ovarian Neoplasms/drug therapy; Antineoplastic Agents/pharmacology/therapeutic use; Humans;