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Ref Type Journal Article
PMID (37129948)
Authors Petrelli A, Rizzolio S, Pietrantonio F, Bellomo SE, Benelli M, De Cecco L, Romagnoli D, Berrino E, Orrù C, Ribisi S, Moya-Rull D, Migliore C, Conticelli D, Maina IM, Puliga E, Serra V, Pellegrino B, Llop-Guevara A, Musolino A, Siena S, Sartore-Bianchi A, Prisciandaro M, Morano F, Antista M, Fumagalli U, De Manzoni G, Degiuli M, Baiocchi GL, Amisano MF, Ferrero A, Marchiò C, Corso S, Giordano S
Title BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.
URL
Abstract Text 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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RAD51C R237* nonsense unknown RAD51C R237* results in a premature truncation of the Rad51c protein at amino acid 237 of 376 (UniProt.org). R237* has been identified in the scientific literature (PMID: 37129948), but has not been biochemically characterized and therefore, its effect on Rad51c protein function is unknown (PubMed, Mar 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RAD51C R237* gastroesophageal adenocarcinoma predicted - sensitive Cisplatin + Fluorouracil + Trastuzumab Case Reports/Case Series Actionable In a retrospective analysis, treatment with the combination of Herceptin (trastuzumab), Platinol (cisplatin), and Adrucil (fluorouracil) resulted in a partial response and a progression-free survival of 13.0 months in a patient with gastroesophageal adenocarcinoma harboring RAD51C R237* (PMID: 37129948). 37129948
ATM R1882* gastroesophageal adenocarcinoma predicted - sensitive Capecitabine + Oxaliplatin Case Reports/Case Series Actionable In a retrospective analysis, treatment with the combination of Xeloda (capecitabine) and Eloxatin (oxaliplatin) resulted in a partial response and a progression-free survival of 12.3 months in a patient with gastroesophageal adenocarcinoma harboring ATM R1882* (PMID: 37129948). 37129948
ATM W1058* ATM S1993fs gastroesophageal adenocarcinoma predicted - sensitive Fluorouracil + Leucovorin + Oxaliplatin Case Reports/Case Series Actionable In a retrospective analysis, treatment with the combination of Adrucil (fluorouracil), Wellcovorin (leucovorin), and Eloxatin (oxaliplatin) resulted in a partial response and a progression-free survival of 7.2 months in a patient with gastroesophageal adenocarcinoma harboring ATM W1058* and S1993fs (PMID: 37129948). 37129948