journal contribution
posted on 2023-05-15, 08:40 authored by Annalisa Petrelli, Sabrina Rizzolio, Filippo Pietrantonio, Sara E. Bellomo, Matteo Benelli, Loris De Cecco, Dario Romagnoli, Enrico Berrino, Claudia Orrù, Salvatore Ribisi, Daniel Moya-Rull, Cristina Migliore, Daniela Conticelli, Irene M. Maina, Elisabetta Puliga, Violeta Serra, Benedetta Pellegrino, Alba Llop-Guevara, Antonino Musolino, Salvatore Siena, Andrea Sartore-Bianchi, Michele Prisciandaro, Federica Morano, Maria Antista, Uberto Fumagalli, Giovanni De Manzoni, Maurizio Degiuli, Gian Luca Baiocchi, Marco F. Amisano, Alessandro Ferrero, Caterina Marchiò, Simona Corso, Silvia Giordano MLH1 KO cells do not display MSI.
Funding
Associazione Italiana per la Ricerca sul Cancro (AIRC)
Ministero della Salute (Italy Ministry of Health)
Fondazione Piemontese per la Ricerca sul Cancro FPRC
Università degli Studi di Torino (都灵大学)
European Society for Medical Oncology (ESMO)
Gruppo Oncologico Italiano di Ricerca Clinica
Fondazione CR Firenze
History
ARTICLE 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.
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.
