Gene mutational profile of BRCAness and clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma

• DOI: 10.1016/j.ejca.2022.05.004
• Publication Date: 2022-06-21T22:02:51Z
• Authors: Margherita Rimini; Teresa Macarulla; Valentina Burgio; Sara Lonardi; Monica Niger; Mario Scartozzi; Ilario G. Rapposelli; Giuseppe Aprile; Francesca Ratti; Federica Pedica; Helena Verdaguer; Floriana Nappo; Federico Nichetti; Eleonora Lai; Martina Valgiusti; Alessandro Cappetta; Carles Fabregat-F...; Matteo Fassan; Filippo De Braud; Marco Puzzoni; Giovanni L. Frass...; Francesca Simionato; Francesco De Cobelli; Luca Aldrighetti; Lorenzo Fornaro; Stefano Cascinu; Andrea Casadei-Ga...
• Keywords: Organoplatinum Compounds; Antineoplastic Agents; Genetic Profile; Prognosis; 3. Good health; Cholangiocarcinoma; 03 medical and health sciences; Bile Ducts, Intrahepatic; 0302 clinical medicine; Bile Duct Neoplasms; Mutation; BRCAness phenotype; Biliary tract cancer; Humans; Biliary tract cancer; BRCAness phenotype; PARP inhibitors; Platinum-based chemotherapy;; PARP inhibitors; Platinum-based chemotherapy

Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown.Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay.72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652).BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.