P-173 Extended molecular profiling in patients with biliary tract cancers: Impact of the BRCAness phenotype in patients management

Although the pathogenetic role of BRCAness phenotype in other malignancies, such as breast and ovarian cancer, has been widely investigated, its role in biliary tract cancer (BTC) is still unclear. Here we report epidemiological, clinical and molecular data from a single-institution BTC cohort of patients. We retrospectively enrolled BTC-patients treated at Pisa University Hospital between 2015 and 2022, whose tissue specimens had been analyzed through FoundationOne (FO) platform. BRCAness-related genes were identified following evaluation of FO results together with a genetic consultant. The following genes have been identified as part of BRCAness-complex: ARID1A, ATM, BAP1, BARD1, BRCA1 and BRCA2, BRIP1, CHECK2, FANCA, NBN, PALB2, RAD51C and TP53 . Alterations were subdivided into 3 clusters: certainly pathogenetic, variants of unknown significance (VUS) and benign variants. In the cohort of BRCAness-mutated patients we included only variants certainly pathogenetic. The primary endpoint was to assess frequency of BRCAness phenotype in BTC; secondary objectives were to explore its relationship with other clinical-pathological features and with outcome. Of 60 enrolled patients, 33 were diagnosed with intrahepatic cholangiocarcinoma, 11 with Klatskin tumor, 5 with extrahepatic cholangiocarcinoma, 6 with gallbladder cancer and 5 with ampullary neoplasm. All but three patients underwent first line chemotherapy for advanced disease. Twenty-one patients (35%) had a family history of neoplasm in at least one first-degree relative and 11 of them (18%) had a personal anamnesis of pre-existing neoplasia. Thirty-three patients (55%) presented mutation of BRCAness complex. Between BRCAness mutated patients, 15 arbored pathogenic alteration, 13 VUS and 5 benign variants. The most common mutation occurred at ARID1A (44.8%), BRCA1 and BRCA2 (17.2%), BAP1 (13.8%), ATM (10.3%), FANCA (6.9%), CHECK2 (3.4%) and PALB2 (3.4%) genes. Four patients with somatic pathogenetic variant of BRCA1 and BRCA2 underwent genetic counseling and germline testing; the germline presence of pathogenic somatic variant was confirmed with a rate of concordance between somatic and germline of 100%. No correlation was found between BRCAness phenotype and age (p = 0.352), family history (p = 0.251) and site of primary tumor (p = 0.079). At a median follow up of 36.7 months, (95% CI 29.5-43.9), BRCAness mutated patients had a significantly longer median overall survival (mOS) compared with BRCAness wild type ones, respectively 53.9 (95% CI 20.7-87.1) vs 28.8 (95% CI 25.9- 31.7) months (p=0.018). At a multivariate analysis, BRCAness status (HR 0.31; 95% CI 0.11-0.86, p = 0.024) confirmed its independent prognostic role for OS. In the 78% of patients receiving a platinum-based first-line chemotherapy, no significant difference was observed in OS from stage IV diagnosis according to BRCAness status (mOS 29.4 vs 20.1 months, respectively, p > 0.05). In our retrospective series, a significant proportion of patients with hereditary forms linked to BRCA1 and BRCA2 was found. The implementation of a wider molecular characterization is important not only for therapeutical implication but also for identifying any potential carriers of somatic alteration that could refer patients to a specific genetic counseling. BRCAness phenotype, moreover, seems to identify patients with a better prognosis, thus shedding light on its clinical significance.