Abstract 68P
Background
Biliary tract cancers (BTC), which include intra-hepatic cholangiocarcinoma (ICC) and extra-hepatic cholangiocarcinoma (ECC), and gallbladder cancers (GC), is an aggressive disease with poor prognosis. The role of DDR pathway genes alterations as a predictive biomarker for the response to platinum-based chemotherapy and Immunotherapy has been reported in many cancers. But the DDR gene characteristics in different subtype BTCs, and its correlation with immunogenic marker such as tumor mutation burden (TMB), microsatellite instability (MSI) and PD-L1 expression was unknown.
Methods
Tumor tissue samples from biliary tract cancers (BTC) were analyzed using next generation sequencing (panel on 381/733-gene). TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (SP142). Prognostic data of 102 Chinese ICC patients were obtained from cbioportal (Shanghai, Nat Genet 2014). Germ-line or somatic mutations of 180 DDR pathway genes (including Mismatch Repair and Homologous Recombination) were classified as DDR gene mutations.
Results
The DDR mutation frequency in BTC was 19% (191/1193), among 15.33% (125/815) of ICC, 16.67% (4/24) of ECC, and 17.51% (62/354) of GC. ATM mutation was the highest frequency gene in both three type tumors (4.91% of ICC, 5.60% of GC and 8.57% of ECC). In ICC, the highest frequency DDR germ-line mutation gene was BRCA2 (20.00%), followed by PALB2 (12.31%) and BRCA1 (9.23%). In DDR mutation ICC group, the most frequently mutated genes were TP53 (8.93%), KRAS (5.21%) and ARID1A (3.87%), which were both significantly lower than wild-type. DDR mutation was associated with higher TMB (P < 0.01), further in MSS tumors (P < 0.001). No correlation was found with PD-L1 expression. The overall survival (OS) of DDR mutation group (n=32) were shorter than wild-type group (n=70) (OS, median, 10.00 vs 21.00 months; HR 1.5; P = 0.079).
Conclusions
The DDR pathway genes alteration characteristics was presented in different BTC subtypes, and was associated with a higher TMB level. These data provide rationale for future investigation of clinical therapy in DDR mutation BTC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University.
Funding
Has not received any funding.
Disclosure
T. Chen, W. Xie, M. Huang: Full/Part-time employment: 3D Medicines Inc. All other authors have declared no conflicts of interest.