The DNA damage repair (DDR) pathway in biliary tract cancer (BTC): a new Pandora’s box?

TPS4166 Background: Ceralasertib (AZD6738) is a selective ATR inhibitor that causes stalled replication forks to collapse, leading to accumulation of double-strand DNA breaks, which is expected to have synergistic anti-tumor effects with immune checkpoint inhibitors (ICI) or PARP inhibitors. First, accumulation of DNA damage by ceralasertib induces tumor cell death, leads to the release of tumor-specific antigen, changing the tumor microenvironment to promote antigen presentation and enhances the anti-tumor effect of ICI. Second, by simultaneously inhibiting two DNA-damage response (DDR) pathways downstream of PARP and ATR, cancer cells are unable to repair damaged DNA, leading to cell death. Ceralasertib has demonstrated promising anti-tumor activity and manageable toxicity in combination with durvalumab or olaparib in solid tumors in a phase 1 study (NCT02264678). In preclinical studies, ceralasertib has shown potent anti-tumor effects in biliary tract cancer (BTC) as a monotherapy and in combination with chemotherapy (Nam, et al, 2019). Methods: This is an open-label, phase 2 umbrella study assessing the efficacy of ceralasertib in combination with durvalumab or olaparib in patients with advanced BTC. Eligible patients have histologically confirmed BTC (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), have failed at least one chemotherapy and have ECOG performance status of 0-1. Patients who have received prior ICI, ATR or PARP inhibitor are excluded. Each cycle consists of 4 weeks. In ceralasertib /durvalumab cohort, 37 patients will receive durvalumab 1.5g on day 1 and ceralasertib 240mg twice daily on days 15-28. In ceralasertib /olaparib cohort, 37 patients receive ceralasertib 160mg once daily on days 1-7 and olaparib 300mg twice daily on days 1-28. The primary endpoint is disease control rate, with key secondary endpoints including overall response rate, progression-free survival, overall survival, and safety. Tissue and blood samples are being collected for translational biomarker studies. Clinical trial information: NCT04298021.

Download Full-text

Identification and prognostic impact of PBRM1 mutations in biliary tract cancers: Results of a comprehensive molecular profiling study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4022 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4022-4022

Author(s):

Kai Zimmer ◽

Florian Kocher ◽

Gerold Untergasser ◽

Alberto Puccini ◽

Joanne Xiu ◽

...

Keyword(s):

Dna Damage ◽

Chromatin Remodeling ◽

Biliary Tract ◽

Dna Damage Repair ◽

Parp Inhibitors ◽

Molecular Profiling ◽

Gene Set Enrichment Analysis ◽

M1 Macrophages ◽

Biliary Tract Cancers ◽

Damage Repair

4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p < 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p < 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p < 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p < 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p < 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p < 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.

Download Full-text