109P - DNA damage repair pathways in biliary tract cancer: A new target for precision medicine?

Background

Biliary tract cancers (BTC) show a high mortality quote and heterogeneity in terms of clinical and molecular profile. Aim of this work is the molecular characterisation of a BTC cohort focusing on genomic alterations of DNA damage repair (DDR) genes.

Methods

A retrospective analysis of the clinical course and mutation status of patients with locally advanced or metastatic BTC treated at the West German Tumour Centre of the University.113 (96%) patients received the MAPK-TRON DNA-based NGS panel (47 included genes), 81 (72%) patients the AmoyDx HRD Focus panel (32 genes), which focuses on DDR genes. DNA mismatch repair (MMR) status was determined in 59 patients by immunohistochemistry and DNA sequencing. 33 patients received an RNA fusion assay (FusionPlex CTL panel [Archer]) too. The primary endpoints of the study were the time in first palliative regime till disease progression (Time on Treatment=TTE) and the overall survival (OS). To form a clear defined DDR cohort, the annotation of DDR gene alterations was not only performed by the local Institute of Pathology but also by quering the databases ClinVar and COSMIC.

Results

The cohort of the present study was divided in 7 molecular subgroups: TP53 (34/118, 29%), KRAS (25/118, 21%), IDH1/2 (18/118, 15.2%), PIK3CA (8/118, 7%) and BRAF (6/118, 5%) and FGFR2 (5/33, 15%, with different fusion partners). BRAF- und PIK3CA-mutated BTC showed a slight benefit in primary endpoints, whereas KRAS- and TP53- mutated showed worse prognosis. 13 DDR-mutated BTC were identified (13.5%). The patients with DDR mutations showed a weak but coherent benefit in all primary endpoints (OS, TTE, TTE under platinum-based therapy). Comparison of our data with BTC data of The Cancer Genome Atlas (TCGA) in cbioportal showed a similar trend in OS (19,1 months in TCGA data vs 22,7 months in the studied cohort).

Conclusions

Pathogenic alterations in DDR pathway genes were seen in 13.5% of the cases studied. DDR-deficient BTC patients showed a trend for better OS and TTE representing a potential subgroup that could benefit from targeted treatment strategies, like PARP-inhibitors. Moreover the slight benefit of DDR-mutated BTC under platinum-based therapy supports the hypothesis of better response of DDR-mutated tumours to platinum.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Kasper-Virchow: Other, Personal, Sponsor/Funding, Honoraria from Merck Serono, MSD, Novartis, BMS, Amgen, Roche, Sanofi-Aventis, Servier, Incyte and Lilly; Research Funding from Merck Serono, Lilly, BMS, Roche: Merck Serono, MSD, Novartis, BMS, Amgen, Roche, Sanofi-Aventis, Servier, Incyte and Lilly. All other authors have declared no conflicts of interest.