56P - Multi-omic profiling in cholangiocarcinoma to enable scientific advancement within the DKFZ/NCT/DKTK MASTER study

Background

Current international guidelines recommend tumor molecular profiling to be performed in all patients affected by advanced cholangiocarcinoma (CCA) and eligible for systemic treatment. While targeted genomic panels are most widely adopted in clinical practice, the role of a comprehensive, multi-omic characterization is still to be demonstrated.

Methods

We report molecular and clinical results of patients affected by CCA and enrolled in the German Cancer Consortium (DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) program between February 2014 and December 2021. Tumor whole-genome/whole-exome (WGS/WES) and RNA sequencing (RNAseq) was performed according to MASTER's standardized workflow, and eligibility for molecularly-informed therapies was discussed within MASTER’s molecular tumor board. In addition, we report reverse translational experiments investigating novel biological findings identified in this cohort.

Results

Among 131 registered patients, molecular profiling was successful in 115 cases (89%). RNAseq was obtained in 89 (77%) cases. Comparative evaluation of molecular profiles highlighted ultra-rare distinctive features of CCA, including an enrichment of PTPRM gene fusions (5.6% vs. 2%; in the entire MASTER cohort, p=0.018), likely causing loss of PTPRMś phosphatase tumor suppressor function. PTPRM knockdown in vitro resulted in increased migration and invasion in CCA cell lines. After a median of 3 prior treatment lines, MASTER-informed therapy was implemented in 23 (20%) patients, of whom 4 were treated according to a composite biomarker of homologous recombination deficiency (HRD, i.e. the TOP-ART score), while 12 according to RNAseq-based recommendations (gene fusions and/or overexpression), including 1 case with a MET fusion. Median PFS on molecularly-informed therapy was 4.6 (3.7 - 12.7) months, while ORR and DCR were 30% and 43%, respectively.

Conclusions

Multi-omic profiling of CCA within the MASTER program uncovers novel biological mechanisms and therapeutic opportunities. By the identification of ultra-rare and composite biomarkers, MASTER-guided therapies resulted in significant clinical benefit also in heavily pretreated patients.

Clinical trial identification

NCT05852522.

Editorial acknowledgement

Legal entity responsible for the study

National Center for Tumor Diseases - NCT.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.