# Clinical practice and implications of biomarker testing in biliary tract cancer: An observational study

## TL;DR

This study examines how biomarker testing is used in biliary tract cancer and finds that standardized testing improves patient outcomes.

## Contribution

The study provides real-world insights into molecular testing practices and highlights the prognostic significance of specific genomic alterations in biliary tract cancer.

## Key findings

- Multiple NGS panels are used, leading to variability in genomic variant detection rates across centers and platforms.
- Targeted treatment based on actionable alterations was associated with improved patient survival.
- Genomic alterations like BRAFV600E and ERBB2 copy number variations may be linked to poor survival.

## Abstract

Biliary tract cancers (BTC) are aggressive malignancies with limited treatment options. Owing to the high frequency of actionable genomic alterations (GA) and the availability of targeted therapies, molecular testing has become increasingly important; however, its clinical implementation remains inconsistent. This study aimed to evaluate real-world molecular testing practices, characterize the BTC molecular landscape, and assess the prognostic and predictive relevance of selected GA.

We retrospectively analyzed genomic and clinical data from 1,521 patients treated at 18 centers in Germany and Austria. A side-by-side comparison of clinical grade reports generated on two different sequencing platforms was performed for 90 patients.

Twenty-four different NGS panels were used across 18 centers. A comparative analysis highlighted the significant variability in reports used to inform therapeutic decisions in clinical practice. Although there were substantial differences in the number of GA covered, the broader panels identified a similar number of actionable GA, indicating that key therapeutic targets are sufficiently represented. Integration with clinical data suggested that certain GA, such as HER2 amplifications (3%), BRAFV600E mutations (2%), and FGFR2 alterations (14%), may have prognostic significance beyond their predictive value. Patients with actionable alterations (610, 40%) that were treated accordingly (n = 204, 13%) had prolonged overall survival (31.8 months vs. 22.8 months, p <0.01).

Standardized biomarker testing is crucial for effective integration of targeted therapies in the management of BTC. Our findings reinforce the value of targeted treatments and underscore the predictive and prognostic significance of selected GA.

Genomic profiling is recommended in patients with biliary tract cancers (BTC) but lacks harmonization across platforms and centers. By retrospectively analyzing genomic and clinical information from 1,521 patients with BTC diagnosed and treated at 18 centers in Germany and Austria, we provide real-world insights into the implementation of molecular profiling in BTC, highlighting variability in next generation sequencing-based testing and its impact on the detection of genomic alterations. Standardized molecular testing strategies will be key to enable the integration of more consistent and comparable genomic datasets across studies. Further, by elucidating the prognostic relevance of individual genomic alterations, our insights carry significant implications for interpreting single-arm clinical trials within genomically stratified patient cohorts and underscore the importance of randomized studies to delineate the benefit of targeted therapies.

Image 1

•Multiple NGS panels are used to assess actionable alterations in cholangioarcinoma.•Detection rates of genomic variants vary by center and platform.•Key actionable alterations were consistently reported.•BRAFV600E and copy number variations in ERBB2 and MTAP/CDKN2A/B may be associated with poor survival.•Targeted treatment was associated with improved outcomes.

Multiple NGS panels are used to assess actionable alterations in cholangioarcinoma.

Detection rates of genomic variants vary by center and platform.

Key actionable alterations were consistently reported.

BRAFV600E and copy number variations in ERBB2 and MTAP/CDKN2A/B may be associated with poor survival.

Targeted treatment was associated with improved outcomes.