Biomarker testing in biliary tract cancer

Biomarker testing in biliary tract cancer (BTC) has emerged as a critical tool for guiding precision therapy, improving treatment outcomes, and understanding the molecular landscape of this heterogeneous disease. Below is a detailed overview of biomarker testing in BTC based on the context provided:

### Importance of Biomarker Testing in BTC

Biomarker testing, particularly through next-generation sequencing (NGS), is essential for identifying actionable genomic alterations (GA) that can be targeted with precision therapies. BTC is a rare and aggressive cancer with limited treatment options, and molecular profiling enables clinicians to identify specific genetic mutations or alterations that can inform personalized treatment strategies.

### Implementation of NGS in BTC

1. **Study Overview**: A large multicenter study involving 1,521 BTC patients across 18 centers in Germany and Austria analyzed the implementation of NGS-based testing in clinical practice.

2. **Testing Platforms**: Twenty-four different sequencing panels were used across centers, revealing significant variability in assay design, gene coverage, and reporting. Despite this variability, broad sequencing assays captured a similar number of actionable genomic alterations, indicating that essential targets are generally well-represented across platforms.

3. **Standardization Challenges**: A comparison between FoundationOne CDx and TruSight Oncology 500 demonstrated discrepancies in reported alterations due to differences in panel coverage and analysis pipelines. This highlights the need for harmonized biomarker testing protocols across Europe to ensure consistent clinical interpretations.

### Key Findings from Biomarker Testing in BTC

1. **Most Frequent Mutations**: The most commonly detected mutations were TP53 and KRAS, followed by FGFR2, IDH1, and ERBB2 (HER2), which showed subtype-specific distribution across intrahepatic and extrahepatic tumors.

2. **Subtype Distribution**:

• **Intrahepatic cholangiocarcinoma (iCCA)**: Comprising 65% of cases, iCCA was enriched with FGFR2 fusions and IDH1 mutations.
• **Extrahepatic tumors**: KRAS and ERBB2 alterations were more frequent in extrahepatic cholangiocarcinoma and gallbladder cancers.

3. **Actionable Alterations**: Approximately 40% of BTC patients harbored actionable mutations, with key targets including:

• FGFR2 alterations (14%)
• HER2 amplifications (3%)
• BRAFV600E mutations (2%)
• IDH1 mutations

### Clinical Impact of Biomarker Testing

1. **Targeted Therapy Utilization**: Despite the identification of actionable alterations in 40% of patients, only 13.5% (205 patients) actually received genotype-matched targeted therapy, highlighting a significant implementation gap between testing and treatment.

2. **Survival Benefits**: Patients who received targeted therapies based on biomarker testing had significantly improved outcomes:

• Median overall survival (mOS) of 31.8 months with targeted therapy versus 22.8 months without targeted therapy (p<0.01).
• FGFR2 alterations treated with FGFR inhibitors led to an mOS exceeding 48 months from diagnosis.
• HER2-amplified tumors showed poor prognosis without targeted therapy (10.5 months mOS) but improved markedly (27.6 months) with HER2-directed agents.
• BRAFV600E mutations were associated with a poor prognosis without treatment (7.4 months mOS) but demonstrated significant improvement (31.8 months) under targeted therapy.

3. **Other Findings**:

• IDH1 mutations were not independently prognostic, but treatment with ivosidenib showed a trend toward improved survival in real-world settings.
• BRCA1/2 mutations may benefit from PARP inhibitors or platinum-based therapies, as some patients achieved long-term survival.
• Negative prognostic markers included TP53 mutations, MTAP deletions, and CDKN2A/B deletions, which were associated with worse survival.
• Positive prognostic markers included BAP1 alterations, which correlated with improved survival (31.2 months vs. 24.6 months) and often co-occurred with FGFR2 fusions.

### Advances and Challenges in Biomarker Testing

1. **Improved Testing Timelines**: The median time from diagnosis to molecular testing decreased significantly from 107 days (before 2021) to 37 days (after 2021), reflecting better integration of molecular profiling into clinical workflows.

2. **Need for Standardization**: The study emphasizes the importance of standardized, comprehensive molecular profiling to reduce discrepancies across testing platforms and ensure consistent clinical interpretations.

3. **Real-World Integration**: Despite advances in biomarker testing, the low rate of targeted therapy utilization underscores the need for improved access to precision treatments and better alignment between testing results and clinical decision-making.

### Core Conclusion

Biomarker testing, particularly through NGS, is a transformative approach for BTC management. By identifying actionable genomic alterations, clinicians can tailor treatments to improve patient outcomes. However, challenges such as variability in testing platforms, delays in testing, and limited access to targeted therapies must be addressed. The study advocates for harmonized biomarker testing protocols and broader integration of molecular profiling into routine clinical practice to maximize the benefits of precision medicine for BTC patients.