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Supplementary biomarker testing in molecular tumor boards increases actionable therapy recommendations: a prospective
Alexander Scheiter1,2, Simon Mellin3, Felix Keil3
1Institute of Pathology, University of Regensburg, 93053, Regensburg, Germany. Alexander.Scheiter@klinik.uni-regensburg.de.
Background:
Molecular tumor boards (MTBs) are essential for selecting therapies for patients with rare and advanced cancers. We hypothesized that integrating biomarkers beyond targeted DNA/RNA next-generation sequencing (NGS) could increase actionable findings. Human epidermal growth factor receptor 2 (HER2)-low status has emerged as a critical biomarker in breast cancer, with potential relevance across other tumor types. Homologous recombination deficiency (HRD) is pivotal for the application of Poly(ADP-Ribose)-Polymerase (PARP) inhibitors in ovarian and breast cancer, although its role in other malignancies remains unclear. Antibody-drug conjugates (ADCs) are expanding precision oncology, with promising biomarkers like Trop-2, Nectin-4, and folate receptor alpha (FRα) showing potential across multiple tumor entities.
Methods:
Tumors were analyzed using the TSO500® panel, enabling tumor mutational burden (TMB) readout. HER2 status was assessed via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), alongside antibody-drug conjugate (ADC) IHC, microsatellite instability (MSI) polymerase chain reaction (PCR), mismatch repair (MMR) IHC, programmed death-ligand 1 (PD-L1) IHC, and HRD analysis. Cases were discussed weekly, and outcomes were systematically tracked. Data analysis evaluated the benefit of additional biomarker assessments.
Results:
Among 658 patients, 329 received therapy recommendations, 182 based on supplementary biomarker analyses. One hundred recommendations were implemented, with 37% attributed to supplementary diagnostics. Among 64 response-evaluable patients, the clinical benefit rate (complete response + partial response + stable disease) was 45.3%. HER2-low status notably expanded targeted therapy options across tumor types, with similar implementation rates for HER2-low and HER2-amplified tumors. HRD analysis refined stratification in tumors with mutations in homologous recombination repair (HRR) genes beyond BRCA1/2, including PALB2, ATM, and CHEK2. ADC IHC supported 20 recommendations and two therapy implementations.
Conclusions:
The integration of additional biomarker assessments into MTB workflows enhances precision oncology by expanding the pool of patients eligible for targeted therapies.
Insights
Integrating additional biomarkers beyond next-generation sequencing (NGS) in molecular tumor boards (MTBs) significantly expands eligibility for targeted therapies in advanced cancers. This approach improves clinical benefit rates and enhances precision oncology outcomes.
Area of Science:
- Oncology
- Genomics
- Biomarker Discovery
Background:
- Molecular tumor boards (MTBs) are crucial for guiding therapy selection in rare and advanced cancers.
- Next-generation sequencing (NGS) is a standard diagnostic tool, but integrating additional biomarkers may uncover more actionable findings.
- Emerging biomarkers like Human Epidermal Growth Factor Receptor 2 (HER2)-low, homologous recombination deficiency (HRD), and targets for antibody-drug conjugates (ADCs) show promise across various tumor types.
Purpose of the Study:
- To investigate the impact of integrating supplementary biomarker analyses beyond standard NGS on therapy recommendations and clinical outcomes within molecular tumor boards.
- To assess the utility of biomarkers such as HER2-low status, HRD, and ADC targets in expanding treatment options for patients with advanced cancers.
- To evaluate the clinical benefit rate in patients receiving therapies guided by comprehensive biomarker assessments.
Main Methods:
- Tumor samples were analyzed using the TSO500® panel for tumor mutational burden (TMB).
- HER2 status was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).
- Additional assessments included ADC IHC, microsatellite instability (MSI) PCR, mismatch repair (MMR) IHC, programmed death-ligand 1 (PD-L1) IHC, and HRD analysis. Weekly MTB discussions and outcome tracking were performed.
Main Results:
- Of 658 patients, 329 received therapy recommendations, with 182 based on supplementary biomarkers. One hundred recommendations were implemented, 37% stemming from these supplementary diagnostics.
- The clinical benefit rate was 45.3% among 64 response-evaluable patients.
- HER2-low status broadened targeted therapy options, HRD analysis refined stratification for PARP inhibitors, and ADC IHC supported 20 recommendations and 2 implementations.
Conclusions:
- Integrating additional biomarker assessments into MTB workflows significantly enhances precision oncology.
- This comprehensive approach expands the pool of patients eligible for targeted therapies, leading to improved treatment strategies.
- The study highlights the value of multi-modal biomarker analysis in maximizing therapeutic opportunities for cancer patients.
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