Supplementary biomarker testing in molecular tumor boards increases actionable therapy recommendations: a prospective real-world study of 658 patients

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.