Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

SIMPLE SUMMARY: Sarcomas are a heterogeneous group of diagnostically complex tumors with a poor prognosis and limited number of therapy options. Molecular profiling can aid pathological classification by detection of diagnostic biomarkers, and identify therapeutic opportunities for biomarker-based targeted treatment. Furthermore, pathogenic germline variants are present in ~10% of sarcoma patients, but remain often unrecognized. To explore the full spectrum of possible biomarkers in current molecular diagnostics, multiple and often iterative testing is required. In clinical practice, molecular profiling is selectively performed for specific patient groups with certain diagnoses already in mind. As a result, relevant diagnostic and/or actionable biomarkers are potentially overlooked. Whole genome sequencing (WGS) provides a complete, unbiased genomic characterization and detection of all possible genomic events within one diagnostic test. By applying prospective WGS in (suspected) advanced sarcoma patients in a tertiary sarcoma referral center, we uncover the missed potential of a targeted approach of molecular diagnostics. ABSTRACT: With more than 70 different histological sarcoma subtypes, accurate classification can be challenging. Although characteristic genetic events can largely facilitate pathological assessment, large-scale molecular profiling generally is not part of regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of diagnostic and actionable genomic characteristics, and of underlying hereditary conditions. WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcomas in a tertiary referral center. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. In 12/83 patients (14%), the genomic profile led to revision of cancer diagnosis, with change of treatment plan in eight. All twelve patients had undergone multiple tissue retrieval procedures and immunohistopathological assessments by regional and expert pathologists prior to WGS analysis. Actionable biomarkers with therapeutic potential were identified for 30/83 patients. Pathogenic germline variants were present in seven patients. In conclusion, unbiased genomic characterization with WGS identifies genomic biomarkers with direct clinical implications for sarcoma patients. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcoma patients, WGS can be an important extension of the diagnostic arsenal of pathologists.