Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

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.

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

“… 26 A recent clinical WGS study of 83 patients with sarcoma demonstrated refinement of diagnosis in 14% of cases, nomination of actionable biomarkers in 36% of tumors, and detection of germline cancer predisposition variants in 8% of patients. 27 WGS may be particularly impactful in sarcoma given its position as one of the most heterogeneous of all cancers, with the newest WHO classification denoting 175 different soft tissue and bone tumors, many distinguishable by genomic features. 28 , 29 WGTS may also prevent patients from being misassigned to therapies that are unlikely to provide any efficacy while at the same time bringing considerable clinical toxicity to patients and financial burden to the health care system.…”

Sporadic Metastatic Malignant Peripheral Nerve Sheath Tumour with an NF1 Mutation Responding to Trametinib: A Case Report

“…Historically, many sarcoma subtypes have been grouped together for diagnosis and treatment purposes, leading to suboptimal outcomes. Recent studies have highlighted the importance of molecular characterization to improve diagnostic accuracy and impact treatment plans [8] . At present, the use of NGS in soft tissue sarcomas has not been defined but is likely to become more widely used.…”

Complete genomic characterization in patients with cancer of unknown primary origin in routine diagnostics

“…Three patients have been described elsewhere. 16 CUPs were defined as tumors with unknown origin or histological type. CUPPA was tested prospectively in all patients in the independent validation cohort.…”