Analytic Validation of Cancer Genomic Profiling Assay Demonstrated

A 24-month, multi-institution collaboration demonstrated the analytic validation of a cancer genomic profiling assay.

The Foundation Medicine (Cambridge, MA, USA) assay, called Foundation One, is a next-generation sequencing based test used to characterize all classes of molecular alterations across 287 cancer-related genes from routine formalin-fixed, paraffin-embedded clinical specimens. The results were published in the October 2013 online edition of Nature Biotechnology. The publication also describes clinical application of this assay across 2,221 consecutive patient cases.

Genomic testing is becoming critical to deliver the most effective care for patients with cancer. However, analytic validation of NGS-based tests presents a challenge to clinical application due to the fact that thousands of potential variants may be detected, and most have no gold standard with which to compare. The publication in Nature Biotechnology is the first to apply and extend the guidelines established by the Next-Generation Sequencing: Standardization of Clinical Testing workgroup2 to validate a clinical sequencing-based assay for cancer, therefore setting the standard for validation of targeted NGS in cancer.

Foundation Medicine assessed the accuracy and precision of FoundationOne using reference samples of pooled cell lines and hundreds of clinical cancer specimens with diagnostic testing results generated by established clinical assays. FoundationOne was found to be highly accurate in identifying genomic alterations, including sensitivity greater than 99% for detection of base substitutions, 98% for detection of insertions and deletions, and greater than 95% for detection of copy number alterations, while maintaining greater than 99% specificity. Application of FoundationOne to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumor samples, three times the number of actionable alterations detected by other currently available diagnostic tests. Alterations are defined as clinically actionable if linked to an FDA approved targeted therapy in the tumor under study or another solid tumor, a known or suspected contraindication to a given therapy, or an open clinical trial for which the alteration confers patient eligibility.

"Clinical cancer care is undergoing a fundamental shift toward treating patients based on the specific molecular drivers of their disease, and a sequencing-based diagnostic assay that comprehensively and accurately characterizes the genomic alterations occurring within an individual's tumor is essential for the implementation of this therapeutic strategy," stated Lajos Pusztai, MD, co-director of the Cancer Genetics and Genomics Research Program at Yale Cancer Center and coauthor of the study. "This study is instrumental in establishing the technical validity of next-generation sequencing in the clinic and enables the practice of precision medicine wherein the molecular characterization of a patient's tumor informs the patient's individual treatment."

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