A research article titled, “Personalized genomic analyses for cancer mutation discovery and interpretation” was published yesterday in the Science Translational Medicine. In brief, the research asserts that matched tumor and normal DNA from the same patient is necessary to prevent an unacceptably high number of false positive associations of genomic changes with targeted therapeutics in advanced cancer.
One of the biggest challenges facing physicians seeking informed targeted treatment decisions for their patients with cancer is the proliferation of unvalidated diagnostic tests with poor accuracy that fail to identify targetable alterations in their patients. While the article only describes research being performed at one institution, we believe this paper will fuel further confusion for physicians, and we are compelled to provide our perspective.
Foundation Medicine strongly disagrees that matched tumor and normal DNA from the same patient significantly improves the accuracy of identification of actionable mutations enabling better targeting for potential treatments in the vast majority of patients with cancer. We believe the only genomic alterations that should be considered for targeted treatment decisions are alterations with strong evidence that they are important in transforming a normal cell into cancer or maintaining a cancer cell’s viability once transformed, regardless of whether they are somatically acquired or are germline alterations; examples include activating point mutations (e.g. EGFR L858R), amplification of known oncogenes (e.g. HER2), loss of function alterations in tumor suppressor genes (e.g. PTEN), and gene fusions (e.g. ALK).
Foundation Medicine’s comprehensive genomic profiling assays are designed and validated to accurately detect these types of genomic change in real world clinical specimens. Through our proprietary sample preparation and computational biology algorithms, we identify the full complement of genomic alterations in all cancer-related genes, and we then remove the variants that should not be considered for treatment decisions. Such variants, whether somatically acquired or germline, are “variants of unknown significance” (VUS), and we believe they should not be used for treatment decisions because the overwhelming majority will prove to be non-pathogenic and could indeed expose the patient to costly and ineffective therapies.
This belief is echoed in our FoundationOne reports. The clinically and biologically relevant alterations tied to available targeted therapy options appear on the first page, which serves as a summary for the clinician. VUS’s, on the other hand, appear on the last page for completeness; they are noted but highlighted as not having evidence-based clinical relevance today.
In an ideal world, routinely obtaining a matched normal would allow more rapid discernment of the minority of VUS’s that may be pathogenic, which could be valuable for research efforts, but not for evidence-based treatment decisions. In addition, a matched normal can more quickly discriminate germline pathogenic mutations, which were identified in ~3% of patients in the research study, but reporting such findings to physicians (and patients) is still a matter of intense debate and if reported, should come with appropriate genetic counseling. Foundation Medicine’s approach of recommending germline testing (performed by other accredited labs) to the ordering physician when such variants are identified allows physicians the necessary versatility in how best to approach such variants with patients and to involve a genetic counselor, if required.
Genomic sequencing is a serious responsibility, and important decisions will be made with the test results. For this reason, we remain strong advocates of the FDA’s involvement in this area. Foundation Medicine’s comprehensive genomic profiling approach identifies close to 100 percent of the clinically relevant alterations, even in impure clinical specimens, without the need for a matched normal specimen.