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TRENDS & PERSPECTIVES

New reports by an independent working group supported by CDC add fuel to the debate over the benefits of and need for further scrutiny of the hundreds of genetic tests that have been developed in recent years for use in treating cancer patients.

The debate comes at a time when hope is on the rise for more personalized medicine, including determining which patients will benefit from which therapies from molecular tests, many of which are laboratory developed tests (LDTs) and in vitro diagnostic multivariate index assays (IVDMIAs).

Three reports released in the January issue of Genetics in Medicine by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group looked at genetic tests that have been developed for three clinical situations involving cancer: Lynch syndrome, a hereditary cancer syndrome caused by mutations in MMR genes; early-stage breast cancer; and metastatic colorectal cancer.

In one report, the group said it had found enough scientific evidence to recommend offering genetic testing for Lynch syndrome to newly diagnosed colorectal cancer patients to reduce morbidity and mortality in their relatives. However, the EGAPP working group did not find enough evidence to recommend for or against two other types of genetic tests: one for breast cancer prognosis (e.g., MammaPrint and Oncotype DX), and the other to predict responses to a chemotherapy drug in metastatic colorectal cancer patients (e.g., Invader UGT1A1 molecular assay).

Alfred Berg, MD, a professor in the University of Washington Department of Family Medicine and chairman of the EGAPP working group, said of the hundreds of genetic tests available, the group chose to review those for diseases that are fairly common, not rare single-gene disorders. “Our goal was to evaluate those tests that would be important for those in the primary care setting (e.g., family medicine, pediatrics, nurse practitioners) to know whether they are helpful in improving clinical outcomes,” he said.

Manufacturers of the tests said that while they welcomed EGAPP’s initiative, the working group did not base its recommendations on all available evidence, and in some cases, were counter to earlier recommendations by other groups.

Berg said he was confident in the group’s work and its recommendations: “I feel good about how we reached our conclusions.”

Publishing its recommendations and methodology as EGAPP did should encourage others to evaluate the genomic tests as they become available, Berg said. “In the end,” he said, “we hope that there will be several organizations around the world that will be doing this kind of work. We may be trading reviews, and each will make recommendations appropriate to the healthcare systems we have. But the science should be the same regardless of who is looking for it.”

A month after the EGAPP reports were released, Agendia (Amsterdam) published a study in Breast Cancer Research and Treatment demonstrating the direct predictive ability of its IVDMIA MammaPrint. Bernhard Sixt, PhD, Agendia’s president and CEO, said this study and the others that will follow provide the direct evidence that EGAPP said was lacking and that it needed before it could give anything other than a neutral recommendation on MammaPrint. “The study provides evidence for MammaPrint and persuasively establishes gene expression profiling to improved outcomes,” Sixt said. He did not fault EGAPP because the evidence was not available at the time it did its report. “If EGAPP had known about it, its conclusions would have been different,” he said.

Sixt said the issue dramatizes the need for FDA to be the agency responsible for regulating IVDMIAs. To avoid confusion and conflicting reports, “oversight should reside with one body, and that body should be FDA,” he said. MammaPrint has received FDA clearance, and all MammaPrint tests are conducted in labs certified under the Clinical Laboratory Improvement Amendments (CLIA).

Emily Faucette, director of corporate communications at Genomic Health (Redwood City, CA), makers of Oncotype DX, said it clearly disagrees with EGAPP’s findings. EGAPP’s neutral recommendation flies in the face of those made by other leading oncology-based clinical organizations including the National Comprehensive Cancer Network and the American Society of Clinical Oncology. The test is used in patients with stage I or II estrogen receptor-positive, node-negative breast cancer to predict the benefit from chemotherapy and the risk for recurrence, and has broad acceptance from physicians and payers, she said.