More Work Needed Before Multigene Mutation Testing Ready for Routine Clinical Practice
Circulating free tumor DNA techniques might improve the ability to match tumor mutations to genotype-matched targeted therapies.
Circulating free tumor DNA techniques might improve the ability to match tumor mutations to genotype-matched targeted therapies and bring precision medicine to the clinic, according to a presentation at the 2016 San Antonio Breast Cancer Symposium.
But “further evidence is needed before multigene testing can be recommended in routine clinical practice,” reported Philippe Bedard, MD, FRCPC, of the Princess Margaret Cancer Centre in Toronto, Canada.
Multigene testing panels are designed to identify driver mutations that promote tumor cell proliferation and survival, and inform individualized treatment decisions involving targeted drugs, Dr Bedard noted. “Druggable” genomic aberrations are now known.
Several precision medicine programs and initiatives use multigene panels to match patients whose tumors harbor particular driver mutations, with agents that target the signaling pathways involved.
Despite a “high level of enthusiasm,” however, only a small proportion of patients in these programs wind up receiving a genotype-matched therapy, he reported.
MD Anderson Cancer Center's Institutional Profiling program has sequenced tumor mutations for 2000 patients, for example. But only 54 (3%) of patients received genotype-specific treatment as a result. Similarly, for the National Cancer Institute (NCI)-MATCH program's preliminary phase, 2.5% of 645 patients received gene-specific therapies.
To move from promising concept and lab results into the clinic, gene tests must exhibit both clinical validity and clinical utility, meaning that results lead to clinical decisions “shown with a high level of evidence to improve outcomes,” Dr Bedard said. “They decrease toxicity or improve quality of life, or improve survival.”
One problem is that relatively few mutations are “druggable,” Dr Bedard noted. “Access to ‘best in class' targeted therapies is limited,” he said. “There are geographic and institutional barriers for trial referrals, especially for patients with advanced metastatic disease who must travel to participate.”
An alternative to biopsying metastatic tumors for gene testing, which is not always feasible, is to search patients' blood for circulating free tumor DNA—“a very exciting platform,” Dr Bedard said. “It offers opportunities like greater sensitivity for PCR and next-generation sequencing. Collecting blood at the point of care is a nice alternative to biopsying.”
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Serial “liquid biopsies” of circulating DNA also should allow detection and characterization of treatment-emergent and polyclonal mutations, and the monitoring of tumor responses to treatment, he said.
Before these tests can be routinely used in the clinic, however, assays must be standardized, optimal thresholds for clinical decision-making must be identified, and discordance with tissue-based gene testing must be reconciled.
- Bedard P. Clinical utility of multi-gene testing in metastatic breast cancer. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.