Liquid Biopsy to Detect BRAFV600 Mutations in Advanced Cancers Shows Promise

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Cell-free DNA is released into circulation by cancer cells undergoing apoptosis or necroptosis.
Cell-free DNA is released into circulation by cancer cells undergoing apoptosis or necroptosis.

The PCR-based Idylla BRAF mutation test, a liquid biopsy that measures BRAFV600 mutations in cell-free DNA, appears to be feasible and concordant with standard tests of archival tumor biopsy samples, according to a new study published in Molecular Cancer Therapeutics. The test has a 60- to 90-minute turnaround time and may help predict therapy response.1

Investigators found that cell-free DNA is released into circulation by cancer cells undergoing apoptosis or necroptosis in the primary or metastatic cancer lesions. This DNA can be detected in the blood. “It is really only 60 minutes to do this. So, the speed is unprecedented,” said study investigator Filip Janku, MD, PhD, who is assistant professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston. “The real cost should not be higher than a few hundred dollars, making it very cost effective.”

According to Dr Janku, obtaining blood samples to isolate cell-free DNA is a minimally invasive procedure that involves less patient risk and comes at a lower cost, in contrast with tissue biopsies. The samples can be collected at multiple time points and provide valuable information about the genetic changes that occur during the course of the disease. This information may be vital because the genetic changes are ongoing.

Dr Janku and his colleagues used plasma samples collected from 160 patients with a range of advanced cancers known to have BRAFV600 mutation status, as determined using paraffin-embedded tumor tissue samples. The most common tumor types were colorectal cancer and melanoma. The researchers analyzed the plasma samples for BRAFV600 mutations using the Idylla system, which is a fully integrated, quantitative, allele-specific, real-time, PCR-based test that uses a single disposable cartridge.

The test had 88% concordance with the results from the standard tests that used paraffin-embedded tissues in samples collected at baseline. The concordance was 90% when results from samples collected at any time point during the course of the treatment were compared. The new test had 73% sensitivity and 98% specificity, with a positive-predictive value of 96% and a negative-predictive value of 85%.

The researchers also found that the amount of BRAFV600 mutations in cell-free DNA was predictive of overall survival. Patients who had a lower percentage of BRAF-mutant cell-free DNA percentage (2% or less) had an overall survival rate of 10.7 months, compared with 4.4 months in those with a higher percentage of BRAFV600 mutations in their samples (more than 2%). The study showed, however, that the amount of cell-free DNA present in the plasma alone was not predictive of survival outcomes.

RELATED: BRAF mutations in non-small cell lung cancer

In patients whose baseline samples were negative for BRAFV600 mutations, the time to treatment failure (TTF) was 13.1 months with BRAF and/or MEK inhibitors. The TTF was just 3 months for those whose baseline samples were positive for the mutation. Patients whose baseline samples were negative for BRAFV600 mutations were 69% less likely to experience therapy failure than those whose baseline samples were positive for the mutation.

Dr Janku said that high amounts of BRAF-mutant cell-free DNA before therapy is a negative prognostic biomarker for overall survival and outcomes of targeted therapy. “The test works for all tumor types. However, there are differences in shedding of cell-free DNA into circulation. For instance, brain tumors or papillary thyroid cancers have smaller amounts of tumor cell-free DNA,” Dr Janku told Cancer Therapy Advisor. “I think the test can be commercially available within 18 to 24 months. In fact, it was launched in the European Union for testing of tumor tissue in fall 2014.”2

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