Hypermutated circulating tumor DNA on “liquid biopsy” predicts responses to checkpoint inhibitor-based immunotherapy in patients with various malignancies, researchers report.
"The most surprising result was the significant difference in response rate of 45% versus 15% in the high versus low number of alterations groups,” Dr. Yulian Khagi from University of California San Diego (UCSD) Moores Cancer Center, in La Jolla, told Reuters Health by email. “Additionally, though the study was small, a significant difference could be identified for a longer survival without progression of cancer and a longer survival overall in the high versus low VUS (variant of unknown significance) group.”
“Immunotherapy is transforming cancer treatment,” he explained. “In particular, the revolutionary checkpoint inhibitors that can reactivate the immune system in patients with cancer are helping people live longer and can sometimes eradicate the cancer. However, overall only about 20% of patients respond to these drugs, and the drugs sometimes have significant side effects. Therefore, it is important to have vetted biomarkers that can help predict response to these new drugs.”
Dr. Khagi, Dr. Razelle Kurzrock, and their UCSD-based team investigated the utility of blood-derived circulating tumor DNA (ctDNA) in determining a hypermutated state and response to immunotherapy. They retrospectively studied 69 patients with diverse malignancies who received inhibitor-based immunotherapy and next-generation sequencing of 54-70 genes.
The findings were published online October 1 in Clinical Cancer Research.
More than 90% of patients had at least one ctDNA alteration. The median VUS number per patient was 2; the median number of total ctDNA alterations was 3.
Overall, 29% of patients had >3 VUS alterations and 33.3% had at least 6 total ctDNA alterations.
Therapy response rates were significantly higher among patients with >3 VUS alterations than among those with 3 or fewer (45% vs. 15%) - and among patients with at least 6 total ctDNA alterations than among those with fewer than 6 (41% vs. 16%).
Median progression-free survival was significantly longer for patients with more, versus fewer, alterations (3.84 vs. 2.07 months for VUS and 2.85 vs. 2.19 months for ctDNA).
Median overall survival was 10.72 months for patients with 3 or fewer VUS alterations and 10.79 months for those with fewer than 6 total ctDNA alterations. Overall survival numbers were “not reached” for the subgroups with more alterations.
“Unlike traditional predictive biomarkers for checkpoint inhibitors, which require invasive and often costly tissue biopsy, the Guardant360 test used in this study is a simple blood test,” Dr. Khagi explained. “To our knowledge, this is the first study demonstrating that high circulating tumor DNA alteration number can correlate with response to checkpoint inhibitor therapy. This potentially makes available these effective new drugs to a broader population of patients with a variety of cancers.”
“As technology improves and we are able to assess more genes, it may be that we get an even better estimate of total mutational burden,” he concluded. “Thus, we believe the power of cell-free DNA sequencing in terms of its predictive ability for checkpoint inhibitor use is only beginning to be realized.”
Dr. Justin M. Balko from Vanderbilt University Medical Center, Nashville, Tennessee, who recently reviewed emerging biomarkers for cancer immunotherapy and melanoma, told Reuters Health by email, "The use of a minimally invasive technique such as cell-free plasma tumor DNA to measure total mutation burden is an interesting tool that could play a role in assessing possible benefit for cancer patients from immunotherapy.”
“Eventually cell-free DNA may partially replace tumor biopsy DNA in use for personalized medicine,” he said. “Although total mutation burden is a suboptimal predictor of immunotherapy response, eventually this information could play a role in identifying possible micro-satellite instable patients, or could be used in multivariable clinical predictors to assess possible immunotherapy benefit.”
“There are a large number of possible confounders that cannot be controlled for in the data,” Dr. Balko said, “but physicians should begin to consider patients with a high number of alterations identified by cell-free tumor DNA assays as possible candidates for immunotherapy trials. However, the data are far too preliminary to make use of this information as a clear biomarker of potential response.”
Two of the eight study authors, including Dr. Kurzrock, report financial relationships with Guardant, which makes the Guardant360 blood test used in this study.
SOURCE: http://bit.ly/2yjxvad
Clin Cancer Res 2017.
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