FROM CLINICAL CANCER RESEARCH
The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.
Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).
Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.
“Our current results may be clinically exploitable. … Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD , a hematology-oncology fellow at the university.
In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the … results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”
The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.
For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing ( Guardant360 ) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.
The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.
Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.
Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.
“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.
The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.