Cancer investigators led by researchers at Vanderbilt-Ingram Cancer Center (VICC) have co-developed a liquid biopsy blood-based assay used to identify specific gene mutations associated with the development or relapse of small-cell lung cancer (SCLC).
Working in conjunction with researchers at Resolution Bioscience, Bellevue, Washington, the group used circulating tumor DNA (ctDNA) to monitor the progression of the disease using non-invasive methods.
In several cases, analysis of ctDNA provided evidence of disease relapse before it could be detected by standard imaging.
The study, led by first authors Karinna Almodovar, Ph.D., and Wade Iams, M.D., and principal investigator Christine Lovly, M.D., Ph.D., assistant professor of Medicine, was published online Sept. 23 in the Journal of Thoracic Oncology.
Patients with SCLC have few treatment options and face a poor prognosis. While the disease may initially respond to chemotherapy, resistance to therapy occurs quickly in most patients.Lung cancer is the leading cause of cancer-associated death in the U.S., and small-cell lung cancer (SCLC) is an especially aggressive form of the disease with a propensity to metastasize to distant sites in the body.
The current standard of care includes imaging to identify active disease and track cancer progression but such imaging cannot detect treatment-induced changes in tumor genotypes.
Surgery rarely is performed in these patients, so cancer investigators trying to study the disease have limited access to tumor tissue samples.
Over 26 months, the investigators studied 140 blood samples from 27 patients. They isolated ctDNA from each blood sample and detected disease-associated gene mutations in 85 percent of these samples. More than half (59 percent) of those patients had advanced disease and the most common mutations occurred in the TP53 and RB1 genes.
The researchers also found alterations in 10 additional genes, including PTEN, NOTCH1-4, PIK3CA, KIT and BRAF.
To determine if ctDNA sequencing can be used to monitor a patient’s response to systemic therapy, the investigators analyzed blood samples from 25 patients before, during and after therapy.
In several patients, ctDNA mutation tracking provided early evidence of resistance to therapy, and in all of those cases the authors noted an obvious rise in mutation abundance during treatment. In nine patients, researchers found a marked increase in the number of mutations before there was radiographic evidence of disease progression.
“With current imaging, it is sometimes difficult to discern disease progression from other issues like treatment side effects, infection or inflammation,” said Lovly. “Patients often must wait or undergo repeat imaging before clinicians can determine the need for changes in therapy. The use of ctDNA monitoring has the potential to add valuable insight in these cases with ambiguous imaging findings. Ultimately, we hope that ctDNA monitoring may be a useful tool for patients with SCLC.”
Funding for the study was provided by a VICC Ambassadors Award, the National Institutes of Health and the National Cancer Institute (R01CA121210, U10CA180864, 2P30CA06-8485-19), a Damon Runyon Clinical Investigator Award, an AACR-Genentech Career Development Award, and a Ruth L. Kirschstein NRSA Fellowship (T32HL094296).
Other investigators who contributed to the study include Catherine Meador, Zhiguo Zhao, Sally York, Leora Horn, Yingjun Yan, Heidi Chen, Yu Shyr, Vanderbilt; Jennifer Hernandez, Lee Lim and Christopher Raymond, Resolution Bio.