So-called liquid biopsy identified cancer mutations in 85% of all advanced tumors, in the largest-ever evaluation of circulating tumor DNA (ctDNA) in the blood.1Error loading Partial View script (file: ~/Views/MacroPartials/TAP Article Portrait Widget.cshtml)
Detection of tumor-specific mutations in a blood draw is an attractive alternative when tissue biopsies are not feasible. It is easy to do in any clinic and avoids biopsy-treated complications.— Philip C. Mack, PhD
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In 49% of the cases, these biomarkers were associated with an approved targeted drug, Philip C. Mack, PhD, reported at the 2016 ASCO Annual Meeting. Dr. Mack is Professor and Director of Molecular Pharmacology at the University of California Davis Comprehensive Cancer Center, Sacramento, and Vice President for Research at California Northstate University.
“Detection of tumor-specific mutations in a blood draw is an attractive alternative when tissue biopsies are not feasible,” Dr. Mack said. “It is easy to do in any clinic and avoids biopsy-treated complications.” The ctDNA assay also facilitates disease monitoring and can potentially identify mutations in metastatic lesions and treatment-induced resistant mutations not observed in the original tumor biopsy, he added.
Study Details and Results
The study used the commercially available Guardant360 assay, a highly sensitive next-generation sequencing technique, to look for patterns of genetic changes in 17,628 blood specimens from 15,191 patients. Guardant360 is one of a number of ctDNA assays now available and looks for 70 actionable somatic alterations across all solid tumor sites. The patients in this study had primarily lung (37%), breast (14%), and colorectal (10%) cancers, plus a variety other cancers (38%).
The results of the assay were compared with publicly available, population-scale tumor-sequencing data, most notably from The Cancer Genome Atlas. “We found that ctDNA mutation patterns were highly consistent with distribution in tumor tissue by the [The Cancer Genome Atlas],” Dr. Mack reported, noting this was seen with commonly altered tumor suppressors and oncogenes alike. “In the cancer genes we evaluated, we saw the exact same hot-spot and activating mutations as observed in The Cancer Genome Atlas and other publications, at very similar frequencies. Furthermore, we identified additional mutations associated with emergent resistant mechanisms that are not normally present at the time of initial biopsy.”
Across multiple cancer genes and different classes of alterations, correlations with The Cancer Genome Atlas ranged from 0.92 to 0.99. The epidermal growth factor receptor (EGFR) T790M mutation, a marker of resistance, was seen in the blood but not the tumor biopsies, since it emerges after treatment with EGFR inhibitors, which were given after tumor biopsy.
Most of the ctDNA alterations were found at very low levels, with half occurring at a frequency below 0.4% of the total DNA in the circulation. “Anecdotally, alterations observed at ctDNA fractions as low as 0.06% responded to treatment, which highlights the importance of assay sensitivity.”
Taking into account U.S. Food and Drug Administration (FDA)-approved agents and eligibility for clinical trials, the ctDNA assay identified a possible treatment option for 63.6% of the more than 15,000 patients. Dr. Mack added that targeted drugs approved by the FDA are usually for very narrow indications and in many of these cases have not been evaluated in the specific tumor type where we identified the genetic marker. Additional clinical testing is critically needed to expand the use of targeted agents.
In a subset of 386 patients, liquid biopsies were matched to tumor tissue from the same patient, showing the mutational profile in blood closely mirrored that identified by traditional tumor biopsies. The overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87% (336 of 386), Dr. Mack reported. The accuracy increased to 98% when blood and tumor were collected less than 6 months apart, the investigators reported.
Biggest Role Down the Road
Dr. Mack and other experts emphasized that ctDNA results will not necessarily replace tissue biopsy but will be an additional tool. “I think there is always going to be a role for tissue-based biopsy,” he commented, emphasizing that tumor biopsy will remain the gold standard, as it yields important information about morphology, tumor type, possible site of origin, and somatic mutations. “That will always be required.” More likely, liquid biopsy will be used when tissue is of insufficient quality or quantity to allow a broader array of testing.
“Probably, the biggest role for plasma analysis will be occurring down the road, as patients are progressing on therapies, as their tumors are evolving, as a way to monitor progression of those cancers,” offered Dr. Mack.
The next step for these researchers is to work to increase the sensitivity of the Guardant360 assay to detect mutations at an extremely low ctDNA level, which is necessary for some tumors and will also enable its use in earlier-stage cancers.
He added that in about 15% of patients, no tumor DNA could be detected by the ctDNA test. “There are simply tumors that do not shed DNA into the circulation at detectable levels, so we are bound to miss them,” he acknowledged. ■
Disclosure: This study was supported by funding from Guardant Health. Dr. Mack has received honoraria from Guardant Health; research funding from Boehringer Ingelheim; reimbursement for travel, accommodations, and expenses from Guardant Health; and has had a consulting/advisory role with MolecularMD, Apton Biosystems, AstraZeneca, and Novartis.
1. Zill OA, Mortimer S, Banks KC, et al: Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. 2016 ASCO Annual Meeting. Abstract LBA11501. Presented June 7, 2016.
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The authors have demonstrated not only the feasibility of the test in detecting alterations, but that the results are often potentially actionable as well... .— Sumanta K. Pal, MD