Circulating tumor DNA detection linked to high risk for breast cancer relapse
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Circulating tumor DNA detection during follow-up for early-stage breast cancer appeared associated with high risk for future relapse, according to study results published in JAMA Oncology.
“Breast cancer is the most frequently diagnosed cancer worldwide, with approximately 95% of women presenting with early-stage breast cancer without macroscopic metastatic disease. Better tools to establish individuals at risk [for] relapse are needed,” Isaac Garcia-Murillas, PhD, staff scientist at the Institute of Cancer Research in London, and colleagues wrote. “Detecting which patients have molecular residual disease that has not been eradicated by treatment would allow clinical trials of adjuvant therapies focused on those at highest risk.”
Garcia-Murillas and colleagues evaluated the clinical validity of molecular relapse detection with circulating tumor DNA analysis in a prospective, sample collection validation study that recruited 170 women with early-stage breast cancer from five hospitals in the U.K. The women had been scheduled to undergo neoadjuvant chemotherapy followed by surgery (n = 140) or surgery before adjuvant chemotherapy (n = 30).
Researchers collected plasma samples every 3 months during the first year of follow-up and every 6 months for 5 years thereafter. They sequenced the primary tumor to identify somatic mutations and used personalized, tumor-specific digital polymerase chain reaction assays to follow mutations.
Sequencing revealed mutations in 101 women (mean age, 54 years; standard deviation, 11 years), who comprised the main cohort. The researchers conducted secondary analyses of a combined group of 144 women, including 43 who had been assessed in a prior proof-of-principle study.
Researchers assessed extracted plasma DNA from 695 samples (median samples per patient, 7; interquartile range [IQR], 5-8) for the presence of circulating tumor DNA.
RFS, evaluated with Cox proportional hazards regression models, served as the primary endpoint.
Median follow-up was 35.5 months (IQR, 27.9-43).
The researchers found an association between the detection of circulating tumor DNA during follow-up and increased risk for relapse (HR = 25.2; 95% CI, 6.7-95.6). Circulating tumor DNA detection at diagnosis, prior to treatment, also correlated with poorer RFS (HR = 5.8; 95% CI, 1.2-27.1).
Among the combined cohort, molecular residual disease was detected in 29 women. Researchers observed a median lead time between detection of circulating tumor DNA and relapse of 10.7 months (95% CI, 8.1-19.1), and associations between detection and relapse in all breast cancer subtypes.
Twenty-two of 23 women (96%) who experienced distant extracranial metastatic relapse had circulating tumor DNA detected before relapse. Circulating tumor DNA appeared less effective in detecting brain-only metastases (17%; n = 1 of 6), indicating that relapses in some areas are less likely to be detected through circulating tumor DNA analysis.
Researchers noted the results do not show clinical utility of circulating tumor DNA mutation tracking and, in the absence of evidence that it can improve patient outcomes, should not be recommended for routine clinical practice.
Ultimately, determining the clinical value of circulating tumor DNA detection in early-stage breast cancer will require additional study, according to a related editorial by Swathi Karthikeyan, MS, graduate student in the pathology department at Johns Hopkins University School of Medicine, and Ben Ho Park, MD, PhD, director of precision oncology at Vanderbilt-Ingram Cancer Center.
“Proof of clinical utility can be accomplished through prospective, multi-institutional trials randomizing circulating tumor DNA-positive patients to therapy vs. control and demonstrating reductions in disease-free and overall survival,” the editorial authors wrote. “The use of real-time testing and rapid turnaround time may prove to be challenging if we are to implement circulating tumor DNA testing as an integral biomarker for decision-making.” – by Jennifer Byrne
Disclosures: Garcia-Murillas reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Park reports royalties from Horizon Discovery Ltd.; scientific advisory board membership with and ownership interest in Loxo Oncology; consultant roles with AstraZeneca, Casdin Capital, Eli Lilly, H3 Biomedicine, Jackson Laboratories and Roche; and research contracts with AbbVie, Foundation Medicine Inc. and Pfizer. Karthikeyan reports no relevant financial disclosures.
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