In a study reported in JAMA Oncology, Nicholas C. Turner, PhD, and colleagues found that detection of circulating tumor DNA (ctDNA) during follow-up after initial treatment for early breast cancer was associated with a high risk of relapse. Detection at diagnosis was also associated with poorer relapse-free survival.
Nicholas C. Turner, PhD
The multicenter study involved a main cohort of 101 women enrolled between November 2011 and October 2016 with early-stage breast cancer—irrespective of hormone receptor or HER2 status—in whom somatic mutations were identified. Patients had to be receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. Primary tumor samples were sequenced to identify somatic mutations, with personalized tumor-specific digital polymerase chain reaction assays being used to monitor the mutations in serial plasma samples every 3 months for the first year of follow-up and then every 6 months. Additional analyses were performed in a combined cohort of 144 patients (including 43 patients from a prior proof-of-principle study).
The primary endpoint was relapse-free survival. Median follow-up was 35.5 months. In the main cohort of 101 patients, ctDNA was detected in 16 during follow-up. Median relapse-free survival was 38.0 months in patients with detectable ctDNA vs not reached in those without detectable ctDNA (standard hazard ratio [HR] = 16.7, P < .001). Most of the patients with detectable ctDNA tested negative at the first time point during follow-up and tested positive in a subsequent follow-up sample. Use of a Cox proportional hazards regression time-dependent model to account for this also showed significantly poorer relapse-free survival in patients with vs without detectable ctDNA (time-dependent HR = 25.2, P < .001).
ctDNA was detected at diagnosis (prior to any treatment) in 41 of 80 assessable patients. Relapse-free survival was significantly poorer among those with detectable ctDNA (HR = 5.8, P = .01).
In the combined cohort of 144 patients, ctDNA was detected during follow-up in 29 patients. Detection of ctDNA occurred at a median of 10.7 months before identification of clinical relapse and was associated with relapse across all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients. Brain-only metastases were detected by ctDNA in one of six patients.
The investigators concluded, “The findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.” ■