BREAST CANCER: The design of patient-specific ctDNA assays for the detection of minimal residual disease (MRD), based on whole exome sequencing of the primary tumour, significantly increased the detection sensitivity for MRD+ patients

Kevin Sovet

March 24, 2020



Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer

Clinical Cancer Research, Published OnlineFirst March 13, 2020

DOI: 10.1158/1078-0432.CCR-19-3005



Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1000-fold lower error rate than conventional sequencing. Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within six months following metastatic diagnosis and 142 patients with stage 0-III breast cancer who received curative-intent treatment with most sampled at surgery and one year post-op. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples. Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median 57, range 2-346). Clinical sensitivity was 81% (n=13/16) in newly diagnosed MBC, 23% (n=7/30) at post-op and 19% (n=6/32) at one year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at one year was strongly associated with distant recurrence (HR=20.8 [95%CI: 7.3-58.9]). Median lead time from first positive sample to recurrence was 18.9 months (range: 3.4-39.2 months). Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.

• Received September 23, 2019.

• Revision received November 26, 2019.

• Accepted February 13, 2020.

• Copyright ©2020, American Association for Cancer Research.

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