1. Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.
- Author
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Parsons HA, Rhoades J, Reed SC, Gydush G, Ram P, Exman P, Xiong K, Lo CC, Li T, Fleharty M, Kirkner GJ, Rotem D, Cohen O, Yu F, Fitarelli-Kiehl M, Leong KW, Hughes ME, Rosenberg SM, Collins LC, Miller KD, Blumenstiel B, Trippa L, Cibulskis C, Neuberg DS, DeFelice M, Freeman SS, Lennon NJ, Wagle N, Ha G, Stover DG, Choudhury AD, Getz G, Winer EP, Meyerson M, Lin NU, Krop I, Love JC, Makrigiorgos GM, Partridge AH, Mayer EL, Golub TR, and Adalsteinsson VA
- Subjects
- Adult, Breast Neoplasms blood, Breast Neoplasms genetics, Breast Neoplasms therapy, Circulating Tumor DNA blood, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Neoplasm Recurrence, Local blood, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local therapy, Neoplasm, Residual blood, Neoplasm, Residual genetics, Neoplasm, Residual therapy, Prognosis, Prospective Studies, Retrospective Studies, Survival Rate, Breast Neoplasms pathology, Circulating Tumor DNA genetics, Estrogen Receptor alpha metabolism, Neoplasm Recurrence, Local pathology, Neoplasm, Residual pathology
- Abstract
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 1,000-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 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. 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 postoperative and 19% ( n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 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., (©2020 American Association for Cancer Research.)
- Published
- 2020
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