journal contribution posted on 2023-03-31, 22:26 authored by Heather A. Parsons, Justin Rhoades, Sarah C. Reed, Gregory Gydush, Priyanka Ram, Pedro Exman, Kan Xiong, Christopher C. Lo, Tianyu Li, Mark Fleharty, Gregory J. Kirkner, Denisse Rotem, Ofir Cohen, Fangyan Yu, Mariana Fitarelli-Kiehl, Ka Wai Leong, Melissa E. Hughes, Shoshana M. Rosenberg, Laura C. Collins, Kathy D. Miller, Brendan Blumenstiel, Lorenzo Trippa, Carrie Cibulskis, Donna S. Neuberg, Matthew DeFelice, Samuel S. Freeman, Niall J. Lennon, Nikhil Wagle, Gavin Ha, Daniel G. Stover, Atish D. Choudhury, Gad Getz, Eric P. Winer, Matthew Meyerson, Nancy U. Lin, Ian Krop, J. Christopher Love, G. Mike Makrigiorgos, Ann H. Partridge, Erica L. Mayer, Todd R. Golub, Viktor A. Adalsteinsson
Patients who were recurrence free after treatment for early stage breast cancer. cfDNA time points for all patients who did not experienced recurrence. Those marked with poor detection limits had an estimated detection limit worse than 1/1,000. End points represent time of last follow up or death.
Koch Institute for Integrative Cancer Research
Harvard Cancer Center
Terri Brodeur Breast Cancer Foundation
Friends of Dana-Farber
Cheryl Tessler Solit Foundation
Breast Cancer Research Foundation
National Comprehensive Cancer Network
Pfizer Collaborative Grant Program
Fashion Footwear Association of New York
ARTICLE ABSTRACTExisting 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.
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.
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).
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.