|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||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, KWai, 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, J Love, C, G Makrigiorgos, M, Partridge, AH, Mayer, EL, Golub, TR, Adalsteinsson, V|
|Journal||Clin Cancer Res|
|Date Published||2020 Mar 13|
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.
|Alternate Journal||Clin. Cancer Res.|