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Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Jun 01; Vol. 26 (11), pp. 2556-2564. Date of Electronic Publication: 2020 Mar 13. - Publication Year :
- 2020
-
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.<br />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.<br />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).<br />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.<br /> (©2020 American Association for Cancer Research.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 26
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 32170028
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-19-3005