Personalized Blood Test Improves MRD Detection in Patients with Breast Cancer


Tracking large numbers of individualized tumor mutations in cell-free DNA improved minimal residual disease detection in breast cancer patients, though the sensitivity is driven by the number of mutations available to track.

A study, published in Clinical Cancer Research, found that tracking large numbers of individualized tumor mutations in cell-free DNA (cfDNA) can improve minimal residual disease (MRD) detection in patients with breast cancer; however, its sensitivity is driven by the number of tumor mutations available to track.1

Given these findings, researchers predict that tracking even more mutations might increase assay sensitivity without compromising specificity, with studies currently underway. 

“By taking an individualized approach – searching for many mutations that are specific to one patient’s cancer – we could greatly increase our sensitivity to detect traces of cancer DNA in patients who had completed their initial treatment plan,” senior author Viktor Adalsteinsson, PhD, associate director of the Gerstner Center at the Broad Institute, said in a press release.2 “And with that sensitivity, we could identify residual cancer from blood samples taken many months to years before a recurring case was diagnosed through standard approaches.”

In order to create a sensitive, personalized blood biopsy test, the research team used whole-exome DNA sequencing from a patient’s tumor biopsy in order to determine the genetic mutations for each patient. The researchers found they were able to track up to several hundred various cancer-related mutations in the samples, improving their likelihood of detecting traces of cancer DNA in the blood. 

Researches compared the sensitivity of their approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified 2 cohorts of patients who had undergone prospective plasma sampling and clinical data collection. The first group included 16 patients with ER-positive/HER2-negative metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and the second included 142 patients with stage 0-III breast cancer who received curative-intent treatment with most sampled at surgery and 1-year post-op. 

“We’re working to further improve the technology now to catch as many of these patients as possible,” Adalsteinsson said. “When we did detect residual disease in blood, following initial courses of treatment, it was a strong predictor of future recurrence. While this was a retrospective study, if a blood biopsy can give clinicians this early warning in real-time, that might provide the opportunity to alter a patient’s outcome.” 

Their approach was found to be 100-fold more sensitive than ddPCR when tracking 488 mutations, although 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 1 year in early stage disease. Moreover, clinical sensitivity was highest in patients with the most tumor mutations available to track.

MRD detection at 1 year was strongly correlated 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). 

“Our goal is to be able to turn patients who would have developed metastatic disease into patients who won’t,” co-first author Heather A. Parsons, MD, MPH, medical oncologist at Dana-Farber Cancer Institute, instructor of medicine at Harvard Medical School, and associate scientist at the Broad Institute, said in a press release. “In the future, if we can find those patients with residual cancer early enough, determine whether they would benefit from another course of therapy, and give them an effective additional treatment, we could potentially change the course of their disease.” 

Following this research, the authors are conducting whole genome sequencing instead of whole exome sequencing in hopes of collecting even more information per patient to boost the blood biopsy’s sensitivity. Additionally, they are also evaluating opportunities to study blood samples taken more frequently from patients over long periods of time to further investigate whether real-time interventions for patients with detectable residual disease could have a meaningful clinical impact.

“This study is an important demonstration that a customized biopsy test has the sensitivity needed to predict which patients are at risk of cancer recurrence,” co-author Todd R. Golub, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute and a faculty member of the Dana-Farber Institute, said in a press release. “Our vision is that, in the future, we will use tests like this to help patients and their doctors determine whether additional treatment is needed to prevent recurrence.”


1. Parsons HA, Rhoades J, Reed SC, et al. Sensitive detection of minimal residual disease: methods and application to patients treated for early-stage breast cancer. Clinical Cancer Research. doi: (will update once the embargo lifts).

2. Personalized blood biopsies demonstrate potential as early-warning signal of breast cancer recurrence [news release]. Published March 12, 2020. Accessed March 12, 2020.

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