Novel Blood Biopsy Detects MRD in Early-Stage Breast Cancer

Metastatic disease is the leading cause of death in the over 600,000 people worldwide who die of breast cancer each year. A new blood-based assay to detect minimal residual disease (MRD) in patients with stage 0 to 3 breast cancer was shown to have 100-fold greater sensitivity compared with digital droplet polymerase chain reaction, according to results published online with Clinical Cancer Research.

The new test was developed by a team of Boston-based investigators, who cited the need for “more sensitive liquid biopsies, with greater dynamic range, to identify patients with MRD sooner.” They noted the new tests could also help identify higher-risk patients in some instances and avoid deleterious treatment in others.

“Our goal is to be able to turn patients who would have developed metastatic disease into patients who won’t,” stated co-first author Heather Parsons, a medical oncologist at Dana-Farber Cancer Institute and associated scientist at the Broad Institute of Massachusetts Institute of Technology. “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.”

The investigators used retrospective analysis to identify 142 patients who underwent treatment for early-stage disease, tracking their MRD levels after curative-intent surgery at 2 main time points: post-op (median, 3.53 months; range, 0.23-8.43) and 1 year out (median, 14.2 months; range, 6.77-21.7). The patients were followed for up to 13 years.

The patients’ tumors were first analyzed via whole-exome sequencing (WES), with those results used to tailor individualized MRD tests that were run on the patients’ 370 circulating cell-free DNA samples. A median of 57 mutations (range, 2-346) were targeted in each patient. Seventy-eight percent (111) of patients had post-op samples available, while 86% (122) had 1-year samples. In addition, the median lead time between the first MRD-positive result and disease recurrence was 18.9 months (range, 3.4-39.2) in the patients with the most mutations tracked.

Distant disease recurrence was shown to be more likely if MRD was detected at the 1-year mark (HR, 20.8; 95% CI, 7.3-58.9) compared with the post-op setting (HR, 5.1; 95% CI, 2.0-12.7). Also in these patients, the positive and negative predictive values came in at 0.70 and 0.77, respectively. Overall, the clinical sensitivities were 81% in patients with newly diagnosed metastatic breast cancer, 23% in the post-op setting, and 19% at the 1-year mark.

“We’re working to further improve the technology now to catch as many of these patients as possible,” said Viktor Adalsteinsson, PhD, associate director of the Gerstner Center for Cancer Diagnostics at Broad. “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.”

Despite the positive results, the authors did bring attention to 2 important study limitations. They mentioned how their blood sampling was infrequent, compared with other studies, and took place close to the same time as treatment decisions. In addition, WES was not able to identify enough mutations in every patient.

As a next step, the authors recommend that future blood-based assays aiming for extra sensitivity use whole-genome sequencing “to identify more mutations to track in all patients.” The also call for prospective studies of MRD in breast cancer that can further prove its value to the field.

References

Parsons HA, Rhoades J, Reed SC, et al. Sensitive detection of minimal residual disease in patients treated for early-1 stage breast cancer [published online March 13, 2020]. Clin Can Res. doi: 10.1158/1078-0432.CCR-19-3005.