Study Supports Using MRD as a Stratification Variable for Patients with TNBC

Researchers suggested that these findings support using minimal residual disease as a major stratification variable in all clinical trials to be conducted in patients with triple negative breast cancer.

A preplanned secondary analysis of the BRE12-158 randomized clinical trial found that the presence of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in patients with early-stage triple negative breast cancer (TNBC) after neoadjuvant chemotherapy are critical indicators for the prediction of disease recurrence and disease-free survival.1

Researchers indicated that this research, published in JAMA Oncology,supports the routine use of this technology for proper risk stratification across clinical trials in the curative setting.

“This is an important step forward in the treatment of women with triple negative breast cancer, who have not had much scientific evidence to point to—until now—for treatment of their disease,” Bryan Schneider, MD, researcher at the Indiana University School of Medicine and Bren Simon Comprehensive Cancer Center, said in a press release.2 “We are going to use these findings and continue on until we find a treatment that works for each individual woman. This effort not only involves finding the best way to kill cancer, but to minimize side effects.”

The multicenter, randomized phase 2, trial included 196 female patients randomized to receive either postneoadjuvant genomically directed therapy or physician’s choice of treatment. Participants had blood samples collected for ctDNA and CTCs at time of their treatment assignment. Overall, ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months).

The primary outcome measures were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS).

Among the total cohort, detection of ctDNA was significantly associated with inferior DDFS (median, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = 0.006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Similarly, detection of ctDNA was associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = 0.009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = 0.002).

Importantly though, the combination of ctDNA and CTCs afforded additional information with regard to increased sensitivity and discriminatory capacity.

Patients who were found to be ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = 0.009). At 24 months, DDFS probability was 52% for those who were ctDNA positive and CTC positive compared with 89% for patients who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = 0.04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = 0.007).

“Our findings now support using [minimal residual disease; MRD] as a major stratification variable in all clinical trials to be conducted in this setting,” the authors wrote. “In addition, the ability to sequence ctDNA broadly for important gene variations affords the possibility of not only uncovering an ultra-high-risk population for relapse but also revealing drug targets.”

“Perhaps equally important, if the results from the group of patients who are ctDNA negative and CTC negative hold, this may be a subgroup in which the patients do not benefit from additional therapy, and this may be an ideal place to study novel de-escalation strategies,” the authors continued. “At the present time, we would discourage the use of MRD as a marker for relapse or to guide therapy in routine clinical practice because there is no evidence that early detection improves outcomes.”

Moving forward, researchers suggested that future trials should determine if genomically guided therapeutic interventions in patients who have molecular MRD can improve outcomes. Specifically, the planned successor trial to BRE12-158, the PERSEVERE trial, will focus on this concept. Patients with TNBC and ctDNA positivity after surgery will be included in the trial and assigned to receive a targeted agent matched to the patients’ plasma sequencing results.


1. Radovich M, Jiang G, Hancock BA, et al. Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer. JAMA Oncology. doi: 10.1001/jamaoncol.2020.2295.

2. IU School of Medicine findings set new standard for use of blood-based biomarkers in clinical trials for prediction of cancer recurrence [news release]. Indianapolis. Published July 9, 2020. Accessed July 29, 2020.