Genomically directed therapy did not improve outcomes in patients who had residual triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy, according to phase 2 results published in the Journal of Clinical Oncology

In the phase 2 BRE12-158 trial ( Identifier: NCT02101385), researchers compared physician’s choice of therapy with drugs selected based on targets identified through next-generation sequencing (NGS) of the residual tumor.

“BRE12-158 represents one of the largest randomized trials to test a precision medicine approach against the standard of care in the curative setting,” the researchers wrote.

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The study enrolled 193 patients with TNBC who had residual disease after neoadjuvant chemotherapy, and all tumors were sequenced using a certified NGS test.

Among the patients who had actionable alterations, 71 were randomly assigned to receive genomically directed therapy, and 73 were randomly assigned to physician’s choice of therapy. All 49 patients without actionable targets were assigned to physician’s choice.

Patients in the NGS-directed arm received 1 of 11 different therapies. Patients in the physician’s choice arm received 1 of 6 different regimens (most often capecitabine) or no therapy. 


The median follow-up was 34.2 months, and the primary endpoint was 2-year disease-free survival (DFS) among randomized patients. The 2-year DFS rate was similar between randomized patients in the NGS-directed arm and the physician’s choice arm — 56.6% and 62.4%, respectively.

Among the randomized patients, there were no significant differences between the arms for DFS (hazard ratio [HR], 1.55; 95% CI, 0.94-2.55; P =.83), distant disease-free survival (DDFS; HR, 1.81; 95% CI, 1.04-3.13; P =.035), or overall survival (OS; HR, 1.83; 95% CI, 0.97-3.45; P =.062). 

Likewise, there were no significant differences between the arms when the non-randomized patients without actionable targets were included in the analysis.

The study was not powered to determine statistical superiority of specific drugs. However, an exploratory analysis showed that patients who received therapy had better DFS, DDFS, and OS than patients who did not receive therapy.

Similarly, patients who received capecitabine had better DFS, DDFS, and OS than patients who received no therapy. There were no significant differences in outcomes between patients who received capecitabine and those who received pembrolizumab or gemcitabine. Outcomes were inferior with olaparib, when compared with capecitabine.

Patients who were circulating tumor DNA-positive had significantly inferior DFS (HR, 1.93; 95% CI, 1.05-3.52; P =.03), DDFS (HR, 2.68; 95% CI, 1.32-5.46; P =.0065), and OS (HR, 2.64; 95% CI, 1.18-5.91; P =.02). 

Based on these findings, the researchers discouraged using NGS to guide therapy in the curative setting outside of a clinical trial.

“Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides a rationale for testing optimal combinations to improve outcomes,” the researchers wrote. “Circulating tumor DNA should be considered a standard covariate for trials in this setting.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Schneider BP, Jiang G, Ballinger TJ, et al. BRE12-158: A postneoadjuvant, randomized phase 2 trial of personalized therapy versus treatment of physician’s choice for patients with residual triple-negative breast cancer. J Clin Oncol. Published online December 15, 2021. doi:10.1200/JCO.21.01657