BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer

Abstract

PURPOSE Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). PATIENTS AND METHODS From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. RESULTS One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. CONCLUSION Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.

Clinical Utility of Precision Medicine in Early Breast Cancer: What Is the Optimal Framework to Develop Precision Medicine?

“…In their article in the Journal of Clinical Oncology , Schneider et al 1 reported the results of the BRE12-158 trial, which confirmed that directed therapy was not superior to the treatment of physician's choice (TPC) for patients with residual triple-negative breast cancer after neoadjuvant chemotherapy. Despite the impressive results, it may have some points to consider for further discussion.…”

Precision Breast Cancer Medicine: Early Stage Triple Negative Breast Cancer—A Review of Molecular Characterisation, Therapeutic Targets and Future Trends

“…The theoretical advantage for olaparib use includes targeting a known tumour susceptibility in a selected population, leading to an improved response and improved tolerability compared to standard cytotoxics. Interestingly, a phase 2 trial that assessed the value of molecularly targeted postneoadjuvant treatment vs choice of clinician in TNBC patients with residual disease did not demonstrate the superiority of this approach ( 86 ). Despite the limitations with regard to the primary outcome, an example was set for biomarker-driven clinical trials and the use of ctDNA in optimising the selection of biomarker-treatment partners.…”

Reply to K. Nozawa et al

“…We appreciate the interest in our work 1 highlighted by the letter from Nozawa et al 2 We are also grateful for the opportunity to reflect on the interesting points highlighted.…”