Improving outcomes in triple-negative breast cancer (TNBC) using molecular characterization and diagnostic imaging to identify and treat chemo-insensitive disease

Abstract

Background: TNBC treated using neoadjuvant chemotherapy (NACT) has a varied prognosis with 50% of patients ( pts) having excellent response to treatment (pCR/ RCB‐I) and excellent prognosis, while 50% have marked residual disease (RCB‐II‐III) and significantly worse prognosis. Lack of response to an initial NACT regimen also indicates a low chance (5%) of achieving pCR with subsequent chemotherapy, even if drugs are changed. Trial design: This randomized study will determine the impact of predicting chemosensitivity to NACT using molecular characterization combined with diagnostic imaging and determine if offering a clinical trial of selected targeted therapy will impact outcomes (as measured by pCR and RCB) in predicted chemo‐insensitive disease. The algorithm uses a pre‐defined genomic signature (JAMA, 2011;305:1873‐81) and response to an intitial course of anthracycline based NACT to determine predicted sensitivity to chemotherapy. Pts undergo biopsy of the primary tumor prior to NACT and are randomized 2:1 to know the molecular testing results versus not (control). For the second phase of neoadjuvant therapy, pts who fit molecular/imaging criteria for chemo‐insensitive disease after AC are offered a clinical trial based upon comprehensive molecular profiling (if known) or based upon physician/patient choice if randomized to the control arm. Pts with chemo‐sensitive disease continue with taxane based NACT. Success is defined as improvement in the rate of excellent pathologic response (pCR/RCB‐I) from 50%‐ > 64% using the platform. A maximum of 360 pts will be randomized using a group sequential design with one‐sided O'Brien‐Fleming boundaries, with up to two equally spaced binding interim tests for both futility and superiority and one final test, having an overall Type I error .05 and power .80 to detect a response rate improvement from a null rate of .50 to a target value of .642.