Abstract OT3-2-05: Improving outcomes in triple-negative breast cancer (TNBC) using molecular triaging and diagnostic imaging to guide neoadjuvant therapy
Authors: Moulder-Thompson Stacy , Yang Wei , Ueno Naoto T , Ensor Joe , Valero Vicente , Alvarez Ricardo , Litton Jennifer , Murthy Rashmi , Ibrahim Nuhad , Arun Banu , Mittendorf Beth , Hunt Kelly , Meric-Bernstam Funda , Piwnica-Worms Helen , Candelaria Rosalind , Tripathy Debu , Symmans Fraser 
Published: May 2015

Abstract
BACKGROUND:
Known disparities exist in patients with TNBC treated using neoadjuvant chemotherapy (NACT) with 30-50% having excellent response to treatment (pCR/RCB-I) and good survival prognosis, while 50-70% demonstrate marked residual disease (RCB-II-III) with significantly worse prognosis. Lack of response early into NACT also indicates a low chance (5%) of achieving pCR. Thus, it is important to develop diagnostic platforms predictive of pCR, in order to direct patients with responsive disease toward standard NACT and non-responsive disease toward experimental therapies within clinical trials.
TRIAL DESIGN
This study will determine the impact of predicting response to NACT using both molecular and imaging diagnostics and will determine if offering a clinical trial of selected targeted therapy will impact outcomes (as measured by pCR and RCB) in predicted non-responsive disease. An algorithm that incorporates pre-defined genomic signatures will determine predicted sensitivity to chemotherapy (JAMA, 2011; 305:1873-81). All patients will undergo biopsy of the primary tumor for molecular analyses, but will then be randomized 2:1 to know these results (Arm A) versus not (Arm B). All patients will begin anthracycline-based NACT with diagnostic imaging to assess response after 4 cycles. Patients who fit molecular/imaging criteria for non-responsive disease will be offered a clinical trial based upon molecular profiling (Arm A) or based upon physician/patient choice (Arm B). Patients who fit criteria for responsive disease in either arm will continue with taxane based NACT.
ELIGIBILITY CRITERIA
INCLUSION: Candidate for biopsy of the primary tumor site; tumor size &gt; 1.5 cm diameter; TNBC by standard pathologic assays; &gt;18 years of age; LVEF &gt; 50%; adequate organ and bone marrow function
EXCLUSION: Stage IV disease; history of invasive cancer within 5 years; excisional biopsy of the primary tumor; biopsy site changes that limit response assessment; medically unfit for chemotherapy; prior anthracycline; &gt;grade II neuropathy; Zubrod performance status of &gt;2; history of serious cardiac event
PRIMARY AIM
Primary Aim: to prospectively determine the impact of implementation of a research platform that includes molecular (genomic) testing from a primary tumor biopsy to predict response, and diagnostic imaging to assess response to standard NACT in patients with localized invasive TNBC. Secondary Aims: compare rates of clinical trial enrollment between study arms, compare DFS, integrated "prospective-retrospective" biomarker analysis, correlative science studies to identify therapeutic targets for resistant disease
STATISTICAL METHODS AND TARGET ACCRUAL
Success will be defined as an improvement in the rate of excellent pathologic response (pCR/RCB-I) from 50%--&gt;64% using the triaging platform. A maximum of 360 patients will be randomized 2:1 to the experimental arm vs. the control arm 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.
Citation Format: Stacy Moulder-Thompson, Wei Yang, Naoto T Ueno, Joe Ensor, Vicente Valero, Ricardo Alvarez, Jennifer Litton, Rashmi Murthy, Nuhad Ibrahim, Banu Arun, Beth Mittendorf, Kelly Hunt, Funda Meric-Bernstam, Helen Piwnica-Worms, Rosalind Candelaria, Debu Tripathy, Fraser Symmans. Improving outcomes in triple-negative breast cancer (TNBC) using molecular triaging and diagnostic imaging to guide neoadjuvant therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-05.