Abstract CT076: Women's triple-negative, first-line treatment: Improving outcomes in triple-negative breast cancer using molecular triaging and diagnostic imaging to guide neoadjuvant therapy
Authors: Mitri Zahi , Ueno Naoto T. , Yang Wei , Valero Vicente , Litton Jennifer K. , Murthy Rashmi , Lim Bora , Ibrahim Nuhad K. , Arun Banu K. , Mittendorf Elizabeth A. , Hunt Kelly K. , Meric-Bernstam Funda , Thompson Alastair , Gilcrease Michael , Piwnica-Worms Helen , Tripathy Debasish , Symmans William Fraser , Moulder-Thompson Stacy 
Published: July 2016

Abstract
BACKGROUND: Triple negative breast cancer (TNBC) is a heterogeneous disease with identified biologically diverse subtypes. There are known differences in response to neoadjuvant chemotherapy (NACT) in TNBC patients with 50% having excellent response to treatment (pCR/Residual cancer burden [RCB]-I) and good survival prognosis, while 50% demonstrate marked residual disease (RCB-II-III) with significantly worse prognosis. Lack of response early into NACT 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.
METHODS: All patients will undergo biopsy of the primary tumor for molecular analyses, but will then be randomized 2:1 to know these results versus not (control). An algorithm that incorporates pre-defined genomic signatures will determine predicted sensitivity to NACT, which contains anthracyclines and taxanes. All patients will begin standard of care anthracycline based NACT with diagnostic imaging to assess response after 4 cycles. Patients who fit molecular/imaging criteria for non-responsive disease will undergo a second biopsy to confirm tumor cellularity and be offered a clinical trial based upon the initial molecular profiling (if known) or based upon physician/patient choice if randomized to the control arm. Patients who fit criteria for responsive disease in either arm will be recommended to continue with taxane-based NACT. Rates of excellent therapy response (pCR/RCB-I) will be compared between the randomized arms. One additional core and two FNAs will be obtained at the time of each planned biopsy and used to generate cell lines and PDX models for study of therapy resistance.
Inclusion criteria include: Tumor size ?1.5 cm diameter; TNBC by standard assays; ?18 years of age; LVEF ?50%; adequate organ and bone marrow function. Exclusion criteria include: 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.
The study was activated on 11/09/2015. To date, 10 patients have been enrolled.
PRIMARY AIM: Prospectively determine the impact of a molecular diagnostic/imaging platform to guide neoadjuvant therapy in patients with localized invasive TNBC.
SECONDARY AIMS: -Determine the impact of targeted therapy to improve pathological response in chemotherapy resistant disease in patients who are selected for clinical trials based upon molecular features of their tumors. -Generate a translational research platform to facilitate molecular diagnostic development, study mechanisms of acquired resistance, and inform the next generation of clinical trials.
STATISTICAL METHODS: A maximum of 360 patients will be randomized (2:1)using a group sequential design with one-sided O’Brien-Fleming boundaries, with two equally spaced binding interim tests for futility and superiority and one final test, having an overall Type I error .05 and power .80 to detect an improvement in pCR/RCB-I from 50% to 64%.
Citation Format: Zahi Mitri, Naoto T. Ueno, Wei Yang, Vicente Valero, Jennifer K. Litton, Rashmi Murthy, Bora Lim, Nuhad K. Ibrahim, Banu K. Arun, Elizabeth A. Mittendorf, Kelly K. Hunt, Funda Meric-Bernstam, Alastair Thompson, Michael Gilcrease, Helen Piwnica-Worms, Debasish Tripathy, William Fraser Symmans, Stacy Moulder-Thompson. Women's triple-negative, first-line treatment: Improving outcomes in triple-negative breast cancer using molecular triaging and diagnostic imaging to guide neoadjuvant therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT076.