Abstract 858: Combining sensitivity markers to identify triple-negative breast cancer patients most responsive to veliparib/carboplatin: results from the I-SPY 2 TRIAL
Authors: Wolf Denise M. , Yau Christina , Sanil Ashish , Brown-Swigart Lamorna , Hirst Gillian , Buxton Meredith , Paoloni Melissa ,   I-SPY 2 TRIAL Investigators, Olopade Olufunmilayo , Rugo Hope , De Michele Angela , Symmans Fraser , Berry Don , Esserman Laura , van ‘t Veer Laura 
Published: July 2016

Abstract
BACKGROUND: In the I-SPY 2 TRIAL, HER2-negative patients received standard chemotherapy alone or with the PARP inhibitor veliparib and carboplatin (VC). VC graduated in the triple-negative (TN) subtype, and we’ve previously shown that MammaPrint High1/High2 (MP1/2) risk class and the PARPi-7 signature may predict VC response. Here we evaluate whether combining these signatures identifies a subset of TN patients especially likely to respond to VC.
METHODS: This analysis includes 60 TN patients (VC: 39 and controls: 21). PARPi-7 and MP1/2 signature scores are computed from Agilent 44K arrays. We further stratify TN patients by VC-sensitivity biomarkers (MP2, PARPi7-high). We use Bayesian modeling to estimate pCR rates in each arm and the predictive probability of VC demonstrating superiority to control in a 1:1 randomized phase 3 trial of 300 ‘biomarker-positive’ patients. Our study is exploratory and does not adjust for multiplicities of biomarkers outside this study.
RESULTS: Though 90% of TNs are PARPi7-high or MP2, concordance between these biomarkers is 50%. The estimated pCR rates to VC are 69% in PARPi7-high and 64% in MP2 TN patients, compared to 53% in the entire TN subgroup. TN patients positive for both sensitivity markers (assessed as PARPi7-high and MP2) achieved an estimated pCR rate of 79% in the VC arm vs. 23% in the control arm, with a predictive probability of success in phase 3 of 99.6%. In contrast, TN patients negative for at least one VC sensitivity marker (PARPi7-low and/or MP1) only had an estimated response rate to VC of 35%. Estimated pCR rates in biomarker subsetsBiomarker subsets within TNEstimated pCR rate in V/C [95% CI]Estimated pCR rate in controls [95% CI]Predictive probability of phase 3 success (300 pt)Unselected TN (n = 60)53% [39 - 67]27% [13 - 43]0.904PARPi7-high and MP2 (n = 24; 40%)79% [60 - 93]23% [5.8 - 49]0.996PARPi7-low and/or MP1 (n = 36; 60%)35% [17 - 55]29% [13 - 49]0.386
CONCLUSION: Our analysis suggests TN patients who are also MP2 and PARPi7-high may be more sensitive to V/C than patients with fewer markers in the ‘sensitive’ state.
Citation Format: Denise M. Wolf, Christina Yau, Ashish Sanil, Lamorna Brown-Swigart, Gillian Hirst, Meredith Buxton, Melissa Paoloni, I-SPY 2 TRIAL Investigators, Olufunmilayo Olopade, Hope Rugo, Angela De Michele, Fraser Symmans, Don Berry, Laura Esserman, Laura van ‘t Veer. Combining sensitivity markers to identify triple-negative breast cancer patients most responsive to veliparib/carboplatin: results from the I-SPY 2 TRIAL. [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 858.