Abstract S2-06: DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk breast cancer
Authors: Wolf DM , Yau C , Sanil A , Glas A , Petricoin C , Wulfkuhle J , Brown-Swigart L , Hirst G ,   I-SPY 2 TRIAL Investigators, Buxton M , DeMichele A , Hylton N , Symmans F , Yee D , Paoloni M , Esserman L , Berry D , Rugo H , Olapade O , van 't Veer L 
Published: March 2017

Abstract
Background: The PARP inhibitor veliparib in combination with carboplatin (VC) was one of the experimental regimens evaluated in the phase 2 neoadjuvant I-SPY 2 standing trial for high risk breast cancer patients. VC graduated in the triple negative (TN) signature. However, not all TN patients achieved pathologic complete response (pCR) and some HR+HER2- patients responded. The I-SPY 2 biomarker component provides a platform for rigorous evaluation of mechanism-of-action-based markers in the context of established biomarkers (HR, HER2, MammaPrint) within the trial. Here, we report results from 5 investigator-submitted biomarker proposals and the MammaPrint High1/High 2 (MP1/2) classification as specific predictors of VC response.
Methods: Data from 116 HER2- patients (VC: 72 and concurrent controls: 44) were available. BRCA1/2 germline mutation was assessed by Myriad Genetics. 3 expression signatures relating to DNA damage repair deficiency (PARPi-7, BRCAness and CIN70) and MP1/2 classification were evaluated on Agilent 44K arrays. PARP1 levels were measured using reverse phase protein arrays. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of VC response if it associates with response in the V/C arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p&lt;0.05). In an exploratory analysis, we combined successful biomarkers to refine the 'predicted sensitive' group and used Bayesian modeling to estimate the pCR rates of 'predicted sensitive' TN and HR+HER2- patients in each arm.
Results: BRCA1/2 germline mutation status associates with VC response, but its low prevalence in the control arm precludes further evaluation. Of the biomarkers evaluated, three (PARPi-7, BRCAness, and MP1/2) associate with response in the VC arm but not the control arm, and have biomarker x treatment interactions with p &lt; 0.05 that retains significance upon adjusting for HR status. These signatures are only moderately correlated. When we combined the PARPi-7 and MP1/2 classifications using a simple voting scheme, the 40% of TN patients who are PARPi7-high and MP2 have an estimated pCR rate of 79% in the VC arm. In contrast, TN patients negative for at least one of these signatures (PARPi7-low and/or MP1) only have an estimated pCR rate of 35%. Only 9% of HR+/HER2- patients are PARPi7-high and MP2; but these patients also appear more responsive to VC with estimated pCR rates of 49%, compared to 13% in 'biomarker-negative' HR+HER2- patients.
Conclusion: If verified in a larger trial, PARPi7, BRCAness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care. Evaluation of the combined signature for patients treated with platinum-based chemotherapy is ongoing.
Citation Format: Wolf DM, Yau C, Sanil A, Glas A, Petricoin C, Wulfkuhle J, Brown-Swigart L, Hirst G, I-SPY 2 TRIAL Investigators, Buxton M, DeMichele A, Hylton N, Symmans F, Yee D, Paoloni M, Esserman L, Berry D, Rugo H, Olapade O, van 't Veer L. DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-06.