Abstract P3-06-05: Evaluation of an in vitro derived signature of olaparib response (PARPi-7) as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL
Authors: Wolf Denise M , Yau Christina , Sanil Ashish , Daemen Anneleen , Heiser Laura , Gray Joe , Brown-Swigart Lamorna , Flynn Susan , Hirst Gillian ,   I-SPY 2 TRIAL Investigators, Buxton Meredith , DeMichele Angela , Hylton Nola , Symmans Fraser , Yee Doug , Paoloni Melissa , Esserman Laura , Berry Don , Rugo Hope , Olopade Olufunmilayo , van 't Veer Laura 
Published: May 2015

Abstract
Background: We developed a 7-gene DNA-repair deficiency signature (PARPi-7) that predicts breast cancer cell line sensitivity to the PARP inhibitor olaparib [PMID: 22875744]. We hypothesized that this signature would also predict response to other PARP inhibitors including veliparib. In the I-SPY 2 TRIAL, HER2- patients were randomized to receive standard chemotherapy or the oral PARP inhibitor veliparib in combination with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) signature. Here we assess the PARPi-7 as a specific biomarker of V/C response.
Methods: 115 HER2- patients (V/C: 71 and concurrent controls: 44) were considered in this analysis. The PARPi-7 signature score is computed from Agilent 44K array data as published using expression levels of BRCA1, CHEK2, MAPKAPK2, MRE11A, NBN, TDG, and XPA. We assess association between PARPi-7 and response in the V/C and control arms alone (Wald p &lt; 0.05), and relative performance between arms (biomarker x treatment interaction, likelihood ratio p &lt; 0.05) using a logistic model. In an exploratory analysis, we dichotomized patients by the PARPi-7 score using the published in vitro derived cutpoint (0.037). To assess PARPi-7 in the context of the graduating signature, we added the PARPi-7 High patients to the graduating TN subset and evaluated the treatment effect in this ‘biomarker-positive’ group. Our study is exploratory with no claims for generalizability of the data. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Our analyses do not adjust for multiplicities of other biomarkers in the trial but outside this study.
Results: The PARPi-7 signature associates with patient response in the V/C arm (OR = 3.9, p=0.00056) but not in the control arm (OR = 0.87, p=0.68). There is a significant biomarker x treatment interaction (OR in V/C arm relative to control arm = 4.48, p=0.0028), which remains significant upon adjusting for HR status (p=0.0018). In an exploratory analysis, PARPi-7 dichotomized using the published in vitro derived cutpoint yields 62 PARPi-7 Low and 53 PARPi-7 High patients. 26% of PARPi-7 High patients are not TN. The distribution of pCR rates among PARPi-7 dichotomized groups are in Table 1.
V/C (n=71)Control (n=44)PARPi-7 Low (n=38)PARPi-7 High (n=33)PARPi-7 Low (n=24)PARPi-7 High (n=20)TN (n=59)5 / 1317 / 251 / 74 / 14HR+HER2- (n=56)2 / 253 / 84 / 170 / 6
When the PARPi-7 High patients are added to the graduating TN subset, the OR associated with V/C is 5.12, which is comparable to that of the TN signature (OR: 4.29), while increasing the prevalence of biomarker-positive patients by ∼12%. Evaluation of PARPi-7 in the context of the graduating signature under the I-SPY 2 Bayesian model is pending.
Conclusion: Our sample size is small. Our pre-specified analysis suggests the PARPi-7 signature shows promise for predicting response to veliparib/carboplatin combination therapy relative to control. If verified in a larger trial, this cell-line derived signature may contribute to the selection criteria of PARP inhibitor trials in the future.
Citation Format: Denise M Wolf, Christina Yau, Ashish Sanil, Anneleen Daemen, Laura Heiser, Joe Gray, Lamorna Brown-Swigart, Susan Flynn, Gillian Hirst, I-SPY 2 TRIAL Investigators, Meredith Buxton, Angela DeMichele, Nola Hylton, Fraser Symmans, Doug Yee, Melissa Paoloni, Laura Esserman, Don Berry, Hope Rugo, Olufunmilayo Olopade, Laura van 't Veer. Evaluation of an in vitro derived signature of olaparib response (PARPi-7) as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL [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 P3-06-05.