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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<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 < 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.

#1063 Introduction
 By using gene expression profiling, Van 't Veer and colleagues developed a 70-gene prognosis profile to identify breast cancer patients who are at low risk of developing distant metastases and therefore might be safely spared chemotherapy. This 70-gene profile has been developed using tumors from a selected group of patients, i.e. women under the age of 55 years at diagnosis with stage I or II tumors. However, the majority of breast cancer patients are older, postmenopausal women who are increasingly being offered adjuvant chemotherapy despite the more favorable biological characteristics of their tumors, such as a lower proliferation rate and a high endocrine sensitivity. The aim of this study was to evaluate the prognostic value of the 70-gene prognosis profile in postmenopausal women with node-negative breast cancer.
 Methods
 Frozen tumor samples from 148 node-negative, breast cancer patients aged between 55 and 70 years at diagnosis were selected. Patients were treated with breast conserving therapy or mastectomy with axillary lymph node dissection between 1984 and 1996 at the Netherlands Cancer Institute. Eighteen percent received adjuvant tamoxifen, none of the patients received adjuvant chemotherapy. Samples were evaluated by gene expression profiling for the 70-gene profile and were classified as genomic high risk or genomic low risk. Clinical risk was assessed using Adjuvant! Online. The median follow-up was 11.6 years.
 Results
 Among the 148 patients, 91 (61%) were classified as genomic low risk, whereas 57 (39%) were classified as genomic high risk. The breast cancer specific survival (BCSS) at 5 and 10 years were 99% (SE 0.01) and 90% (SE 0.04), respectively, for the genomic low risk group versus 80% (SE 0.05) and 69% (SE 0.06), respectively, for the genomic high risk group (log rank p=0.036). The 70-gene prognosis profile was a predictor for BCSS at 5 and 10 years with hazard ratios (HR) of 19.1 (95% CI 2.5-148; p=0.005) and 3.9 (95% CI 1.7-9.0; p=0.002), respectively. In a multivariate model for BCSS including the genomic risk classification by the 70-gene prognosis profile and the clinical risk assessment by Adjuvant! online the profile outperformed the clinical risk assessment with a HR of 14.4 (95% CI 1.7-122.2; p=0.01) for BCSS at 5 years. The adjusted HR for the 70-gene profile for BCSS at 10 years was 2.2 (0.9-5.5; p=0.08).
 Conclusion 
 Our results show that the 70-gene prognosis profile is also a strong predictor of BCSS in postmenopausal women. In addition, the profile can accurately select patients at high risk of early metastases within 5 years of diagnosis. Since the beneficial effect of chemotherapy in older women predominantly occurs in the first 5 years, the profile can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1063.