Journal
NPJ BREAST CANCER
Volume 3, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41523-017-0025-7
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Funding
- Foundation for the National Institutes of Health
- Quantum Leap
- Safeway Foundation
- Bill Bowes Foundation
- Quintiles Transnational Corporation
- Johnson Johnson
- Genentech
- Amgen
- Eli Lilly
- Pfizer
- Eisai Company
- San Francisco Foundation
- Give Breast Cancer the Boot
- Breast Cancer Research Foundation
- Side Out Foundation
- Harlan Family
- Avon Foundation for Women
- Alexandria Real Estate Equities
- National Cancer Institute Specialized Program of Research Excellence in Breast Cancer
- American College of Radiology Imaging Network
- Cancer and Leukemia Group B
- National Cancer Institute Center for Bioinformatics
- NCI via a Big Data To Knowledge (BD2K) grant
- Bruce and Martha Atwater
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Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2-patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2-patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the 'predicted sensitive' group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline mutation status associated with VC response, but its low prevalence precluded further evaluation. PARPi-7, BRCA1ness, and MP1/2 specifically associated with response in the VC arm but not the control arm. Neither CIN70 nor PARP1 protein specifically predicted VC response. When we combined the PARPi-7 and MP1/2 classifications, the 42% of triple negative patients who were PARPi7-high and MP2 had an estimated pCR rate of 75% in the VC arm. Only 11% of HR+/HER2-patients were PARPi7-high and MP2; but these patients were also more responsive to VC with estimated pathologic complete response rates of 41%. PARPi-7, BRCA1ness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care.
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