TY - JOUR
T1 - DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial
AU - Wolf, Denise M.
AU - Yau, Christina
AU - Sanil, Ashish
AU - Glas, Annuska
AU - Petricoin, Emanuel
AU - Wulfkuhle, Julia
AU - Severson, Tesa M.
AU - Linn, Sabine
AU - Brown-Swigart, Lamorna
AU - Hirst, Gillian
AU - Buxton, Meredith
AU - Demichele, Angela
AU - Hylton, Nola
AU - Symmans, Fraser
AU - Yee, Doug
AU - Paoloni, Melissa
AU - Esserman, Laura
AU - Berry, Don
AU - Rugo, Hope
AU - Olopade, Olufunmilayo
AU - van ‘t Veer, Laura
N1 - Funding Information:
We thank the patients, patient advocates and investigators who participated in the I-SPY 2 study. We are grateful for support from our study sponsors: the Foundation for the National Institutes of Health (2010 to 2012) and Quantum Leap (2013 to present). We are thankful for support from the Safeway Foundation, Bill Bowes Foundation, Quintiles Transnational Corporation, Johnson & Johnson, Genentech, Amgen, Eli Lilly, Pfizer, Eisai Company, the San Francisco Foundation, Give Breast Cancer the Boot, the Breast Cancer Research Foundation, Side Out Foundation, Harlan Family, the 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, the NCI via a Big Data To Knowledge (BD2K) grant, and Bruce and Martha Atwater.
Publisher Copyright:
© The Author(s) 2017.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85028518510&partnerID=8YFLogxK
U2 - 10.1038/S41523-017-0025-7
DO - 10.1038/S41523-017-0025-7
M3 - Article
AN - SCOPUS:85028518510
SN - 2374-4677
VL - 3
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 31
ER -