March 1, 2017
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
NPJ Breast Cancer. 2017 Aug 25;3:31. doi: 10.1038/s41523-017-0025-7.
Wolf D.M., Yau C., Sanil A., Glas A., Petricoin E., Wulfkuhle J., Severson T.M., Linn S., Brown-Swigart L., Hirst G., Buxton M., DeMichele A., Hylton N., Symmans F., Yee D., Paoloni M., Esserman L., Berry D., Rugo H., Olopade O., van ‘t Veer L.
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.