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

PUBLICATION: 
NPJ Breast Cancer. 2017 Aug 25;3:31. doi: 10.1038/s41523-017-0025-7.

AUTHORS: 
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.

ABSTRACT: 
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.

Read more: Wolf et al MammaPrint as biomarker in PARPi response Nature 2017