DNA repair deficiency biomarkers identify HR+/HER2- breast cancer patients who may benefit from veliparib/carboplatin: results from the I-SPY 2 TRIAL

Author(s): L. van 't Veer, L. Esserman, A. Sanil, A. Glas, T. Severson, S. Linn, L. Brown-Swigart, G. Hirst, I-SPY 2 TRIAL Investigators, O. Olapade, H .Rugo, D. Berry, D. M. Wolf, and C. Yau

Background

In I-SPY 2, HER2- patients were adaptively randomized to receive standard chemotherapy or the PARP inhibitor veliparib with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) subtype, and we have previously shown that DNA repair deficiency signatures [PARPi-7 and BRCAness] may predict V/C response. Here we combine these signatures into a composite measure of DNA repair deficiency and investigate whether this measure can identify a subset of HR+/HER2- patients likely to respond to V/C.

Conclusion:

  • Here, HR+/Her2- tumors are identified as DNA repair deficient if carrying a BRCA1/2 mutation or BRCA-like or PARPi7-high.
  • Our exploratory analysis suggests that 38% of HR+/HER2- patients in I-SPY 2 are DNA repair deficient and may benefit from V/C.
  • If validated, DNA repair deficiency biomarkers may merit further investigation for selecting HR+/HER2- patients for future early phase PARP inhibitor trials.

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ASCO 2015 Abstract# 521

About the I-SPY 2 Trial
  • Adaptive clinical trial for women with newly diagnosed, locally advanced breast cancer to enrich for pre-specified breast cancer subtypes defined by HR, HER2 and MammaPrint showing highest efficacy
  • Inclusion: ‘MammaPrint high risk’ or ‘MammaPrint low risk and HR- OR HER2+’
  • Goal: To identify (graduate) regimens that have ≥ 85% predictive probability of success in a neoadjuvant 300-patient phase 3 trial of patients in 1 of 10 possible signatures defined by HR, HER2, and MammaPrint High1/2 risk status.
  • I-SPY 2 Biomarker component: Designed to facilitate evaluation of novel biomarkers of response in conjunction with the pre-defined signatures