Breast Cancer Research (Aug 2017)

The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting

  • Tesa M. Severson,
  • Denise M. Wolf,
  • Christina Yau,
  • Justine Peeters,
  • Diederik Wehkam,
  • Philip C. Schouten,
  • Suet-Feung Chin,
  • Ian J. Majewski,
  • Magali Michaut,
  • Astrid Bosma,
  • Bernard Pereira,
  • Tycho Bismeijer,
  • Lodewyk Wessels,
  • Carlos Caldas,
  • René Bernards,
  • Iris M. Simon,
  • Annuska M. Glas,
  • Sabine Linn,
  • Laura van ‘t Veer

DOI
https://doi.org/10.1186/s13058-017-0861-2
Journal volume & issue
Vol. 19, no. 1
pp. 1 – 9

Abstract

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Abstract Background Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. Methods A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic complete response in the V-C and control arms alone using Fisher’s exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p < 0.05) using a logistic model and adjusting for hormone receptor status (HR). Results We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p = 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p = 0.023) after correcting for HR. Conclusions A genomic-based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone. Trial registration I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379 .

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