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Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research article

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

Authors: 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

Published in: Breast Cancer Research | Issue 1/2017

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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.
Appendix
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Metadata
Title
The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting
Authors
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
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-017-0861-2

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