The BRCA1ness signature is associatedsignificantly with response to PARP inhibitor treatment versus control in theI-SPY 2 randomized neoadjuvant setting

Journal article (2017)

Authors

Tesa M. Severson Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Denise M. Wolf University of California
Bernard Pereira Cancer Research UK
Tycho Bismeijer Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
L.F.A. Wessels Pattern Recognition and Bioinformatics - EEMCS
Carlos Caldas Cancer Research UK
Rene Bernards Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Iris M. Simon Agendia NV
Annuska M. Glas Agendia NV
Sabine C. Linn University Medical Center Utrecht, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Laura van 't Veer Agendia NV
Christina Yau University of California
Justine Peeters Agendia NV
Diederik Wehkam Agendia NV
Philip C. Schouten Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Suet-Feung Chin Cancer Research UK
Ian J. Majewski Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, Walter and Eliza Hall Institute of Medical Research
Magali Michaut Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Astrid Bosma Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Research Group
Pattern Recognition and Bioinformatics (EEMCS) (TU Delft)
Copyright: © 2017 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, L.F.A. Wessels, Carlos Caldas, Rene Bernards, Iris M. Simon, Annuska M. Glas, Sabine C. Linn, Laura van 't Veer
DOI: https://doi.org/10.1186/s13058-017-0861-2
More Info
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Published Date

2017

Language

English

Faculty

Electrical Engineering, Mathematics and Computer Science

Department

Intelligent Systems

Research Group

Pattern Recognition and Bioinformatics

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 BRCA1 ness 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 BRCA1 ness 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 signif
icantly 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.