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

Journal Article (2017)
Author(s)

Tesa M. Severson (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Denise M. Wolf (University of California)

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)

Bernard Pereira (Cancer Research UK)

Tycho Bismeijer (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Lodewyk Wessels (TU Delft - Pattern Recognition and Bioinformatics)

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)

Research Group
Pattern Recognition and Bioinformatics
DOI related publication
https://doi.org/10.1186/s13058-017-0861-2
More Info
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Publication Year
2017
Language
English
Research Group
Pattern Recognition and Bioinformatics
Volume number
2017
Pages (from-to)
1-9
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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 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.