The BRCA1ness signature is associatedsignificantly with response to PARP inhibitor treatment versus control in theI-SPY 2 randomized neoadjuvant setting
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)
PC Schouten (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Suet-Feung Chin (Cancer Research UK)
I 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)
C Caldas (Cancer Research UK)
Rene Bernards (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
IM 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)
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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.
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