The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting
Authors/Creators
- Severson, Tesa M.1
- Wolf, Denise M.2
- Yau, Christina2
- Peeters, Justine3
- Wehkam, Diederik3
- Schouten, Philip C.1
- Chin, Suet-Feung4
- Majewski, Ian J.5
- Michaut, Magali5
- Bosma, Astrid5
- Pereira, Bernard4
- Bismeijer, Tycho5
- Wessels, Lodewyk5
- Caldas, Carlos4
- Bernards, René5
- Simon, Iris M.3
- Glas, Annuska M.3
- Linn, Sabine1
- van 't Veer, Laura3
- 1. Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- 2. University of California, San Francisco, CA, USA
- 3. Agendia NV, Amsterdam, The Netherlands
- 4. CRUK Cambridge Institute, Cambridge, UK
- 5. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
Description
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.