The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting
AuthorSeverson, TM; Wolf, DM; Yau, C; Peeters, J; Wehkam, D; Schouten, PC; Chin, S-F; Majewski, IJ; Michaut, M; Bosma, A; ...
Source TitleBreast Cancer Research
University of Melbourne Author/sMajewski, Ian
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsSeverson, T. M., Wolf, D. M., Yau, C., Peeters, J., Wehkam, D., Schouten, P. C., Chin, S. -F., Majewski, I. J., Michaut, M., Bosma, A., Pereira, B., Bismeijer, T., Wessels, L., Caldas, C., Bernards, R., Simon, I. M., Glas, A. M., Linn, S. & van 'T Veer, L. (2017). The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. BREAST CANCER RESEARCH, 19 (1), https://doi.org/10.1186/s13058-017-0861-2.
Access StatusOpen Access
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 .
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