The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting

Severson, TM; Wolf, DM; Yau, C; Peeters, J; Wehkam, D; Schouten, PC; Chin, SF; Majewski, IJ; Michaut, M; Bosma, A; Pereira, B; Bismeijer, T; Wessels, L; Caldas, C; Bernards, R; Simon, IM; Glas, AM; Linn, S; van &#39;t Veer, L

Author(s): Severson, TM; Wolf, DM; Yau, C; Peeters, J; Wehkam, D; Schouten, PC; Chin, SF; Majewski, IJ; Michaut, M; Bosma, A; Pereira, B; Bismeijer, T; Wessels, L; Caldas, C; Bernards, R; Simon, IM; Glas, AM; Linn, S; van 't Veer, L;
Details: Publication Year 2017-08-25,Volume 19,Issue #1,Page 99
Journal Title: Breast Cancer Research
Publication Type: Journal Article
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 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 x 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 .
Publisher: BioMed Central
Research Division(s): Cancer And Haematology
PubMed ID: 28851423
Publisher's Version: https://doi.org/10.1186/s13058-017-0861-2
Open Access at Publisher's Site: https://breast-cancer-research-biomedcentral-com/articles/10.1186/s13058-017-0861-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Severson et al Breast Canc Res_2017.pdf - (1.16MB, application/pdf)

Creation Date: 2017-10-16 02:00:17

Last Modified: 2017-10-17 08:03:50