Journal Article

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

Wehkam, Diederik, Bismeijer, Tycho, Wolf, Denise M., Peeters, Justine, Glas, Annuska M., Pereira, Bernard, Bernards, René, Yau, Christina, Michaut, Magali, Simon, Iris M., Schouten, Philip C., Chin, Suet-Feung, Bosma, Astrid, Severson, Tesa M., van ‘t Veer, Laura, Wessels, Lodewyk, Caldas, Carlos, Linn, Sabine, Majewski, Ian J.

2017

Overview

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 ( BRCA1 ness) 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 BRCA1 ness 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 BRCA1 ness 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 ( BRC1A ness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1 ness 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,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adjuvant treatment / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomarkers / Biomarkers, Tumor / Biomedical and Life Sciences / Biomedicine / BRCA mutations / BRCA1 protein / BRCA1 Protein - genetics / BRCAness / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer / Cancer Research / Cancer therapies / Carboplatin / Chemotherapy / Chemotherapy, Adjuvant / Cluster Analysis / Deoxyribonucleic acid / Discriminant analysis / DNA / DNA damage / DNA methylation / DNA repair / Drug therapy / ErbB-2 protein / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Gene Regulatory Networks / Genetic aspects / Genomics / Humans / Kinases / Medical prognosis / Mutation / Neoadjuvant / Neoadjuvant Therapy / Oncology / PARP inhibition / Physiological aspects / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage / Poly(ADP-ribose) Polymerase Inhibitors - adverse effects / Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use / Research Article / Sensitivity and Specificity / Surgical Oncology / Survival analysis / Targeted cancer therapy / Treatment Outcome / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - pathology / Triple-negative breast cancer / Tumors