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

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 × 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 .

Keywords: BRCAness; Breast cancer; Neoadjuvant; PARP inhibition; Triple-negative breast cancer.

Fig. 1

CONSORT diagram. CONSORT diagram indicating how patients were randomized for the I-SPY 2 TRIAL

Fig. 2

Unsupervised hierarchical clustering of 77 genes in the 128 discovery set samples. The 77 genes were derived from a supervised analysis to identify those genes most informative in distinguishing BRCA1-like from non-BRCA1-like TN breast cancers [33]. Scaled expression value denoted as Z score (red–blue scale: red indicates high expression and blue indicates low expression). Information bar indicates MLPA BRCA1-like status: true (green) or false (brown). MLPA multiplex ligation-dependent probe amplification (Color figure online)

Fig. 3

The 77-gene signature network analysis. a Significant canonical pathways (top) and molecular functions (bottom). Negative log p value is on the x axis. b Network analysis of the 77 genes in the BRCA1ness signature. Grey shading indicates genes found in signature, solid lines show direct relationships between proteins and dashed lines show indirect relationships

Fig. 4

I-SPY 2 TRIAL. a Mosaic plot depicting the number of patients with pathological complete response (pCR) in each treatment group and signature group. Top row indicates patients in the trial enrolled in the control arm and bottom row indicates patients in the V-C arm. Number of patients with pCR is shown in green and number of patients without pCR is shown in tan. Black outlined boxes indicate the patients with a non-BRCA1ness status (left), red outlined boxes depict those with BRCA1ness status (right). b Histological subtype of the patients in the trial divided by treatment arm (V-C) and control arm and pCR rate per group. c Odds ratio (OR) and likelihood ratio test (LR) for treatment and control arms of the trial and the biomarker x treatment interaction test. HER2 human epidermal growth factor receptor 2, HR hormone receptor status, TN triple-negative, V/C veliparib-carboplatin (Color figure online)