Abstract P5-10-02: A copy number aberration driven endocrine response gene signature stratifies risk in estrogen receptor positive breast cancer
Authors: Luo Jingqin , Chang Li-Wei , Tao Yu , Hoog Jeremy , Leung Samuel , Nielsen Torsten O , Ellis Matthew J 
Published: May 2015

Abstract
Background: Many prognostic gene signatures have been developed for estrogen receptor positive (ER+) breast cancer (BC); however, most have been solely based on mRNA expression data without integrated information on underlying primary drivers such as genomic aberrations. We therefore coupled gene expression and copy number aberration (CNA) in an attempt to improve upon prognostic signatures for ER+ BC.
Methods: mRNA expression based discovery was conducted between 172/59 ER+ BC with low/high Ki67 levels after neoadjuvant aromatase inhibition and significant genes (significance analysis of microarray, q-value less than 0.05) were screened by correlation (Mann-Whitney-Wilcoxon test P less than 0.05) with CNA using Agilent comparative genomic hybridization array. Further interrogation on prognosis of relapse-free survival (RFS) by univariate survival analysis (P less than 0.05) in patients treated with adjuvant endocrine monotherapy from a public data set produced a Copy Number Aberration Driven Endocrine Response (CADER) signature consisting of treatment sensitive/resistant genes. MetaCore (GeneGo Inc) pathway analysis was conducted for enriched pathways. We subsequently applied Nanostring nCounter technology to formalin fixed archival tumor RNA from 620 ER+ adjuvant tamoxifen treated BC (UBC TAM-series) for CADER gene profiling. Patients in multiple independent public data sets and the TAM-series were classified into treatment sensitive defined by up-regulated sensitive gene centroid and down-regulated resistant gene centroid by the median cutoffs, treatment resistant defined with the reverse pattern and indeterminate otherwise. CADER risk stratifications were associated with patient survival outcomes in public cohorts and the TAM-series. The Kaplan-Meier (KM) analysis and Cox models were used for survival analysis. Published PAM50 intrinsic subtypes and subtype based risk of relapse (ROR-S) assignments were used (Nielsen CCR 16:5222, 2010).
Results: A 54-gene CADER signature, 27 resistant/27 sensitive genes, was derived. Pathway analysis indicated that CADER was enriched with sensitive genes of cell survival functions while resistant genes were largely drivers of cell cycle progression. CADER stratifications were significantly prognostic of relapse free survival (RFS) in all public cohorts (log rank test P=0.05 for all) and in the UBC TMA-series (P=0.0001, BC specific survival and RFS). CADER showed an additional value (likelihood ratio test P=0.05) in all cohorts when both standard clinical variables and ROR-S were incorporated in multivariate Cox models. CADER were highly concordant with intrinsic subtypes and ROR-S (p=0.0001) in all data sets. However, CADER may stratify risk within ROR-S medium risk patients (P=0.002 METABRIC; P=0.003 and 0.036 in TAM-series for BC specific survival and RFS).
Conclusions: We have developed a signature that is prognostic of long-term survival in postmenopausal BC, further splits risk within ROR-S medium risk group and identifies some highly resistant BC in presence of ROR-S and clinical variables (see Ellis et. al. abstract for evaluation of a CADER single sample predictor in the MA12 Phase 3 clinical trial).
Citation Format: Jingqin Luo, Li-Wei Chang, Yu Tao, Jeremy Hoog, Samuel Leung, Torsten O Nielsen, Matthew J Ellis. A copy number aberration driven endocrine response gene signature stratifies risk in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-02.