Abstract P4-11-11: CADER prognostic gene signature for disease free survival in hormone receptor positive breast cancer: NCIC CTG MA.12 phase III placebo-controlled tamoxifen trial
Authors: Ellis Matthew J , Chen Bingshu , Chapman Judy-Anne W , Luo Jingqin , Ma Diana , Shepherd Lois , Hoog Jeremy , Leung Samuel , Mardis Elaine , Davies Sherri R , Nielsen Torsten O , Bramwell Vivien 
Published: May 2015

Abstract
Background: The copy number aberration derived endocrine response (CADER) gene signature was developed as a prognostic marker for hormone receptor positive breast cancer; it combines information derived from both gene expression and copy number aberration and was trained on samples from both the neoadjuvant and adjuvant settings (see separate CADER nanostring assay methodology abstract, Luo et al). We examined the effects of CADER on outcome in the MA.12 trial to evaluate the association of CADER and PAM 50 with relapse.
Methods: From 1993 to 2000, MA.12 accrued 672 women to a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumors. The 9.7 years median follow-up was used here. A secondary endpoint was disease free survival (DFS), defined as time from randomization to the earliest date of recurrence or death; censoring was at the last date the patient was known to be alive. Stratification factors were type of chemotherapy (CMF vs CEF vs AC), hormone receptor status (ER and/or PgR positive vs ER and PgR negative), and nodal status (0 vs 1–3 vs 4–9 vs 10+). Exact Fisher tests were used to compare baseline characteristics of those assessed, or not, for CADER. We examined the effects of the CADER classifications (sensitive, indeterminate, resistant) for hormone receptor positive patients. The prognostic effects of CADER, and preexisting qPCR PAM50 ROR-S, and PAM50 intrinsic subtype (Chia et al, CCR 16, 4465, 2012) on DFS were examined with stratified multivariate Cox regression, adjusted for treatment and baseline patient characteristics. An interaction test with treatment was used to assess evidence for CADER as a predictive signature. Graphical depiction was with adjusted Cox survivor plots.
Results: CADER was assessed in 434 (65%) of the 672 patients: 213 patients on the tamoxifen arm; 221, on the placebo arm. Proportionately more patients profiled for CADER underwent CEF adjuvant chemotherapy (p=0.03) so we performed only stratified analyses. Of the 434 patients, 317 (73%) had hormone receptor breast tumors. The CADER classifications significantly impacted DFS (p=0.04): hazard ratio (HR) of indeterminate CADER to sensitive=2.29 (95% CI 0.93-5.62; p=0.07); HR of resistant to sensitive=3.72 (95% CI 1.33-10.42, p=0.01). Patients with low ROR-S had longer DFS (p=0.04), while PAM50 intrinsic subtype did not significantly impact DFS (p=0.51). CADER and ROR-S were not predictive factors.
Conclusions: In MA.12 hormone-receptor patients, both CADER and ROR-S had significant prognostic effects on disease free survival. Neither CADER nor PAM50 ROR were predictive in this placebo-controlled tamoxifen trial. We confirmed here the earlier clinical prognostic relevance of CADER that was seen during the signature’s development.
Citation Format: Matthew J Ellis, Bingshu Chen, Judy-Anne W Chapman, Jingqin Luo, Diana Ma, Lois Shepherd, Jeremy Hoog, Samuel Leung, Elaine Mardis, Sherri R Davies, Torsten O Nielsen, Vivien Bramwell. CADER prognostic gene signature for disease free survival in hormone receptor positive breast cancer: NCIC CTG MA.12 phase III placebo-controlled tamoxifen trial [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 P4-11-11.