Abstract P4-12-01: Independent validation of EarlyR gene signature in BIG 1-98: A randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer
Authors: Buechler S , Gray KP , Gökmen-Polar Y , Willis S , Thürlimann B , Kammler R , Leyland-Jones B , Badve SS , Regan MM 
Published: March 2017

Abstract
Background: EarlyR is a prognostic gene signature score in ER+ breast cancer (BC) computed from the expression values of ESPL1, SPAG5, MKI67, PLK1 and PGR using a novel algorithm. EarlyR has been validated in multiple cohorts profiled on Affymetrix and Illumina microarrays. This study sought to verify prognostic features of EarlyR in a cohort of BIG 1-98.
Patients and Methods: Illumina DASL assay was used to measure gene expression in FFPE tissue of primary BC from a case-cohort sampling subset of postmenopausal women in BIG 1-98 treated with adjuvant endocrine therapy (letrozole or tamoxifen). Chemotherapy treatment was at the discretion of individual physicians and patients. Among the 1218 patients centrally reviewed with sufficient RNA material for the DASL assay, 1174 with ER+ status and assessed for EarlyR are included in the analytic cohort. EarlyR scores and pre-specified risk strata (≤25=low, 26-75=intermediate, &gt;75=high) were computed, while blinded to clinical data. The analysis endpoints included distant recurrence free interval (DRFI) defined as time from randomization to BC recurrence at a distant site within 8 years and BC free-interval (BCFI) defined as time from randomization to first invasive BC recurrence at a local, regional or distant site or invasive contralateral BC within 8 years. Weighted proportional hazards models (univariate and multivariate, stratified by treatment assignment) were used to adjust for Kaplan-Meier, hazard ratio estimates and Wald test statistics to obtain unbiased analyses and to give consistent estimates.
Results: The distribution of the EarlyR risk groups was 67% low, 19% intermediate and 14% high risk in this ER+ cohort. EarlyR was prognostic for 8-year DRFI (P-trend=0.008). Patients with high EarlyR risk score (&gt;75) had significantly increased risk of distant recurrence within 8 years (univariate HR=1.73, 95%CI: 1.14-2.64) compared to low EarlyR risk group (≤25). The estimated 8-year DRFI (95%CI) is 84%(80%-88%) for high risk vs. 91%( 89%-92%) for low risk, corresponding to an absolute DRFI risk reduction of 7% (low vs high). EarlyR is also prognostic of 8-year BCFI in ER+ (P-trend=0.002) with the estimated 8-year BCFI (95%CI) 79%(75%-84%) for high risk vs. 88%( 86%-89%) for low risk. Consistent results were observed in ER+, HER2- (P-trend=0.01 for DRFI, P-trend=0.004 for BCFI), in ER+, LN- (P-trend=0.05 for DRFI, P-trend=0.03 for BCFI) and ER+, LN+ (P-trend=0.08 for DRFI, P-trend=0.03 for BCFI) subsets.
Conclusions: This study confirmed the prognostic significance of EarlyR using FFPE tissue from the BIG 1-98 trial. In analyses of all ER+ patients and subsets LN-, LN+ and HER2-, EarlyR classifies 65%-70% of patients as low risk, 11-16% as high risk, and &lt; 20% as intermediate risk. In these subsets, the size of the low risk group is larger and the size of the intermediate risk group is smaller than those reported for commercially available signatures. EarlyR identifies a set of high-risk patients with relatively poor prognosis who may be considered for additional treatment. The clinical utility of EarlyR requires further study.
Citation Format: Buechler S, Gray KP, Gökmen-Polar Y, Willis S, Thürlimann B, Kammler R, Leyland-Jones B, Badve SS, Regan MM. Independent validation of EarlyR gene signature in BIG 1-98: A randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-01.