Abstract P1-06-08: Independent validation of EarlyR gene signature in E2197: A randomized clinical trial comparing doxorubicin plus docetaxel to doxorubicin plus cyclophosphamide as adjuvant chemotherapy in breast cancer
Authors: Badve S , Wang V , Willis S , Leyland-Jones B , Gokmen-Polar Y , Shulman L , Martino S , Sparano J , Davidson N , Goldstein L , Buechler S 
Published: February 2018

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 nonlinear mathematical formula. EarlyR has been validated in multiple cohorts profiled on Affymetrix and Illumina microarrays and by RNA-seq. This study sought to assess the prognostic features of EarlyR in a cohort of E2197.
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 women in E2197 treated with doxorubicin plus docetaxel (AT) or doxorubicin plus cyclophosphamide (AC). ER+ patients received hormone therapy at physician's discretion. After 79.5 months median follow-up, disease-free survival was 85% in both treatment arms. Among patients centrally reviewed with sufficient RNA material for the DASL assay, 319 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 endpoint was disease-free survival (DFS), defined as the time from randomization to date of invasive BC recurrence or death from any cause within 8 years. Weighted Cox proportional hazards models were used to associate EarlyR score or risk strata with DFS. Variances of the estimated coefficients were adjusted to account for the case-cohort design.
Results: The distribution of the EarlyR risk groups was 59% low, 11% intermediate and 30% high risk in this ER+ cohort. The continuous EarlyR score was significantly prognostic of DFS up to 8 years after randomization (p = 0.02). Patients with low EarlyR score (≤ 25) had significantly lower risk of BC recurrence within 8 years (p = 0.031, univariate HR=0.562, 95%CI: 0.334-0.948) compared to those with high EarlyR score (&gt; 75). Analysis within the AC arm showed that patients with low EarlyR score had significantly lower risk of 8-year BC recurrence (p = 0.023, univariate HR=0.392, 95%CI: 0.175-0.878) compared to those with high EarlyR score. Within the AT arm there was no significant difference in 8-year DFS prognosis between any of the EarlyR risk groups.
Conclusions: This study confirmed the prognostic significance of EarlyR using FFPE tissue in a cohort of patients treated with AC chemotherapy from E2197. Patients with high EarlyR score who were treated with AC had significantly higher risk of recurrence than low EarlyR score patients treated with AC. On the other hand, prognosis of high EarlyR score AT-treated patients was not significantly lower than the prognosis of low EarlyR score AT-treated patients. Further study in a larger cohort is needed to assess the relative benefits of AC versus AT within the EarlyR high risk group and the EarlyR low risk group.
Citation Format: Badve S, Wang V, Willis S, Leyland-Jones B, Gokmen-Polar Y, Shulman L, Martino S, Sparano J, Davidson N, Goldstein L, Buechler S. Independent validation of EarlyR gene signature in E2197: A randomized clinical trial comparing doxorubicin plus docetaxel to doxorubicin plus cyclophosphamide as adjuvant chemotherapy in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-08.