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. Issue 4 (16th August 2019)

• Record Type: Journal Article
• Authors: Buechler, Steven A; Gray, Kathryn P; Gökmen-Polar, Yesim; Willis, Scooter; Thürlimann, Beat; Kammler, Rosita; Viale, Giuseppe; Leyland-Jones, Brian; Badve, Sunil S; Regan, Meredith M
• Is Part Of: JNCI cancer spectrum. Volume 3:Issue 4(2019)
• Publication Date: 2019-08-16
• DOI: 10.1093/jncics/pkz051
• Languages: English
• ISSNs: 2515-5091

Abstract

Abstract: Background: EarlyR gene signature in estrogen receptor–positive (ER+) breast cancer is computed from the expression values of ESPL1, SPAG5, MKI67, PLK1, and PGR . EarlyR has been validated in multiple cohorts profiled using microarrays. This study sought to verify the prognostic features of EarlyR in a case-cohort sample from BIG 1–98, a randomized clinical trial of ER+ postmenopausal breast cancer patients treated with adjuvant endocrine therapy (letrozole or tamoxifen). Methods: Expression of EarlyR gene signature was estimated by Illumina cDNA-mediated Annealing, Selection, and Ligation assay of RNA from formalin-fixed, paraffin-embedded primary breast cancer tissues in a case-cohort subset of ER+ women (N = 1174; 216 cases of recurrence within 8 years) from BIG 1–98. EarlyR score and prespecified risk strata (≤25 = low, 26–75 = intermediate, >75 = high) were "blindly" computed. Analysis endpoints included distant recurrence–free interval and breast cancer–free interval at 8 years after randomization. Hazard ratios (HRs) and test statistics were estimated with weighted analysis methods. 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 distant recurrence–free interval; EarlyR high-risk patients had statistically increased risk of distant recurrence within 8 years (HR = 1.73, 95% confidence interval = 1.14 to 2.64) compared with EarlyR low-risk patients. EarlyR was also prognostic of breast cancer–free interval (HR = 1.74, 95% confidence interval = 1.21 to 2.62). Conclusions: This study confirmed the prognostic significance of EarlyR using RNA from formalin-fixed, paraffin-embedded tissues from a case-cohort sample of BIG 1–98. EarlyR identifies a set of high-risk patients with relatively poor prognosis who may be considered for additional treatment. Further studies will focus on analyzing the predictive value of EarlyR signature.