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

Steven A Buechler; Kathryn P Gray; Yesim Gökmen-Polar; Scooter Willis; Beat Thürlimann; Rosita Kammler; Giuseppe Viale; Brian Leyland-Jones; Sunil S Badve; Meredith M Regan

doi:10.1093/jncics/pkz051

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

JNCI Cancer Spectr. 2019 Aug 16;3(4):pkz051. doi: 10.1093/jncics/pkz051. eCollection 2019 Dec.

Authors

Steven A Buechler^{1

2}, Kathryn P Gray^{3

4}, Yesim Gökmen-Polar⁵, Scooter Willis⁶, Beat Thürlimann^{7

8}, Rosita Kammler⁹, Giuseppe Viale¹⁰, Brian Leyland-Jones⁶, Sunil S Badve^{5

11}, Meredith M Regan^{3

12}

Affiliations

¹ University of Notre Dame, Notre Dame, IN.
² Harper Cancer Research Institute, Notre Dame, IN.
³ IBCSG Statistical Center Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA.
⁴ Harvard T.H. Chan School of Public Health, Boston, MA.
⁵ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN.
⁶ Avera Cancer Institute, Department of Molecular and Experimental Medicine, Sioux Falls, SD.
⁷ Breast Center, Kantonsspital, St. Gallen, Switzerland.
⁸ Swiss Group for Clinical Cancer Research SAKK, Berne, Switzerland.
⁹ International Breast Cancer Study Group Coordinating Center Pathology Office, Bern, Switzerland.
¹⁰ University of Milan, IEO European Institute of Oncology IRCCS, Milan, Italy.
¹¹ Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
¹² Harvard Medical School, Boston, MA.

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.