The HOXB13:IL17BR Expression Index Is a Prognostic Factor in Early-Stage Breast Cancer Xiao-Jun Ma, Susan G. Hilsenbeck, Wilson Wang, Li Ding, Dennis C. Sgroi, Richard A. Bender, C. Kent Osborne, D. Craig Allred, and Mark G. Erlander A B S T R A C T Purpose We previously identified three genes, HOXB13, IL17BR and CHDH, and the HOXB13:IL17BR ratio index in particular, that strongly predicted clinical outcome in breast cancer patients receiving tamoxifen monotherapy. Confirmation in larger independent patient cohorts was needed to fully validate their clinical utility. Patients and Methods Expression of HOXB13, IL17BR, CHDH, estrogen receptor (ER) and progesterone receptor (PR) were quantified by real-time polymerase chain reaction in 852 formalin-fixed, paraffin-embedded primary breast cancers from 566 untreated and 286 tamoxifen-treated breast cancer patients. Gene expression and clinical variables were analyzed for association with relapse-free survival (RFS) by Cox proportional hazards regression models. Results ER and PR mRNA measurements were in close agreement with immunohistochemistry. In the entire cohort, expression of HOXB13 was associated with shorter RFS (P = .008), and expression of IL17BR and CHDH was associated with longer RFS (P  .0001 for IL17BR and P = .0002 for CHDH). In ER+ patients, the HOXB13:IL17BR index predicted clinical outcome independently of treatment, but more strongly in node-negative patients. In multivariate analysis of the ER+ node-negative subgroup including age, PR status, tumor size, S phase fraction, and tamoxifen treatment, the two-gene index remained a significant predictor of RFS (hazard ratio = 3.9; 95% CI, 1.5 to 10.3; P = .007). Conclusion This tumor bank study demonstrated HOXB13:IL17BR index is a strong independent prognostic factor for ER+ node-negative patients irrespective of tamoxifen therapy. J Clin Oncol 24:4611-4619. © 2006 by American Society of Clinical Oncology INTRODUCTION Breast cancer is a heterogeneous disease with a highly variable clinical course, presenting a great challenge to prognosis and therapeutic decisions. To help guide treatment decision making, several guidelines have been established. 1,2 The most recent (ninth) edition of the St Gallen guidelines considers both endocrine responsiveness and prognostic risk assessment in forming treatment decisions. 2 Histor- ically, hormone receptor status, a target for endo- crine therapies, has been considered the standard for predicting response to treatment. 3,4 However, posi- tive receptor status is not sufficient to ensure a ther- apeutic response because additional molecular alterations such as HER2 amplification and EGFR expression are thought to modify a tumor’s endo- crine responsiveness. 5-7 Similarly, prognosis has largely been based on clinical (eg, age and meno- pausal status) and pathologic parameters (eg, tumor size, grade and lymph node status). However, a sub- set of patients with a “good” prognosis (eg, estrogen receptor–positive [ER+] and node negative) may still develop recurrence after curative surgery and adjuvant therapy. 3 An improved understanding of the underlying molecular pathways that drive breast cancer development offers new opportunities for both predicting a tumor’s responsiveness to treat- ment and assessing a tumor’s intrinsic aggressive- ness. The development of microarray technology has facilitated novel translational research promis- ing significant progress in these areas. 8-16 To discover novel biomarkers predicting ta- moxifen response in the adjuvant setting, we have previously conducted a microarray-based survey of gene expression patterns that correlate with clinical outcome. 15 In the initial cohort of 60 tamoxifen- treated patients, we identified three genes, HOXB13 From AviaraDx Inc, Carlsbad, CA; The Breast Center, Baylor College of Medi- cine, Houston, TX; Department of Pathology, Harvard Medical School, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, MA; and the Department of Hematology/Oncology, Quest Diagnos- tics, Nichols Institute, San Juan Capistrano, CA. Submitted March 20, 2006; accepted July 31, 2006. Supported by Grants No. 5P01CA030195 and 5P50CA058183 (S.G.H.); National Cancer Institute Grant No. RO1-1CA112021-01 (D.C.S.); Department of Defense Grant No. W81XWH-04-1-0606 (D.C.S.); Susan G. Komen Breast Cancer Foundation Grant No. BCTR0402932 (D.C.S.); and a grant from the Avon Foundation (D.C.S.). Presented in part at the 28th San Antonio Breast Cancer Symposium, December 8-11, 2005, San Antonio, TX. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Mark G. Erlander, PhD, 2715 Loker Ave W, Carlsbad, CA 92008; e-mail: merlander@aviaradx.com. © 2006 by American Society of Clinical Oncology 0732-183X/06/2428-4611/$20.00 DOI: 10.1200/JCO.2006.06.6944 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 28  OCTOBER 1 2006 4611 Downloaded from jco.ascopubs.org on October 21, 2016. For personal use only. No other uses without permission. Copyright © 2006 American Society of Clinical Oncology. All rights reserved.