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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, Mark G. Erlander

From AviaraDx Inc, Carlsbad, CA; The Breast Center, Baylor College of Medicine, Houston, TX; Department of Pathology, Harvard Medical School, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, MA; and the Department of Hematology/Oncology, Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA

Address reprint requests to Mark G. Erlander, PhD, 2715 Loker Ave W, Carlsbad, CA 92008; e-mail: merlander{at}aviaradx.com

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.

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 conflicts of interest and author contributions are found at the end of this article.

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