Somatic HOXB13 Expression Correlates with Metastatic Progression in Men with Localized Prostate Cancer Following Radical Prostatectomy

BACKGROUND: Homeobox B13 (HOXB13) expression regulates normal prostate development and mutations are associated with prostate cancer (PCa) formation. OBJECTIVE: To assess the role of HOXB13 mRNA expression in PCa progression following radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide expression profiles were queried from two retrospective prostatectomy cohorts with follow-up data (Mayo Clinic, n = 780; Johns Hopkins Medical Institute [JHMI], n = 355), and a prospective genomic registry (n = 5239). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox regressions were used to analyze metastasis-free survival (MFS). RESULTS AND LIMITATIONS: HOXB13 expression in primary PCa increased with increasing tumor grade and with high metastatic potential based on a genomic signature. The highest quartile of HOXB13 expression was associated with worse MFS compared with the lowest quartile (Mayo Clinic: adjusted hazard ratio [AHR] 1.46, 95% confidence interval [CI] 1.03–2.06, and JHMI: AHR 1.80, 95% CI 1.02–3.19). The combinations of high HOXB13 expression and low expression of its binding partner, MEIS1 (AHR 2.03, 95% CI 1.54–2.66) or MEIS2 (AHR 1.73, 95% CI 1.33–2.26), portended worse MFS. Additionally, high HOXB13 expression in combination with low MEIS1/2 expression correlated with high expression of androgen receptor–mediated genes. The retrospective nature of this study subjects the findings to a bias due to unmeasured variables. CONCLUSIONS: Primary PCa tumors with increased HOXB13 expression have an increased propensity for metastases following prostatectomy, particularly in the setting of low MEIS1/2 expression. High androgen receptor output may account for worse outcomes for these tumors and suggests heightened sensitivity to androgen suppression. PATIENT SUMMARY: Using genomic data from a large number of prostate cancer (PCa) tumors, we found that increased expression of homeobox B13 (HOXB13), a gene related to normal prostate development, was associated with worse outcomes following surgery for PCa. A biomarker signature suggests that these tumors would be more susceptible to androgen suppression, a common treatment for PCa