Homeobox B13 protein expression in a randomized tamoxifen trial of premenopausal breast cancer

• Homeobox B13 (HOXB13), part of the two-gene expression index HOXB13:IL17BR, has proven its capacity as a predictive factor of tamoxifen benefit in breast cancer. HOXB13 mRNA expression, as well as protein levels, have shown predictive value in postmenopausal patients. High levels were associated with decreased tamoxifen benefit and may indicate endocrine resistance. Here, we have analyzed HOXB13 protein expression in premenopausal breast cancer. We quantified the levels of HOXB13 with immunohistochemistry in tumor samples from 487 patients on tissue microarrays. Patients were diagnosed with stage II invasive breast cancer and randomized to tamoxifen or no endocrine treatment. HOXB13 protein analysis was successful for 367 patients. Data were correlated with clinicopathological variables. Investigation of tamoxifen benefit in patients with tumors expressing estrogen receptor (ER) α, progesterone receptor, or both, showed that patients with high HOXB13 levels had benefit from tamoxifen (hazard ratio for recurrences 0.43, 95% CI: 0.28-1.01, p=0.053). Corresponding numbers for the low HOXB13 group were 0.69 (95% CI: 0.44-1.07, p=0.10). For further analysis, we stratified the patients based on tumor ERβ status, which may function as a modifier of the performance of HOXB13 as a treatment predictive factor. For the ERβ positive subset of patients, there was a tendency towards a low HOXB13 expression associated with a better tamoxifen response. However, an increased benefit from tamoxifen, in terms of a longer recurrence-free survival (RFS), was associated with high HOXB13 expression in the ERβ negative group. The interaction between HOXB13 and treatment effect for RFS in the ERβ-negative group was significant in a multivariate model (p=0.04). In conclusion, in our study cohort, ERβ seems to be an additional determinant to HOXB13 protein expression for endocrine treatment prediction in premenopausal breast cancer. To identify patients less likely to respond to tamoxifen therapy, both HOXB13 and ERβ status should be taken into account.

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MEDICIN

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