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Predictive relevance of HOXB13 protein expression for tamoxifen benefit in breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Department of Oncology, Karolinska University Hospital.
Department of Clinical Pathology and Cytology, Karolinska University Hospital.
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2010 (English)In: Breast Cancer Research, ISSN 1465-542X, Vol. 12, no 4Article in journal (Refereed) Published
Abstract [en]

ABSTRACT: INTRODUCTION: The HOXB13:IL17BR index has been identified to predict clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer. Further studies have shown that HOXB13 in particular can indicate benefit of prolonged tamoxifen treatment. Patients with high-expressing tumors did not benefit from prolonged treatment, suggesting that HOXB13 might be involved in tamoxifen resistance. No studies have been made regarding the HOXB13 protein levels in breast cancer. The aim of our study was to investigate whether tamoxifen benefit can be correlated to different levels of HOXB13 protein expression. METHODS: We used immunohistochemistry to analyze protein levels of HOXB13 in tumor samples from 912 postmenopausal node-negative breast cancer patients randomized to adjuvant tamoxifen therapy or no endocrine treatment. RESULTS: Tamoxifen-treated patients with estrogen receptor-positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (DRFS) (hazard ratio = 0.38, 95% confidence interval = 0.23 to 0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared with the untreated patients (hazard ratio = 0.88, 95% confidence interval = 0.47 to 1.65, P = 0.69). Interaction between HOXB13 expression and benefit from tamoxifen was statistically significant for DRFS (P = 0.035). No prognostic value could be ascribed to HOXB13 among systemically untreated patients. CONCLUSIONS: A high HOXB13 expression was associated with decreased benefit from tamoxifen, which indicates that HOXB13 protein level may be used as a predictive marker for tamoxifen treatment.

Place, publisher, year, edition, pages
2010. Vol. 12, no 4
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-58819DOI: 10.1186/bcr2612OAI: diva2:345863
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2014-11-13Bibliographically approved
In thesis
1. Homeobox B13 in breast cancer: Prediction of tamoxifen benefit
Open this publication in new window or tab >>Homeobox B13 in breast cancer: Prediction of tamoxifen benefit
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A major issue in the management of breast cancer is to identify patients who are less likely to be cured after primary treatment and would benefit from adjuvant chemotherapy. Of great importance is also identification of patients with only local disease who traditionally would be given chemotherapy but would survive without. In this thesis we have validated the utility of the two-gene ratio HOXB13:IL17BR, which previously has been demonstrated to predict disease-free survival in tamoxifen-treated breast cancer patients. We have also studied the prognostic and predictive utility of a single gene as a biomarker in breast cancer medicine.

We could confirm that HOXB13:IL17BR may classify patients with different treatment benefit; only patients with a low value showed benefit from prolonged duration of tamoxifen therapy, whereas for the group with high ratios, the long-term recurrence rate did not improve with longer treatment duration.

The combination of HOXB13:IL17BR and the molecular grade index (MGI), another prognostic marker, has been shown to outperform either alone in predicting risk of breast cancer recurrence. We validated the prognostic utility of HOXB13:IL17BR+MGI in a large randomized patient cohort and found that this risk classification identified more than 50% of the tamoxifen-treated lymph node-negative patients as having a less than 3% risk of distant recurrence and breast cancer death. Furthermore, we developed and tested a continuous risk model of HOXB13:IL17BR+MGI called Breast Cancer Index (BCI), for estimation of recurrence risk at the individual level. Our study shows that BCI has the ability to identify more than 50% of patients with a low risk of recurrence more accurately than using traditional risk assessment. These results suggest that BCI may help clinicians to make better informed treatment decisions and spare toxic chemotherapy for a large group of breast cancer patients.

The protein expression of HOXB13 was also shown to be a valuable predictor in postmenopausal patients. High expression was associated with worse outcome after tamoxifen therapy. In a premenopausal cohort, patients with hormone receptor-positive tumors showed benefit from tamoxifen regardless of HOXB13 expression. Further analysis indicated that estrogen receptor β (ERβ) modified the performance of HOXB13 as a predictor of treatment effect and should be taken into account when identifying patients less likely to respond to the therapy given.

In conclusion, BCI identifies patients with a very low risk of distant recurrence. It may be utilized in the management of breast cancer patients to optimize the use of chemotherapy. HOXB13 protein expression may be used as a marker for tamoxifen benefit, but its performance in premenopausal patients might be modified by ERβ.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 69 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1243
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-68137 (URN)978-91-7393-184-7 (ISBN)
Public defence
2011-06-01, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Available from: 2011-05-12 Created: 2011-05-12 Last updated: 2011-05-12Bibliographically approved

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