Predictive Relevance of HOXB13 Expression in Breast Cancer
Predictive Relevance of HOXB13 Expression in Breast Cancer
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 (HR) = 0.38, 95% CI, 0.23–0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared to the untreated patients (HR = 0.88, 95% CI, 0.47–1.65, 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.
Recently, there have been several studies aimed at discovering novel biomarkers and gene signatures usable for predicting risk of recurrence and response to endocrine therapy of breast cancer. With the development of robust, reliable genetic markers for this purpose, it would be possible at an early stage to predict which patients would benefit from alternative hormonal therapies. Resulting gene signatures, based on genome-wide microarray analyses, are often very comprehensive and comprise a large number of genes. However, Ma and colleagues were able to show that their gene expression profiles of hormone receptor positive invasive breast tumors could be reduced into a simple two-gene ratio predictive of tumor relapse in the setting of adjuvant tamoxifen monotherapy. Subsequent studies of the HOXB13:IL17BR index have proven its significance in predicting risk of breast cancer recurrence and tamoxifen response.
Our previous study of the HOXB13:IL17BR expression ratio indicated that the two genes individually could function as separate prognostic and treatment predictive markers in breast cancer. Expression of IL17BR was inversely correlated to a number of factors related to a poor prognosis, whereas HOXB13 could predict recurrence in tamoxifen-treated patients. Patients with tumors expressing a high level of HOXB13 were more likely to be unresponsive to the therapy, suggesting that this gene is involved in tamoxifen resistance.
HOXB13 is a member of the homeobox gene family, a group of genes encoding transcriptional regulators of cell growth and differentiation, predominantly during embryogenesis. Much is known about the function of the homeobox genes in these events, but the role of HOXB13 in breast cancer and endocrine resistance is only beginning to be elucidated. The expression of HOXB13 is known to be upregulated in breast cancer cells compared to normal breast epithelium and it has also been shown that HOXB13 is an estrogen-regulated gene negatively correlated to estrogen receptor (ER) status. Wang and colleagues suggest that a high HOXB13:IL17BR index may indicate impaired ER signaling, which is known to predict resistance to tamoxifen.
To our knowledge, there are no studies investigating the HOXB13 protein levels in breast cancer and its significance in predicting outcome after tamoxifen treatment. In the present study, we used immunohistochemistry to analyze the protein expression of HOXB13 in tumor samples from 912 postmenopausal breast cancer patients. The patients were participants in a randomized trial analyzing the benefit from adjuvant treatment with tamoxifen, which enabled us to investigate the treatment predictive value of HOXB13.
Abstract and Introduction
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 (HR) = 0.38, 95% CI, 0.23–0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared to the untreated patients (HR = 0.88, 95% CI, 0.47–1.65, 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.
Introduction
Recently, there have been several studies aimed at discovering novel biomarkers and gene signatures usable for predicting risk of recurrence and response to endocrine therapy of breast cancer. With the development of robust, reliable genetic markers for this purpose, it would be possible at an early stage to predict which patients would benefit from alternative hormonal therapies. Resulting gene signatures, based on genome-wide microarray analyses, are often very comprehensive and comprise a large number of genes. However, Ma and colleagues were able to show that their gene expression profiles of hormone receptor positive invasive breast tumors could be reduced into a simple two-gene ratio predictive of tumor relapse in the setting of adjuvant tamoxifen monotherapy. Subsequent studies of the HOXB13:IL17BR index have proven its significance in predicting risk of breast cancer recurrence and tamoxifen response.
Our previous study of the HOXB13:IL17BR expression ratio indicated that the two genes individually could function as separate prognostic and treatment predictive markers in breast cancer. Expression of IL17BR was inversely correlated to a number of factors related to a poor prognosis, whereas HOXB13 could predict recurrence in tamoxifen-treated patients. Patients with tumors expressing a high level of HOXB13 were more likely to be unresponsive to the therapy, suggesting that this gene is involved in tamoxifen resistance.
HOXB13 is a member of the homeobox gene family, a group of genes encoding transcriptional regulators of cell growth and differentiation, predominantly during embryogenesis. Much is known about the function of the homeobox genes in these events, but the role of HOXB13 in breast cancer and endocrine resistance is only beginning to be elucidated. The expression of HOXB13 is known to be upregulated in breast cancer cells compared to normal breast epithelium and it has also been shown that HOXB13 is an estrogen-regulated gene negatively correlated to estrogen receptor (ER) status. Wang and colleagues suggest that a high HOXB13:IL17BR index may indicate impaired ER signaling, which is known to predict resistance to tamoxifen.
To our knowledge, there are no studies investigating the HOXB13 protein levels in breast cancer and its significance in predicting outcome after tamoxifen treatment. In the present study, we used immunohistochemistry to analyze the protein expression of HOXB13 in tumor samples from 912 postmenopausal breast cancer patients. The patients were participants in a randomized trial analyzing the benefit from adjuvant treatment with tamoxifen, which enabled us to investigate the treatment predictive value of HOXB13.