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The prognostic significance of Wnt-5a expression in primary breast cancer is extended to premenopausal women.

Sand-Dejmek J, Ehrnström R, Berglund P, Andersson T, Ryden L - PLoS ONE (2013)

Bottom Line: Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype.In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04).Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.

View Article: PubMed Central - PubMed

Affiliation: Experimental Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden ; Surgery, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.

ABSTRACT
Wnt-5a protein expression in primary tumors from unselected breast cancer patients has revealed a tumor suppressive function of the protein. However, in vitro experiments on human breast cancer cells have reported contradictory results, indicating both a tumor suppressive and promoting functions of Wnt-5a. This could be due to various functions of Wnt-5a in different subgroups of patients. The unselected cohorts analyzed to date for Wnt-5a protein expression contained few premenopausal patients. The aim of the present investigation was to evaluate the prognostic significance of Wnt-5a protein expression in a cohort of premenopausal women with comprehensive data on biomarkers, molecular subtypes and long-term outcome. In a randomized trial of adjuvant tamoxifen versus no adjuvant treatment, 564 premenopausal primary breast cancer patients were included. The median follow-up time was 14 years. A tumor tissue array was constructed and 361 samples were evaluated for Wnt-5a reactivity by immunohistochemistry. The primary end-point was recurrence-free survival. Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype. Wnt-5a was a prognostic factor in the whole cohort (p = 0.003). In patients with ER-positive tumors, Wnt-5a was an independent positive prognostic marker (HR 0.51 95% CI: 0.33-0.78 p = 0.002) and HER2 a negative prognostic marker (HR 2.84 95% CI: 1.51-5.31, p = 0.001) in a Cox multivariate analysis adjusted for standard prognostic markers and tamoxifen treatment. In the ER-negative subset, Wnt-5a added no prognostic information. In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04). Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.

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Design of clinical trial and immunoreactivity for Wnt-5a.A. Flow chart defining patients enrolled in clinical trial. B–E. Immunoreactivity for Wnt-5a protein in representative sections of invasive breast carcinomas. B. Tumor with strong (+++) Wnt-5a staining, C. Moderate (++) staining for Wnt-5a, D. Weak (+) staining for Wnt-5a, and E. No (−) Wnt-5a expression (left hand panels: 10× magnification; right hand panels: 40×).
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pone-0070890-g001: Design of clinical trial and immunoreactivity for Wnt-5a.A. Flow chart defining patients enrolled in clinical trial. B–E. Immunoreactivity for Wnt-5a protein in representative sections of invasive breast carcinomas. B. Tumor with strong (+++) Wnt-5a staining, C. Moderate (++) staining for Wnt-5a, D. Weak (+) staining for Wnt-5a, and E. No (−) Wnt-5a expression (left hand panels: 10× magnification; right hand panels: 40×).

Mentions: Premenopausal patients diagnosed with stage II primary breast cancer (n = 564) between January 1984 and September 1991 were enrolled in a randomized controlled multi-center trial comparing two years of adjuvant tamoxifen (TAM) with no adjuvant treatment. A flow-chart of the study is shown in Figure 1. Patients were included irrespective of hormone receptor status and less than 2% of the included patients received additional systemic adjuvant therapy. Tumor blocks could be retrieved from 500 of the 564 randomized patients and a tissue microarray (TMA) was constructed (see below). ER status was determined in 475 of the tumors. The trial design, primary treatment and clinical outcome in relation to treatment arm have been described in detail before and information on age, tumor size, lymph node status and Nottingham Histological Grade (NHG) was available [20]. Recurrence-free survival was the primary end-point in the study and the median follow-up time was 13.9 years for patients alive and free of breast cancer-related events. The study was approved by the Ethical Committees at the University of Lund the University of Linköping. Randomization was performed by the Regional Oncological Center and informed consent was registered for all included patients. The study has been included in the meta-analysis by the Early Breast Cancer Trialists'Collaborative Group [21].


The prognostic significance of Wnt-5a expression in primary breast cancer is extended to premenopausal women.

Sand-Dejmek J, Ehrnström R, Berglund P, Andersson T, Ryden L - PLoS ONE (2013)

Design of clinical trial and immunoreactivity for Wnt-5a.A. Flow chart defining patients enrolled in clinical trial. B–E. Immunoreactivity for Wnt-5a protein in representative sections of invasive breast carcinomas. B. Tumor with strong (+++) Wnt-5a staining, C. Moderate (++) staining for Wnt-5a, D. Weak (+) staining for Wnt-5a, and E. No (−) Wnt-5a expression (left hand panels: 10× magnification; right hand panels: 40×).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750047&req=5

pone-0070890-g001: Design of clinical trial and immunoreactivity for Wnt-5a.A. Flow chart defining patients enrolled in clinical trial. B–E. Immunoreactivity for Wnt-5a protein in representative sections of invasive breast carcinomas. B. Tumor with strong (+++) Wnt-5a staining, C. Moderate (++) staining for Wnt-5a, D. Weak (+) staining for Wnt-5a, and E. No (−) Wnt-5a expression (left hand panels: 10× magnification; right hand panels: 40×).
Mentions: Premenopausal patients diagnosed with stage II primary breast cancer (n = 564) between January 1984 and September 1991 were enrolled in a randomized controlled multi-center trial comparing two years of adjuvant tamoxifen (TAM) with no adjuvant treatment. A flow-chart of the study is shown in Figure 1. Patients were included irrespective of hormone receptor status and less than 2% of the included patients received additional systemic adjuvant therapy. Tumor blocks could be retrieved from 500 of the 564 randomized patients and a tissue microarray (TMA) was constructed (see below). ER status was determined in 475 of the tumors. The trial design, primary treatment and clinical outcome in relation to treatment arm have been described in detail before and information on age, tumor size, lymph node status and Nottingham Histological Grade (NHG) was available [20]. Recurrence-free survival was the primary end-point in the study and the median follow-up time was 13.9 years for patients alive and free of breast cancer-related events. The study was approved by the Ethical Committees at the University of Lund the University of Linköping. Randomization was performed by the Regional Oncological Center and informed consent was registered for all included patients. The study has been included in the meta-analysis by the Early Breast Cancer Trialists'Collaborative Group [21].

Bottom Line: Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype.In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04).Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.

View Article: PubMed Central - PubMed

Affiliation: Experimental Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden ; Surgery, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.

ABSTRACT
Wnt-5a protein expression in primary tumors from unselected breast cancer patients has revealed a tumor suppressive function of the protein. However, in vitro experiments on human breast cancer cells have reported contradictory results, indicating both a tumor suppressive and promoting functions of Wnt-5a. This could be due to various functions of Wnt-5a in different subgroups of patients. The unselected cohorts analyzed to date for Wnt-5a protein expression contained few premenopausal patients. The aim of the present investigation was to evaluate the prognostic significance of Wnt-5a protein expression in a cohort of premenopausal women with comprehensive data on biomarkers, molecular subtypes and long-term outcome. In a randomized trial of adjuvant tamoxifen versus no adjuvant treatment, 564 premenopausal primary breast cancer patients were included. The median follow-up time was 14 years. A tumor tissue array was constructed and 361 samples were evaluated for Wnt-5a reactivity by immunohistochemistry. The primary end-point was recurrence-free survival. Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype. Wnt-5a was a prognostic factor in the whole cohort (p = 0.003). In patients with ER-positive tumors, Wnt-5a was an independent positive prognostic marker (HR 0.51 95% CI: 0.33-0.78 p = 0.002) and HER2 a negative prognostic marker (HR 2.84 95% CI: 1.51-5.31, p = 0.001) in a Cox multivariate analysis adjusted for standard prognostic markers and tamoxifen treatment. In the ER-negative subset, Wnt-5a added no prognostic information. In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04). Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.

Show MeSH
Related in: MedlinePlus