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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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Recurrence-free survival according to Wnt-5a expression.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in A. whole cohort, B. ER+ patients. C–F. Kaplan–Meier estimates of recurrence-free survival according to Wnt-5a status stratified for breast cancer subtype. C. Luminal A, D. Luminal B, E. HER2+, and F. TNBC.
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pone-0070890-g002: Recurrence-free survival according to Wnt-5a expression.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in A. whole cohort, B. ER+ patients. C–F. Kaplan–Meier estimates of recurrence-free survival according to Wnt-5a status stratified for breast cancer subtype. C. Luminal A, D. Luminal B, E. HER2+, and F. TNBC.

Mentions: For survival analyses, a dichotomised variable defined as low or absent staining versus moderate or strong staining was used. As shown in Figure 2, Wnt-5a protein expression in the whole cohort was associated with an improved Recurrence Free Survival (RFS) (Log Rank test, p = 0.03). We proceeded to perform a Cox regression proportional hazards analysis of RFS to demonstrate estimates of relative risk according to expression of Wnt-5a in univariate and multivariate analyses (Table 2). The multivariate analysis was adjusted for age at diagnosis, ER, PR, tumor size, histological grade, lymph node status and HER2 expression. In the univariate analysis, patients with Wnt-5a-expressing tumors showed an improved RFS compared with patients with Wnt-5a-negative tumors (Hazard Ratio [HR] 0.70; 95% confidence interval [CI] 0.51 to 0.97, p = 0.03). In a multivariate analysis, tumor spread to lymph nodes, large tumor size, and high histological grade were independent markers of poor prognosis. Patients with Wnt-5a-expressing tumors had a favorable prognosis of borderline significance (HR 0.74; 95% CI 0.54–1.02, p = 0.06 (Table 2).


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)

Recurrence-free survival according to Wnt-5a expression.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in A. whole cohort, B. ER+ patients. C–F. Kaplan–Meier estimates of recurrence-free survival according to Wnt-5a status stratified for breast cancer subtype. C. Luminal A, D. Luminal B, E. HER2+, and F. TNBC.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0070890-g002: Recurrence-free survival according to Wnt-5a expression.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in A. whole cohort, B. ER+ patients. C–F. Kaplan–Meier estimates of recurrence-free survival according to Wnt-5a status stratified for breast cancer subtype. C. Luminal A, D. Luminal B, E. HER2+, and F. TNBC.
Mentions: For survival analyses, a dichotomised variable defined as low or absent staining versus moderate or strong staining was used. As shown in Figure 2, Wnt-5a protein expression in the whole cohort was associated with an improved Recurrence Free Survival (RFS) (Log Rank test, p = 0.03). We proceeded to perform a Cox regression proportional hazards analysis of RFS to demonstrate estimates of relative risk according to expression of Wnt-5a in univariate and multivariate analyses (Table 2). The multivariate analysis was adjusted for age at diagnosis, ER, PR, tumor size, histological grade, lymph node status and HER2 expression. In the univariate analysis, patients with Wnt-5a-expressing tumors showed an improved RFS compared with patients with Wnt-5a-negative tumors (Hazard Ratio [HR] 0.70; 95% confidence interval [CI] 0.51 to 0.97, p = 0.03). In a multivariate analysis, tumor spread to lymph nodes, large tumor size, and high histological grade were independent markers of poor prognosis. Patients with Wnt-5a-expressing tumors had a favorable prognosis of borderline significance (HR 0.74; 95% CI 0.54–1.02, p = 0.06 (Table 2).

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