Limits...
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.

Show MeSH

Related in: MedlinePlus

Recurrence-free survival according to Wnt-5a expression and tamoxifen treatment in ER+ patients.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in ER+ patients with high/low proliferation rates A. NGH I–II, B. NGH III. Kaplan–Meier estimates of recurrence free survival according to tamoxifen treatment in C. Wnt-5a −/++, and D. Wnt-5a ++/+++ patients.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3750047&req=5

pone-0070890-g003: Recurrence-free survival according to Wnt-5a expression and tamoxifen treatment in ER+ patients.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in ER+ patients with high/low proliferation rates A. NGH I–II, B. NGH III. Kaplan–Meier estimates of recurrence free survival according to tamoxifen treatment in C. Wnt-5a −/++, and D. Wnt-5a ++/+++ patients.

Mentions: When stratifying the cohort according to ER status, subset analysis revealed that the favorable effect on outcome associated with Wnt-5a expression was more pronounced in ER+ tumors. In ER+ patients (n = 235) a significantly decreased risk of recurrence was seen in patients with moderate or strong expression of Wnt-5a (HR 0.56; 95% CI 0.38–0.85, p = 0.006). By multivariate analysis, Wnt-5a remained a statistically significant prognostic marker (HR 0.51; 95% CI 0.33–0.78, p = 0.002) after adjusting for standard prognostic factors including TAM treatment. While neither lymph node status nor tumor grade was significantly associated with outcome in the multivariate analysis, expression of HER2 was independently associated with an increased risk of relapse (HR 2.84; 95% CI 1.51 to 5.31, p = 0.001) (Table 2). In the ER- subgroup, no correlation between Wnt-5a expression and outcome was found (p = 0.95). This was true also when restricting the analysis to patients allocated to no adjuvant treatment (p = 0.8). When analyzing patients according to breast cancer subtypes, we found that Wnt-5a was a robust prognostic marker for luminal A tumors (p = 0.04; n = 161) but not for luminal B, HER2+ or triple-negative tumors (Figure 2). In an exploratory analysis including patients with ER+ disease divided according to histological appearance in low (NHG I–II), and high (NHG III) grade tumors, the prognostic effect of Wnt-5a expression was restricted to NHG I–II tumors, (p = 0.01) (Figure 3A–B). Since the luminal A subgroup encompasses tumors with low proliferation indices, with all likelihood corresponding to NHG I and II tumors, this latter finding is not unexpected and supports the result of the subtype analysis. VEGF-A expression did not add any prognostic information in the whole cohort, nor in the ER+ subset (Table 2). When categorizing tumors according VEGF-A expression and Wnt-5a expression into four groups (Wnt-5a low/VEGF-A high, Wnt-5a low/VEGF-A low, Wnt-5a high/VEGF-A high, Wnt-a5a high/VEGF-A low), we were not able to find any prognostic information by adding VEGF-A status to the information obtained by Wnt-5a (p = 0.17 log rank test).


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 and tamoxifen treatment in ER+ patients.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in ER+ patients with high/low proliferation rates A. NGH I–II, B. NGH III. Kaplan–Meier estimates of recurrence free survival according to tamoxifen treatment in C. Wnt-5a −/++, and D. Wnt-5a ++/+++ patients.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0070890-g003: Recurrence-free survival according to Wnt-5a expression and tamoxifen treatment in ER+ patients.Kaplan–Meier estimates of recurrence free survival according to Wnt-5a status in ER+ patients with high/low proliferation rates A. NGH I–II, B. NGH III. Kaplan–Meier estimates of recurrence free survival according to tamoxifen treatment in C. Wnt-5a −/++, and D. Wnt-5a ++/+++ patients.
Mentions: When stratifying the cohort according to ER status, subset analysis revealed that the favorable effect on outcome associated with Wnt-5a expression was more pronounced in ER+ tumors. In ER+ patients (n = 235) a significantly decreased risk of recurrence was seen in patients with moderate or strong expression of Wnt-5a (HR 0.56; 95% CI 0.38–0.85, p = 0.006). By multivariate analysis, Wnt-5a remained a statistically significant prognostic marker (HR 0.51; 95% CI 0.33–0.78, p = 0.002) after adjusting for standard prognostic factors including TAM treatment. While neither lymph node status nor tumor grade was significantly associated with outcome in the multivariate analysis, expression of HER2 was independently associated with an increased risk of relapse (HR 2.84; 95% CI 1.51 to 5.31, p = 0.001) (Table 2). In the ER- subgroup, no correlation between Wnt-5a expression and outcome was found (p = 0.95). This was true also when restricting the analysis to patients allocated to no adjuvant treatment (p = 0.8). When analyzing patients according to breast cancer subtypes, we found that Wnt-5a was a robust prognostic marker for luminal A tumors (p = 0.04; n = 161) but not for luminal B, HER2+ or triple-negative tumors (Figure 2). In an exploratory analysis including patients with ER+ disease divided according to histological appearance in low (NHG I–II), and high (NHG III) grade tumors, the prognostic effect of Wnt-5a expression was restricted to NHG I–II tumors, (p = 0.01) (Figure 3A–B). Since the luminal A subgroup encompasses tumors with low proliferation indices, with all likelihood corresponding to NHG I and II tumors, this latter finding is not unexpected and supports the result of the subtype analysis. VEGF-A expression did not add any prognostic information in the whole cohort, nor in the ER+ subset (Table 2). When categorizing tumors according VEGF-A expression and Wnt-5a expression into four groups (Wnt-5a low/VEGF-A high, Wnt-5a low/VEGF-A low, Wnt-5a high/VEGF-A high, Wnt-a5a high/VEGF-A low), we were not able to find any prognostic information by adding VEGF-A status to the information obtained by Wnt-5a (p = 0.17 log rank test).

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