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Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients.

Bignotti E, Ragnoli M, Zanotti L, Calza S, Falchetti M, Lonardi S, Bergamelli S, Bandiera E, Tassi RA, Romani C, Todeschini P, Odicino FE, Facchetti F, Pecorelli S, Ravaggi A - Br. J. Cancer (2011)

Bottom Line: Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls.High sHE4 levels were significantly associated with worse EC clinical characteristics.By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort.

View Article: PubMed Central - PubMed

Affiliation: Angelo Nocivelli Institute of Molecular Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. bignottieliana@yahoo.it

ABSTRACT

Background: To date, no good marker for screening or disease monitoring of endometrial cancer (EC) is available. The aims of this study were to investigate HE4 gene, protein expression and serum HE4 (sHE4) levels in a panel of ECs and normal endometria (NEs) and to correlate sHE4 with patient clinicopathological characteristics and prognosis.

Methods: Using quantitative real-time PCR we tested 46 ECs and 20 NEs for HE4 gene expression. Protein expression was analysed by immunohistochemistry on tissue microarrays in 153 ECs and 33 NEs. Pre-operative serum samples from 138 EC and 76 NE patients were analysed with HE4-EIA assay. Association between sHE4 and patient clinicopathological characteristics or outcome was evaluated.

Results: Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls. High sHE4 levels were significantly associated with worse EC clinical characteristics. By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort.

Conclusion: We demonstrate, for the first time, that high sHE4 levels correlates with an aggressive EC phenotype and may constitute an independent prognostic factor for poorly differentiated-ECs. Determination of sHE4 could be clinically useful in identifying high-risk EC patients for a more aggressive adjuvant therapy.

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Kaplan–Meier survival curves for EC patients according to sHE4 levels on the entire patient cohort (A, overall survival; B, progression-free survival; C, disease-free survival) and on poorly differentiated subgroup of EC patients (D, overall survival; E, progression-free survival; F, disease-free survival). P-values refer to the comparison between high vs low tertile, except for C, in which medium vs low tertile shows to be significant.
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fig4: Kaplan–Meier survival curves for EC patients according to sHE4 levels on the entire patient cohort (A, overall survival; B, progression-free survival; C, disease-free survival) and on poorly differentiated subgroup of EC patients (D, overall survival; E, progression-free survival; F, disease-free survival). P-values refer to the comparison between high vs low tertile, except for C, in which medium vs low tertile shows to be significant.

Mentions: As expected, known EC clinical prognostic factors such as FIGO stage, histological type and lymph node involvement showed a statistically significant association with OS, PFS and DFS in univariate analyses (all P<0.05, data not shown), proving the validity of the patient cohort recruited in this study. In addition, as displayed in Figures 4A and B, respectively, higher HE4 serum levels (high vs low HE4 tertiles) showed a significant association with poor OS (P=0.02) and shorter PFS (P=0.03). Regarding DFS (Figure 4C), medium vs low HE4 tertiles was significantly correlated with decreased DFS (P=0.04), whereas the difference between high and low HE4 tertiles showed a marginal significance (P=0.06). FIGO stage, histological type, lymph node involvement and HE4 serum levels were then included in a multivariate analysis. Non-endometrioid EC histological subtype, along with advanced FIGO stage, were identified as independent predictive factors for poor OS (P=0.01 and P=0.04, respectively, Table 4A), whereas sHE4 levels (medium vs low tertile) were shown to be marginally significant as prognostic factor for shorter OS (P=0.08, Table 4A). Regarding PFS, only histological type and, marginally, FIGO stages were of prognostic significance, whereas sHE4 levels were not (Table 4A). Regarding DFS, neither clinical parameters nor sHE4 levels were indicative of disease recurrence, even if elevated sHE4 levels exhibited the highest trend toward significance (P=0.14 and P=0.17, Table 4A). Then we performed a further survival analysis in the subgroup of 54 patients harbouring poorly differentiated ECs. The univariate model revealed that patients with elevated sHE4 levels (high tertile) had a significant poorer OS (P=0.02, Figure 4D), shorter PFS (P=0.02, Figure 4E) and worse DFS (P=0.01, Figure 4F) than patients with reduced sHE4 levels (low tertile). In multivariate analysis, sHE4 levels retained its significance as an independent prognostic factor for poor OS (P=0.04), shorter PFS (P=0.04) and decreased DFS (P=0.01) in the subgroup of patients with poorly differentiated ECs (Table 4B).


Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients.

Bignotti E, Ragnoli M, Zanotti L, Calza S, Falchetti M, Lonardi S, Bergamelli S, Bandiera E, Tassi RA, Romani C, Todeschini P, Odicino FE, Facchetti F, Pecorelli S, Ravaggi A - Br. J. Cancer (2011)

Kaplan–Meier survival curves for EC patients according to sHE4 levels on the entire patient cohort (A, overall survival; B, progression-free survival; C, disease-free survival) and on poorly differentiated subgroup of EC patients (D, overall survival; E, progression-free survival; F, disease-free survival). P-values refer to the comparison between high vs low tertile, except for C, in which medium vs low tertile shows to be significant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101927&req=5

fig4: Kaplan–Meier survival curves for EC patients according to sHE4 levels on the entire patient cohort (A, overall survival; B, progression-free survival; C, disease-free survival) and on poorly differentiated subgroup of EC patients (D, overall survival; E, progression-free survival; F, disease-free survival). P-values refer to the comparison between high vs low tertile, except for C, in which medium vs low tertile shows to be significant.
Mentions: As expected, known EC clinical prognostic factors such as FIGO stage, histological type and lymph node involvement showed a statistically significant association with OS, PFS and DFS in univariate analyses (all P<0.05, data not shown), proving the validity of the patient cohort recruited in this study. In addition, as displayed in Figures 4A and B, respectively, higher HE4 serum levels (high vs low HE4 tertiles) showed a significant association with poor OS (P=0.02) and shorter PFS (P=0.03). Regarding DFS (Figure 4C), medium vs low HE4 tertiles was significantly correlated with decreased DFS (P=0.04), whereas the difference between high and low HE4 tertiles showed a marginal significance (P=0.06). FIGO stage, histological type, lymph node involvement and HE4 serum levels were then included in a multivariate analysis. Non-endometrioid EC histological subtype, along with advanced FIGO stage, were identified as independent predictive factors for poor OS (P=0.01 and P=0.04, respectively, Table 4A), whereas sHE4 levels (medium vs low tertile) were shown to be marginally significant as prognostic factor for shorter OS (P=0.08, Table 4A). Regarding PFS, only histological type and, marginally, FIGO stages were of prognostic significance, whereas sHE4 levels were not (Table 4A). Regarding DFS, neither clinical parameters nor sHE4 levels were indicative of disease recurrence, even if elevated sHE4 levels exhibited the highest trend toward significance (P=0.14 and P=0.17, Table 4A). Then we performed a further survival analysis in the subgroup of 54 patients harbouring poorly differentiated ECs. The univariate model revealed that patients with elevated sHE4 levels (high tertile) had a significant poorer OS (P=0.02, Figure 4D), shorter PFS (P=0.02, Figure 4E) and worse DFS (P=0.01, Figure 4F) than patients with reduced sHE4 levels (low tertile). In multivariate analysis, sHE4 levels retained its significance as an independent prognostic factor for poor OS (P=0.04), shorter PFS (P=0.04) and decreased DFS (P=0.01) in the subgroup of patients with poorly differentiated ECs (Table 4B).

Bottom Line: Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls.High sHE4 levels were significantly associated with worse EC clinical characteristics.By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort.

View Article: PubMed Central - PubMed

Affiliation: Angelo Nocivelli Institute of Molecular Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. bignottieliana@yahoo.it

ABSTRACT

Background: To date, no good marker for screening or disease monitoring of endometrial cancer (EC) is available. The aims of this study were to investigate HE4 gene, protein expression and serum HE4 (sHE4) levels in a panel of ECs and normal endometria (NEs) and to correlate sHE4 with patient clinicopathological characteristics and prognosis.

Methods: Using quantitative real-time PCR we tested 46 ECs and 20 NEs for HE4 gene expression. Protein expression was analysed by immunohistochemistry on tissue microarrays in 153 ECs and 33 NEs. Pre-operative serum samples from 138 EC and 76 NE patients were analysed with HE4-EIA assay. Association between sHE4 and patient clinicopathological characteristics or outcome was evaluated.

Results: Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls. High sHE4 levels were significantly associated with worse EC clinical characteristics. By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort.

Conclusion: We demonstrate, for the first time, that high sHE4 levels correlates with an aggressive EC phenotype and may constitute an independent prognostic factor for poorly differentiated-ECs. Determination of sHE4 could be clinically useful in identifying high-risk EC patients for a more aggressive adjuvant therapy.

Show MeSH
Related in: MedlinePlus