ABSTRACT
HER-2/neu extracellular domain (ECD) can be detected in blood as a soluble circulating protein. The aim of this study was to analyze the relationship between HER-2/neu extracellular domain in the serum and the prognosis in breast cancer patients. We also correlated HER-2/neu ECD with various clinicopathological factors including steroid receptor, HER-2/neu receptor coexpression. The serum from seventy nine patients with invasive breast cancer and twenty individuals without malignancy was analyzed using the enzyme-linked immune adsorbent assay method. The cut-off value was estimated by the ROC curve analysis (15.86 µg/L). HER-2/neu ECD values in the serum of patients with breast cancer were significantly higher than in control subjects. Circulating HER-2/neu ECD was significantly associated with the histological grade of tumors and the status of axillary lymph nodes. Negative correlation was observed between HER-2/neu ECD in the serum and estrogen receptor positivity. When we analyzed HER-2/neu ECD in relation with coexpression of steroid receptor and HER-2/neu receptor in tissue, statistically higher values were found in the subgroup of patients with steroid receptor negative, HER-2/neu negative tumors than in the other subgroups. HER-2/neu ECD was not an independent factor in the univariate and multivariate analysis. However, elevated HER-2/neu ECD levels were found in patients with breast cancer possessing more aggressive phenotype.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/pathology , Neoplastic Cells, Circulating/metabolism , Receptor, ErbB-2/blood , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Case-Control Studies , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Lymphatic Metastasis , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Staging , Neoplastic Cells, Circulating/pathology , Prognosis , Survival RateABSTRACT
OBJECTIVE: To investigate the prognostic value of urokinase-type plasminogen activator (uPA) and its inhibitor, type-1 plasminogen activator inhibitor (PAI-1), in differentiated thyroid cancer. STUDY DESIGN: Prospective cohort study. SETTING: University hospital. SUBJECTS AND METHODS: Cytosolic concentrations of uPA and PAI-1 were determined in 105 patients with differentiated thyroid carcinoma and normal matched tissues using an enzyme-linked immunoassay (ELISA). RESULTS: Both uPA and PAI-1 concentrations were significantly higher in differentiated thyroid tumors (uPA = 0.509 ± 0.767 and PAI-1 = 6.337 ± 6.415 ng/mg) compared to normal tissues (uPA = 0.237 ± 0.051, P < .001; PAI-1 = 2.368 ± 0.418 ng/mg, P < .001). uPA and PAI-1 were significantly higher if extrathyroidal invasion (uPA, P = .015; PAI-1, P < .001) or distant metastasis (PAI-1 P < .001) was present, as well as in tumors whose size exceeded 1 cm in diameter (uPA, P = .002; PAI-1, P = .001). Survival analysis revealed the significant impact of both uPA and PAI-1 on progression-free survival (PFS) (82.22 vs 49.478 months for patients with low and high uPA, respectively, P < .001; 87.068 vs 44.964 months for patients with low and high PAI-1, respectively, P < .001). Univariate analysis showed that gender, tumor size, tumor grade, extrathyroid invasion, local lymph node involvement, distant metastasis, uPA, and PAI-1 were significant predictors of PFS. However, multivariate analysis identified only distant metastasis and tumor tissue uPA and PAI-1 as independent prognostic factors. CONCLUSION: These findings indicate that high uPA and PAI-1 levels represent independent unfavorable prognostic factors in patients with differentiated thyroid carcinoma.
Subject(s)
Thyroid Neoplasms/enzymology , Thyroid Neoplasms/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Plasminogen Activator Inhibitor 1 , Prognosis , Prospective Studies , Thyroid Neoplasms/pathology , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Young AdultABSTRACT
PURPOSE: Higher levels of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) are linked to the poor prognosis in a variety of malignances. uPA and PAI-1 were expressed in most thyroid carcinomas, as had been measured immunohistochemically. However, no relationship between their expression and clinicopathological parameters were found. Aim of the present study was to investigate the expression and clinical relevance of uPA and PAI-1 in thyroid cancer. PATIENTS AND METHODS: uPA and PAI-1 in paired cytosol samples of thyroid tumor and normal tissue were determined in 23 patients using enzyme-linked immunosorbent assay and correlated to the known prognostic features. RESULTS: Both uPA and PAI-1 concentrations were significantly higher in malignant thyroid tumors (uPA=1.342 +/- 2.944 and PAI-1=17.615 +/- 31.933 ng/mg protein) than in normal tissue (uPA=0.002 +/- 0.009, P=0.011 and PAI-1=2.333 +/- 0.338 ng/mg protein, P=0.001) with positive correlation of the two proteins in the tumors. There were no differences in proteins' levels between benign tumors and normal tissue. Both proteins' concentrations were significantly different among various histological grades (uPA P=0.024 and PAI-1 P=0.017), showing higher values in higher tumor grades (grade I uPA=0.116 +/- 0.247 and PAI-1=4.802 +/- 4.151 ng/mg protein; grade III uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). The uPA and PAI-1 levels showed significant differences among different histological types of thyroid cancer (uPA P=0.049 and PAI-1=0.017). The lowest values were in adenomas (uPA=0.013 +/- 0.025 and PAI-1=2.785 +/- 1.069 ng/mg protein) and the highest in anaplastic carcinomas (uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). uPA and PAI-1 were significantly higher in anaplastic vs. well-differentiated cancers (uPA P=0.014 and PAI-1 P=0.026), if extrathyroidal invasion (uPA P=0.019 and PAI-1 P=0.009) or distant metastases (uPA P=0.006 and PAI-1 P=0.003) had been present, and in tumors whose size exceeded 1 cm in diameter (uPA P=0.009 and PAI-1 P=0.035). Only PAI-1, but not uPA was significantly higher in multicentric vs. solitary tumors (P=0.012) and lymph node positive compared to lymph node negative patients (P=0.042). The differences of uPA and PAI-1 did not reach the significant level when patients with well-differentiated tumors below and above 40 years of age had been compared. Survival analysis revealed the significant impact of both uPA and PAI-1 on the Progression-Free Survival (PFS) (38.84 vs. 3.67 months for patients with low and high uPA, respectively, P<0.001; 38.2 vs. 12 months for patients with low and high PAI-1, respectively, P=0.016). CONCLUSIONS: The correlation of high uPA and PAI-1 with the known prognostic factors of poorer outcome and with lower PFS rate in patients with thyroid cancers proved that these proteins could be an additional prognostic parameter.
