Predictive value of CA 125 and CA 72-4 in ovarian borderline tumors

Background: The aim of this study was to assess the prognostic value of cancer antigen (CA) 125 and CA 72-4 in patients with ovarian borderline tumor (BOT). Methods: All women diagnosed and treated for BOT at our institution between 1981 and 2008 were included into this retrospective study (n=101). Preoperatively collected serum samples were analyzed for CA 125 (Architect, Abbott and Elecsys, Roche) and CA 724 (Elecsys, Roche) with reference to clinical data and compared to healthy women (n=109) and ovarian cancer patients (n=130). Results: With a median of 34.7 U/mL (range 18.1-385.0 U/mL) for CA 125 and 2.3 U/mL (range 0.2-277.0 U/mL) for CA 72-4, serum tumor markers in BOT patients were significantly elevated as compared to healthy women with a median CA 125 of 13.5 U/mL (range 4.0-49.7 U/mL) and median CA 72-4 of 0.8 U/mL (range 0.2-20.6 U/mL). In addition, there was a significant difference compared with ovarian cancer patients who showed a median CA 125 of 401.5 U/mL (range 12.5-35,813 U/mL), but no difference was observed for CA 72-4 (median 3.9 U/mL, range 0.3-10,068 U/mL). Patients with a pT1a tumor stage had significantly lower values of CA 125 but not of CA 72-4 compared with individuals with higher tumor stages (median CA 125 29.9 U/mL for pT1a vs. 50.9 U/mL for) pT1a; p=0.014). There was a trend for increased concentrations of CA 125 but not of CA 72-4 in the presence of ascites, endometriosis or peritoneal implants at primary diagnosis. With respect to the prognostic value of CA 125 or CA 72-4, CA 125 was significantly higher at primary diagnosis in patients who later developed recurrence (251.0 U/mL vs. 34.65 U/mL, p=0.012). Conclusions: Serum CA 125 and CA 72-4 concentrations in BOT patients differ from healthy controls and patients with ovarian cancer. CA 125, but not CA 724, at primary diagnosis correlates with tumor stage and tends to be increased in the presence of ascites, endometriosis or peritoneal implants. Moreover, CA 125 at primary diagnosis appears to have prognostic value for recurrence. Clin Chem Lab Med 2009; 47:537-42

Predictive value of CA 125 and CA 72-4 in ovarian borderline tumors

Background: The aim of this study was to assess the prognostic value of cancer antigen (CA) 125 and CA 72-4 in patients with ovarian borderline tumor (BOT). Methods: All women diagnosed and treated for BOT at our institution between 1981 and 2008 were included into this retrospective study (n=101). Preoperatively collected serum samples were analyzed for CA 125 (Architect, Abbott and Elecsys, Roche) and CA 724 (Elecsys, Roche) with reference to clinical data and compared to healthy women (n=109) and ovarian cancer patients (n=130). Results: With a median of 34.7 U/mL (range 18.1-385.0 U/mL) for CA 125 and 2.3 U/mL (range 0.2-277.0 U/mL) for CA 72-4, serum tumor markers in BOT patients were significantly elevated as compared to healthy women with a median CA 125 of 13.5 U/mL (range 4.0-49.7 U/mL) and median CA 72-4 of 0.8 U/mL (range 0.2-20.6 U/mL). In addition, there was a significant difference compared with ovarian cancer patients who showed a median CA 125 of 401.5 U/mL (range 12.5-35,813 U/mL), but no difference was observed for CA 72-4 (median 3.9 U/mL, range 0.3-10,068 U/mL). Patients with a pT1a tumor stage had significantly lower values of CA 125 but not of CA 72-4 compared with individuals with higher tumor stages (median CA 125 29.9 U/mL for pT1a vs. 50.9 U/mL for) pT1a; p=0.014). There was a trend for increased concentrations of CA 125 but not of CA 72-4 in the presence of ascites, endometriosis or peritoneal implants at primary diagnosis. With respect to the prognostic value of CA 125 or CA 72-4, CA 125 was significantly higher at primary diagnosis in patients who later developed recurrence (251.0 U/mL vs. 34.65 U/mL, p=0.012). Conclusions: Serum CA 125 and CA 72-4 concentrations in BOT patients differ from healthy controls and patients with ovarian cancer. CA 125, but not CA 724, at primary diagnosis correlates with tumor stage and tends to be increased in the presence of ascites, endometriosis or peritoneal implants. Moreover, CA 125 at primary diagnosis appears to have prognostic value for recurrence. Clin Chem Lab Med 2009; 47:537-42

The G-Protein Coupled Estrogen Receptor (GPER/GPR30) is a Gonadotropin Receptor Dependent Positive Prognosticator in Ovarian Carcinoma Patients

<div><p>Follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHCGR) were demonstrated to impact upon survival of patients suffering from epithelial ovarian cancer (EOC). Though structure wise the G-protein coupled estrogen receptor (GPER/GPR30) is related to FSHR/LHCGR, its prognostic impact in EOC remains controversial. We recently found that FSHR negative patients represent a specific EOC subgroup that may behave differently in respect to both treatment response and prognosis. Hence, the current study aimed to analyze how GPER may interact with the FSHR/LHCGR system in EOC and whether the prognostic significance of GPER in EOC cases (n = 151) may be dependent on the FSHR/LHCGR immunophenotype of the tumor. Ovarian cancer cell lines were used to study how FSH and LH regulate GPER and whether GPER activation differentially affects in vitro cell proliferation in presence/absence of activated FSHR/LHCGR. In EOC tissue, GPER correlated with FSHR/LHCGR and was related to prolonged overall survival only in FSHR/LHCGR negative patients. Although GPER was found to be specifically induced by LH/FSH, GPER agonists (4-Hydroxy-Tamoxifen, G1) reduced EOC cell proliferation only in case of LH/FSH unstimulated pathways. To the same direction, only patients characterized as LHCGR/FSHR negative seem to gain from GPER in terms of survival. Our combined tissue and in vitro results support thus the hypothesis that GPER activation could be of therapeutic benefit in LHCGR/FSHR negative EOC patients. Further studies are needed to evaluate the impact of GPER activation on a clinical scheme.</p></div

GPER up-regulation is dependent on the respective gonadotropin receptor.

<p>siRNA mediated knockdown of FSHR (A, B) and LHCGR (C, D) was performed in order to evaluate whether the up-regulation of GPER is due to an effect specifically attributed to FSH/LH and FSHR/LHCGR. Gonadotropin treatment failed to up-regulate GPER in cells that had undergone FSHR (E) or LHCGR (F) silencing. c: control treated with the transfection reagent only, scr: control treated with an off target, scrambled siRNA. Stars mark significant (p<0.05) observations as calculated using independent samples Student’s T-test (E, F) and the Rest2009 algorithm for gene transcription ratios (B, D).</p

GPER predicts favorable outcome in gonadotropin receptor negative EOC.

<p>Prognostic significance of GPER was evaluated in subgroups of patients with or without expression of FSHR or/and LHCGR. Survival of patients whose tumors expressed GPER at high levels (solid lines) was compared to those with low GPER expression (dotted lines) by the log rank test and Kaplan-Meier survival plots were drawn. Remarkably, GPER predicted significantly more favorable outcome in subgroups classified as FSHR negative (A) and LHCGR negative (B). Stratification of EOC patients according the combined LH/FSH status revealed that only in case of a double negative immunophenotype GPER appears as a positive prognosticator (C).</p

Hormone receptor correlations.

<p>Spearman correlation of receptor expression IR-scores revealed GPER to be positively correlated with expression of FSHR (rho = 0.178, p = 0.030) as well as LHCGR (rho = 0.218, p = 0.008). No relation of GPER and nuclear steroid hormone receptors (ERα, ERβ) could be detected. Stars (*) indicate significant observations; cc = correlation coefficient, ns = not significant.</p

Clinicopathological features.

<p>Clinicopathological features.</p

GPER signaling activators inhibit proliferation of ovarian cancer cells lines in an FSH and LH dependent manner.

<p>FSHR positive (OVCAR-3) and negative (Caov-3) cells were exposed to GPER agonists (G1; 4-Hydroxy-Tamoxifen (OHT)) in the presence vs. absence of external FSH (A). In the FSH depleted setting G1 and OHT reduced OVCAR-3 cell proliferation by, respectively. Neither G1 nor OHT emerged to significantly affect OVCAR-3 proliferation in the presence of FSH. Caov-3 cells, being negative for GnRs, were sensitive to addition of GPER inducers regardless the presence of FSH, since both G1 and OHT significantly reduced median Caov-3 replication rates. Both G1 and OHT failed to reduce proliferation of LHCGR positive SKOV-3 cells in the presence of LH (B). In LH non stimulated conditions proliferation of SKOV-3 cells was significantly reduced when either G1 or OHT were added to the culture media. Doubling rates of LHCGR negative Caov-3 cells were reduced by G1 as well as by OHT regardless the presence of LH. Independent samples Student’s T-test was employed to test for differences between groups and significant (p<0.05) changes are indicated by stars (*).</p