Evaluation of ovarian cancer biomarkers HE4 and CA-125 in women presenting with a suspicious cystic ovarian mass

Objective

Women presenting with a large or complex ovarian cyst are referred to extensive surgical staging to ensure the correct diagnosis and treatment of a possible epithelial ovarian cancer. We hypothesized that measurement of the biomarkers HE4 and CA-125 preoperatively would improve the assignment of these patients to the correct level of care.

Methods

Patients diagnosed with a cystic ovarian mass and scheduled for an operation at our center of excellence for ovarian cancer surgery from 2001 to 2010 were prospectively included (n=394) and plasma was collected consecutively. Cut-off for HE4 was calculated at 75% specificity (85 pM and 71.8 pM for post and premenopausal women). For CA-125, 35 U/mL cut-off was used. The study population included women with malignant (n=114), borderline (n=45), and benign (n=215) ovarian tumors.

Results

Receiver operator characteristic (ROC) area under the curve (AUC) in the benign versus malignant cohorts was 86.8% for CA-125 and 84.4% for HE4. Negative predictive value was 91.7% when at least one of the biomarkers was positive, with only early stage epithelial ovarian cancer showing false negative results. Sensitivity at set specificity (75%) was 87% for risk of ovarian malignancy algorithm (ROMA) in the postmenopausal cohort (cut-off point, 26.0%) and 81% in the premenopausal cohort (cut-off point, 17.3%). ROC AUC in the benign versus stage I epithelial ovarian cancer was only 72% for HE4 and 76% for CA-125.

Conclusion

In our study, population HE4 did not outperform CA-125. Based on our data a prospective trial with patients already diagnosed with an ovarian cyst may be conducted.     

Comparison of total plasma lysophosphatidic acid and serum CA-125 as a tumor marker in the diagnosis and follow-up of patients with epithelial ovarian cancer

Objective

To evaluate the role of lysophosphatidic acid (LPA) as a tumor marker in diagnosis and follow-up of patients with epithelial ovarian cancer.

Methods

Eighty-seven epithelial ovarian cancer patients, 74 benign ovarian tumor patients, and 50 healthy women were enrolled in the study. Twenty-nine of 87 epithelial ovarian cancer patients were followed up for 6 cycles of paclitaxel-carboplatin chemotherapy. CA-125 and total plasma LPA levels were measured preoperatively and before each chemotherapy cycle.

Results

Preoperative total plasma LPA and serum CA-125 levels were significantly higher in patients with epithelial ovarian cancer compared to patients with benign ovarian tumors and healthy women. Cut-off value for LPA was determined as 1.3 µmol/L and sensitivity, specificity, positive predictive value and negative predictive value were 95%, 92%, 95% and 92%, respectively. Mean total plasma LPA level of 29 patients who received chemotherapy was 7.21±6.63 µmol/L preoperatively and 6.84±6.34 µmol/L, 6.34±5.92 µmol/L, 6.14±5.79 µmol/L, 5.86±5.68 µmol/L, 5.23±5.11 µmol/L and 5.21±5.32 µmol/L in measurements held just before the 1st, 2nd, 3rd, 4th, 5th and 6th chemotherapy cycles, respectively (ANOVA, p=0.832). Total plasma LPA levels decreased slightly with chemotherapy administration and there was a weak negative correlation (Spearman, r_s=-0.151, p=0.034), compared to a significant negative correlation in CA-125 (Spearman, r_s=-0.596, p<0.001).

Conclusion

LPA is a better biomarker for diagnosis of epithelial ovarian cancer compared to CA-125. However, measurement of total plasma LPA levels during chemotherapy administration have no superiority to the serum CA-125 levels.     

The efficacy of sonographic morphology indexing and serum CA-125 for preoperative differentiation of malignant from benign ovarian tumors in patients after operation with ovarian tumors

Objective

To evaluate the value of sonographic morphology indexing (MI) system and serum CA-125 levels in the assessment of the malignancy risk in patients with ovarian tumors.

Methods

From September 2000 to July 2006, 202 patients who underwent surgery for ovarian tumors were reviewed retrospectively. In all patients, the MI score and serum CA-125 level were measured preoperatively. The association of the final pathologic diagnosis with the MI score and serum CA-125 level were examined.

Results

There were 26 malignant tumors out of 141 ovarian tumors with a MI ≥5 (18%). With a cut-off value of 5, the sensitivity, specificity, PPV, and NPV of MI scores were 0.743, 0.293, 0.181, and 0.845, respectively. There were 22 malignant tumors out of 54 ovarian tumors with serum CA-125 >30 u/ml (41%). With a cut-off value of 30 u/ml, the sensitivity, specificity, PPV, and NPV of serum CA-125 level were 0.667, 0.808, 0.407, and NPV 0.925, respectively. On ROC curve, the optimal cut-off value of MI score was 6.5-7.5 and that of serum CA-125 level was 25.6-28.5 u/ml. With a cut-off value of 7, the sensitivity and 1-specificity of MI score were 0.875-0.917 and 0.023-0.203, respectively. After the exclusion of teratoma cases, the sensitivity and 1-specificity of MI score were 0.875-0.917 and 0.046-0.138, respectively. With a cut-off value of 25.6-28.5 u/ml, the sensitivity and 1-specificity of serum CA-125 level were 0.958 and 0.203-0.215, respectively.

Conclusion

The sonographic MI system is an accurate and simple method to differentiate a malignant tumor from a benign ovarian tumor. The accuracy of the sonographic MI system improved when the serum CA-125 level was considered and ovarian teratomas were excluded.     

Distinguishing benign from malignant pelvic mass utilizing an algorithm with HE4, menopausal status,and ultrasound findings

Objective

The purpose of this study was to develop a risk prediction score for distinguishing benign ovarian mass from malignant tumors using CA-125, human epididymis protein 4 (HE4), ultrasound findings, and menopausal status. The risk prediction score was compared to the risk of malignancy index and risk of ovarian malignancy algorithm (ROMA).

Methods

This was a prospective, multicenter (n=6) study with patients from six Asian countries. Patients had a pelvic mass upon imaging and were scheduled to undergo surgery. Serum CA-125 and HE4 were measured on preoperative samples, and ultrasound findings were recorded. Regression analysis was performed and a risk prediction model was developed based on the significant factors. A bootstrap technique was applied to assess the validity of the HE4 model.

Results

A total of 414 women with a pelvic mass were enrolled in the study, of which 328 had documented ultrasound findings. The risk prediction model that contained HE4, menopausal status, and ultrasound findings exhibited the best performance compared to models with CA-125 alone, or a combination of CA-125 and HE4. This model classified 77.2% of women with ovarian cancer as medium or high risk, and 86% of women with benign disease as very-low, low, or medium-low risk. This model exhibited better sensitivity than ROMA, but ROMA exhibited better specificity. Both models performed better than CA-125 alone.

Conclusion

Combining ultrasound with HE4 can improve the sensitivity for detecting ovarian cancer compared to other algorithms.     

Premenopausal early-stage endometrial carcinoma patients with low CA-125 levels and low tumor grade may undergo ovary-saving surgery

Objective

The purpose of this study was to determine the possible predicting factors of coexisting adnexal malignancies, and to evaluate the safety of ovary-saving surgery for early-stage endometrial carcinoma in premenopausal patients.

Methods

A retrospective review of 107 patients with endometrial carcinoma who underwent surgical treatment at our institution was conducted. All patients were younger than 50 years of age and premenopausal status. Statistical analysis was performed.

Results

Of the 107 patients, 78 patients had stage I to II disease and both preoperative CA-125 levels were measured and tumor grades evaluated. On multivariate analysis, preoperative CA-125 levels (p=0.018) and preoperative tumor grade (p=0.029) were independent predicting factors of adnexal diseases. The risk of coexisting ovarian malignancy was 1.8% in patients with preoperative CA-125 levels less than or equal to 34.5 U/ml and preoperative tumor grade 1 or 2. The risk increases to 20% for low CA-125 and grade 3, 13.3% for high CA-125 and grade 1 or 2, and 100% for high CA-125 and grade 3. Between patients who underwent unilateral salpingo-oophorectomy and those who underwent bilateral salpingo-oophorectomy, there was no statistically significant difference in terms of BMI, preoperative CA-125 levels, FIGO stage, histology, tumor grade, lymphadenectomy, and adjuvant treatment.

Conclusion

Ovary-saving surgery for premenopausal, early-stage endometrial cancer patients may be considered as a treatment option in those with low preoperative CA-125 and low tumor grade.     

A longitudinal analysis with CA-125 to predict overall survival in patients with ovarian cancer

Objective

The objective of this study was to explore the association of longitudinal CA-125 measurements with overall survival (OS) time by developing a flexible model for patient-specific CA-125 profiles, and to provide a simple and reliable prediction of OS.

Methods

A retrospective study was performed on 275 patients with ovarian cancer who underwent at least one cycle of primary chemotherapy in our institute. Serial measurements of patients'' CA-125 levels were performed at different frequencies according to their clinical plans. A statistical model coupling the Cox proportional hazards and the mixed-effects models was applied to determine the association of OS with patient-specific longitudinal CA-125 values. Stage and residual tumor size were additional variables included in the analysis.

Results

A total of 1,601 values of CA-125 were included. Longitudinal CA-125 levels, stage, and the residual tumor size were all significantly associated with OS. A patient-specific survival probability could be calculated. Validation showed that, in average, 85.4% patients were correctly predicted to have a high or low risk of death at a given time point. Comparison with a traditional model using CA-125 half-life and time to reach CA-125 nadir showed that the longitudinal CA-125 model had an improved predicative value.

Conclusion

Longitudinal CA-125 values, measured from the diagnosis of ovarian cancer to the completion of primary chemotherapy, could be used to reliably predict OS after adjusting for the stage and residual tumor disease. This model could be potentially useful in clinical counseling of patients with ovarian cancer.     

Comparison of four malignancy risk indices in the detection of malignant ovarian masses

Objective

The aim of this study was to evaluate the ability of four risk of malignancy indices (RMI) to detect malignant ovarian tumors.

Methods

This is a prospective study of 100 women admitted to the Department of Obstetrics and Gynecology of Gulhane Military Medicine Academy for surgical exploration of pelvic masses. To diagnose malignant ovarian tumors, the sensitivity, specificity, negative and positive predictive values and diagnostic accuracy of four RMIs (RMI 1, RMI 2, RMI 3, and RMI 4) were obtained.

Results

In our study we found that there is no statistically significant difference in the performance of four different RMIs in discriminating malignancy. We think that malignancy risk indices is more reliable than the menopausal status, serum CA-125 levels, ultrasound features and tumor size separately in detecting malignancy.

Conclusion

We concluded that any of the four malignancy risk indices described can be used for selection of cases for optimal therapy. These methods are simple techniques that can be used even in less-specialized gynecology clinics to facilitate the selection of cases for referral to an oncological unit.     

Significance of postoperative CA-125 decline after cytoreductive surgery in stage IIIC/IV ovarian cancer

Objective

The purpose of this study was to evaluate whether the decline in serum CA-125 levels following primary cytoreductive surgery prior to starting adjuvant chemotherapy has a prognostic value in patients with stage IIIC/IV ovarian carcinoma.

Methods

A retrospective review was conducted of all patients with stage IIIC/IV ovarian carcinoma who underwent primary cytoreductive surgery followed by platinum-based chemotherapy from 1994 to 2007. Demographic, pathologic, treatment, and survival data were collected. Patients were included if serum CA-125 levels were drawn preoperatively and within one week prior to their first chemotherapy cycle, and whose postoperative CA-125 level declined. Percentage decline was calculated, and was compared with standard statistical tests in groups by 25% declination intervals.

Results

Of the 112 stage IIIC/IV patients, 81 (72.3%) met the above inclusion criteria. The median time from surgery to postoperative CA-125 sampling was 16 days (range: 7-42). A ≥75% decline was associated with a median progression-free survival (PFS) of 25 months (95% CI=0-63). This was significantly longer when compared with each of the other 25% interval groups. After multivariate analysis, independent prognostic factors included a ≥75% decline in CA-125 levels after surgery and the presence of residual tumor. Age, grade, histology, and preoperative CA-125 levels were not statistically significant factors.

Conclusion

A ≥75% decline in serum CA-125 serum levels from primary cytoreductive surgery to the start of adjuvant chemotherapy has independent prognostic value for PFS in patients with stage IIIC/IV ovarian carcinoma.     

Correlation between preoperative serum levels of five biomarkers and relationships between these biomarkers and cancer stage in epithelial overian cancer

Objective

To examine the correlation among the preoperative serum levels of five biomarkers presumed to be useful for early detection of epithelial ovarian cancer and evaluate the relationships between serum levels of these five biomarkers and epithelial ovarian cancer stage.

Methods

We analyzed 56 newly diagnosed epithelial ovarian cancer patients. Preoperative serum levels of leptin, prolactin, osteopontin (OPN), insulin-like growth factor-II, and CA-125 were determined by ELISA. We also examined the correlation between the serum levels of the biomarkers and ovarian cancer stage. Significant differences in the mean serum levels of two proteins, leptin and CA-125, were observed between stage subsets.

Results

There was a significant negative correlation between prolactin and leptin and a significant positive correlation between prolactin and OPN. Of the five biomarkers, only the mean serum CA-125 level showed a significant positive correlation with cancer stage (Spearman ρ=0.24, p<0.01). OPN showed a marginally significant positive correlation with stage (Spearman ρ=0.14, p=0.07).

Conclusion

We demonstrated the relationship between five biomarkers in epithelial ovarian cancer. These tumor markers may be useful in screening for ovarian cancer, in characterizing disease states, and in developing therapeutic interventions targeting these marker proteins. Large-scale studies that include potential confounding factors and modifiers are necessary to more accurately define the value of these novel biomarkers in ovarian cancer.     

Association of kallikrein expression in nipple aspirate fluid with breast cancer risk

Human kallikreins (hK) 2, 3, 6 and 10 are expressed in breast and prostate tissue. hK2 and hK3 (prostate-specific antigen, PSA) are used to screen for prostate cancer. hK6 and hK10 are downregulated in breast cancer compared to normal breast tissue. We demonstrated that levels of PSA in nipple aspirate fluid (NAF) are lower in women with breast cancer than in normal women. We hypothesize that the expression of hK2, 3, 6 and 10 are related and important in detecting breast cancer. The goals of this study are to determine the level of expression of kallikreins in NAF and serum, the association of hK2, 3, 6 and 10 in NAF, and the association of each of the kallikreins with breast cancer. In NAF from 275 women, hK3, 6 and 10 were detectable in >/= 90% and hK2 in 74% of samples analyzed. NAF levels were highest for hK6 and lowest for hK2, regardless of cancer and menopausal status. hK3 was detectable in 15/29 (52%) and hK2 in 0/29 serum samples collected from 6 women. hK2 and hK3 were concentrated in NAF vs. matched serum. The 4 kallikreins were associated with the exception of hK2 with hK6 or hK10. PSA levels were higher in normal pre- than postmenopausal subjects (but not women with breast cancer), whereas levels of hK2, 6 and 10 did not differ by menopausal status. hK2 and PSA were associated with both pre- and postmenopausal breast cancer; hK6 and 10 were not. hK2 and PSA were more associated with pre- than postmenopausal breast cancer. Using logistic regression, PSA and menopausal status provided the best model of breast cancer prediction, with a sensitivity of 91% and specificity of 39%. In conclusion, 4 kallikreins are expressed in NAF. hK2 and PSA, and hK6 and hK10 are highly associated. Higher premenopausal PSA levels suggest the influence of ovarian steroids. PSA shows the most promise in aiding in the early detection of breast cancer.     

CA-125 can be part of the tumour evaluation criteria in ovarian cancer trials: experience of the GCIG CALYPSO trial

Background:

CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression.

Methods:

In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin–paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression.

Results:

In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66–1.10) and 0.84 (95% CI: 0.72–0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment.

Conclusion:

CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.     

Cut-off value of D-dimer for prediction of deep venous thrombosis before treatment in ovarian cancer

Objective

The purpose of the present study was to elucidate the incidence of deep venous thrombosis (DVT) before treatment in ovarian cancer and the appropriate cut-off value of D-dimer (DD) for the diagnosis of DVT.

Methods

Between July 2007 and October 2008, eighty seven patients with presumed ovarian cancer (final diagnosis: ovarian cancer, n=59; borderline malignancy, n=28) were enrolled. Measurement of DD levels and subsequent venous ultrasonography were performed before treatment.

Results

The mean DD level was 4.1 µg/mL. Subsequent venous ultrasonography revealed DVT in 14 of 87 (16.1%) patients (ovarian cancer, 12 cases; borderline malignancy, 2 cases). None were found to have developed DVT if they had a DD level of <1.5 µg/mL. If 1.5 µg/mL was used as a cut-off value for DD levels to diagnose DVT, sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 61.6%, 33.3%, and 100%. There was noclinical onset of postoperative pulmonary thromboembolism.

Conclusion

Our data suggest that presumed ovarian cancer patients with at least more than 1.5 µg/mL should be examined using venous ultrasonogaphy to detect DVT.     

Prediction of a high-risk group based on postoperative nadir CA-125 levels in patients with advanced epithelial ovarian cancer

Objective

We aimed to determine the ideal cut-off of nadir serum CA-125 level for prediction of progression free survival.

Methods

Among 267 patients who achieved complete remission after chemotherapy, the correlation between nadir CA-125 and progression free survival were compared among the subgroups classified according to the distribution of CA-125. The diagnostic odds ratio and area under the receiver operator characteristics curve were compared at various cut-off points.

Results

The nadir CA-125 levels did not have prognostic value under 12 U/mL (to 75 percentile). In contrast, they were significantly correlated with progression free survival only when the CA-125 level was greater than 12, which was 75 percentile (p=0.034). In predicting progression free survival <6 and 12 months, the cut-off value of 18 (90 percentile) showed superior diagnostic performance over 10 or 12 U/mL. Compared with patients who showed nadir levels between 0 and 12 U/mL (0 to 75 percentile), those with nadir >18 U/mL showed a hazard ratio of 2.85 (95% confidence interval, 1.70 to 4.76; p<0.001); patients with nadir levels between 18 and 12 U/mL showed a the hazard ratio of 1.68 (95% confidence interval, 1.11 to 2.56; p=0.015) compared with those whose nadir levels were under 12 U/mL.

Conclusion

The predictive power of the traditional cut-off of 10 U/mL to classify a risk group or to identify high risk patients was unsatisfactory. The optimal diagnostic performance was observed at the cut-off of 18 U/mL and this can be proposed to dichotomize cut-off values to predict outcomes among individual patients.     

The utility and cost of routine follow-up procedures in the surveillance of ovarian and primary peritoneal carcinoma: a 16-year institutional review

Background:

The purpose of this study was to evaluate the number of ovarian cancer and primary peritoneal cancer (PPC) progressive disease cases identified via routine follow-up procedures and the corresponding cost throughout a 16-year period at a single medical institution.

Methods:

Previously undiagnosed epithelial ovarian (n=241), PPC (n=23), and concurrent ovarian and uterine (n=24) cancer patients were treated and then followed via CA-125, imaging (e.g., CT scan, chest X-ray), physical examination and vaginal cytology.

Results:

In the group of 287 patients, there were 151 cases of disease progression. Serial imaging detected the highest number of progressive disease cases (66 initial and 45 confirmatory diagnoses), but the cost was rather high ($13 454 per patient recurrence), whereas CA-125 testing (74 initial and 20 corroborative diagnoses) was the least expensive ($3924) per recurrent diagnosis. The total cost of surveillance during the 16-year period was nearly $2 400 000.

Conclusion:

Ultimately, serial imaging and the CA-125 assay detected the highest number of ovarian cancer and PCC progressive disease cases in comparison to physical examination and vaginal cytology, but nevertheless, all of the procedures were conducted at a considerable financial expense.     

Continuous‐Infusion Topotecan and Erlotinib: A Study in Topotecan‐Pretreated Ovarian Cancer Assessing Shed Collagen Epitopes as a Marker of Invasiveness

Background.

Continuous-infusion topotecan with erlotinib has the potential to reverse topotecan resistance due to drug efflux mechanisms. We assessed the activity of such a regimen in ovarian cancer patients previously failing bolus topotecan. Assay for shed collagen epitopes recognized by antibody HU177 during treatment explored its ability to reflect tumor invasion.

Methods.

Topotecan 0.4 mg/m² per day was administered by continuous infusion for 9–10 days every 3 weeks. Erlotinib, 150 mg orally, was administered on days 1–10 of each cycle. Cycles were repeated until progression or toxicity. Serum for shed HU177 collagen epitopes was collected weekly. This was a two-stage design to detect a CA-125 response rate of at least 20% in 30 patients after completing two treatment cycles. The trial would be terminated early if there were less than two CA-125 responses in 16 patients. Four or more CA-125 responses in 30 patients would justify further study of this regimen in prior topotecan treatment failures.

Results.

Six patients were enrolled, with four receiving three or more cycles and one achieving a partial response by cancer antigen 125 (CA-125) criteria. Shed epitope levels became undetectable on at least one measurement in all patients who received three or more cycles (Fig. 1A) and reappeared concomitantly with rises in CA-125 and clinical progression (Fig. 1B). After logistical delays, the trial was closed by the sponsor’s decision to stop developing erlotinib in ovarian cancer.Open in a separate windowFigure 1.Monitoring of combination treatment. A, B, C, D, and F refer to patients. (A): Topotecan and erlotinib. (B): CA-125 in units/mL.

Conclusion.

Continuous-infusion topotecan with erlotinib was found safe in six pretreated ovarian cancer patients; one met CA-125 criteria for partial response. Serial shed epitope levels to reflect invasiveness deserve further study.     

Prediction of tumour response induced by chemotherapy using modelling of CA-125 kinetics in recurrent ovarian cancer patients

Background:

The main objective of the present study was to establish the relationships between CA-125 kinetics and tumour size changes during treatment.

Methods:

The data from the CALYPSO-randomised phase III trial, comparing two platinum-based regimens in recurrent ovarian cancer (ROC) patients, was randomly split into a ‘learning data set'' to estimate model parameters and a ‘validation data set'' to validate model performances. A kinetic–pharmacodynamic semi-mechanistic model was built to describe tumour size and CA-125 kinetics during chemotherapy. The ability of the model to predict tumour response induced by chemotherapy, based on CA-125 values, was assessed.

Results:

Data from 535 ROC patients were used to model CA-125 kinetics and tumour size changes during the first 513 days after treatment initiation. Using the validated model, we could predict with accuracy the tumour size changes induced by chemotherapy based on the baseline imaging assessment and longitudinal CA-125 values (mean prediction error: 0.3%, mean absolute prediction error: 10.6%).

Conclusions:

Using a semi-mechanistic model, the dynamic relationships between tumour size changes and CA-125 kinetics induced by chemotherapy were established in ROC patients. A modelling approach allowed CA-125 to be assessed as a biomarker for tumour size dynamics, to predict treatment efficacy for research and clinical purposes.     

Neoadjuvant chemotherapy in ovarian,primary peritoneal and tubal carcinoma: can imaging results prior to interval debulking predict survival?

Objective

To assess whether there is an association between improvement of computed tomography imaging results prior to interval debulking with survival in patients treated by neoadjuvant chemotherapy.

Methods

The clinical and outcome data of all advanced ovarian, primary peritoneal and tubal carcinoma patients who after diagnosis had neoadjuvant chemotherapy and underwent interval debulking during the period 2000-2010, were abstracted. Results of computed tomography imaging at diagnosis and prior to interval debulking were compared. Two parameters were assessed: the change of the size and number of abnormal findings and the change in the amount of ascites. CA-125 level response was also calculated. An assessment of progression free survival and of survival by the Kaplan-Meier method was made according to the change in computed tomography imaging results and according to response of CA-125 levels.

Results

The median progression free survival and the median survival of the 37 study group patients were 7.9 and 49.2 months respectively. No significant difference in progression free survival and survival was observed between patients with marked improvement in the computed tomography results and those with less desirable results (7.93 vs. 7.23 months respectively, p=0.89; 45.8% vs. 52.5% months respectively, p=0.95). There were also no statistically significant difference according to CA-125 level response.

Conclusion

It seems that neither improvement in imaging results nor CA-125 level response can predict the survival of ovarian carcinoma patients prior to interval debulking after neoadjuvant chemotherapy.     

Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma.

PURPOSE: The discovery of new ovarian cancer biomarkers that are suitable for early disease diagnosis and prognosis may ultimately lead to improved patient management and outcomes. PATIENTS AND METHODS: We measured, by immunoassay, human kallikrein 6 (hK6) concentration in serum of 97 apparently healthy women, 141 women with benign abdominal diseases, and 146 women with histologically proven primary ovarian carcinoma. We then calculated the diagnostic sensitivity and specificity of this test and examined the association of serum hK6 concentration with various clinicopathologic variables and patient survival. RESULTS: Serum hK6 concentration between normal and benign disease patients was not different (mean, 2.9 and 3.1 micro g/L, respectively). However, hK6 in presurgical serum of ovarian cancer patients was highly elevated (mean, 6.8 micro g/L; P <.001). Serum hK6 decreased after surgery (to a mean of 3.9 micro g/L) in 68% of patients. The diagnostic sensitivity of serum hK6 at 90% and 95% specificity is 52% and 47%, respectively, in the whole patient population. For early stage disease (stage I or II), sensitivity is approximately 21% to 26%. When combined with CA-125, at 90% specificity, sensitivity increases to 72% (for all patients) and to 42% in stage I or II disease. Serum hK6 concentration correlates moderately with CA-125 and is higher in patients with late-stage, higher-grade disease and in patients with serous histotype. Preoperative serum hK6 concentration is a powerful predictor of disease-free and overall survival in both univariate and multivariate analyses. CONCLUSIONS: Serum hK6 concentration seems to be a new biomarker for ovarian carcinoma and may have value for disease diagnosis and prognosis.     

A multiparametric panel for ovarian cancer diagnosis, prognosis, and response to chemotherapy.

PURPOSE: Our goal was to examine a panel of 11 biochemical variables, measured in cytosolic extracts of ovarian tissues (normal, benign, and malignant) by quantitative ELISAs for their ability to diagnose, prognose, and predict response to chemotherapy of ovarian cancer patients. EXPERIMENTAL DESIGN: Eleven proteins were measured (9 kallikreins, B7-H4, and CA125) in cytosolic extracts of 259 ovarian tumor tissues, 50 tissues from benign conditions, 35 normal tissues, and 44 tissues from nonovarian tumors that metastasized to the ovary. Odds ratios and hazard ratios and their 95% confidence interval were calculated. Time-dependent receiver operating characteristic curves for censored survival data were used to evaluate the performance of the biomarkers. Resampling was used to validate the performance. RESULTS: Most biomarkers effectively separated cancer from noncancer groups. A composite marker provided an area under the curve of 0.97 (95% confidence interval, 0.95-0.99) for discriminating normal and cancer groups. Univariately, hK5 and hK6 were positively associated with progression. After adjusting for clinical variables in multivariate analysis, both hK10 and hK11 significantly predicted time to progression. Increasing levels of hK13 were associated with chemotherapy response, and the predictive power of hK13 to chemotherapy response was improved by a panel of five biomarkers. CONCLUSIONS: The evidence shows that a group of kallikreins and multiparametric combinations with other biomarkers and clinical variables can significantly assist with ovarian cancer classification, prognosis, and response to platinum-based chemotherapy. In particular, we developed a multiparametric strategy for predicting ovarian cancer response to chemotherapy, comprising several biomarkers and clinical features.     

Characterization of human kallikreins 6 and 10 in ascites fluid from ovarian cancer patients.

OBJECTIVES: Human kallikreins 6 (hK6) and 10 (hK10) are secreted serine proteases. We previously found that hK6 and hK10 are highly overexpressed in epithelial ovarian tumors and demonstrated that serum levels of hK6 and hK10 are valuable biomarkers for ovarian cancer diagnosis and prognosis. Our aim is to purify and characterize these two kallikreins from ascites fluid of ovarian cancer patients. METHODS: Protein concentrations of hK6 and hK10 in ovarian cancer ascites fluids were measured with ELISA-type immunoassays. hK6 and hK10 were purified from the ascites fluids with immunoaffinity columns, followed by reverse-phase high performance liquid chromatography. Purified hK6 and hK10 were then subjected to N-terminal sequencing. Enzymatic analyses were performed with synthetic fluorogenic peptides. RESULTS: hK6 and hK10 were present in ovarian cancer ascites fluid at concentrations ranging from 0.2-571 and 0.7-220 microg/l, respectively. The majority of hK6 and hK10 in the ascites fluids were present in the free (uncomplexed) form. Both hK6 and hK10 purified from the ascites fluid were zymogens with a molecular mass of 30 kDa. Purified hK6 exhibited trypsin-like enzymatic activity, whereas no enzymatic activity was observed for purified hK10. The enzymatic activity of hK6 could be suppressed by a neutralizing monoclonal antibody. CONCLUSIONS: The majority of hK6 secreted by the ovarian tumor cells into the ascites fluid are present in the uncomplexed, zymogen form, possessing weak trypsin-like enzymatic activity. All hK10 present in ovarian cancer ascites fluids are in the uncomplexed, zymogen form and have no detectable enzymatic activity.