Combination assay of CA125, TPA, IAP, CEA, and ferritin in serum for ovarian cancer

The levels of CA125, TPA, IAP, CEA, and ferritin in the serum were measured simultaneously in 68 healthy nonpregnant females and 133 patients with various gynecological diseases, and were subjected to statistical discriminant analysis for the diagnosis of ovarian cancer. The usefulness and the limits for diagnosis of various gynecological diseases were investigated for each tumor marker. Also, the diagnostic usefulness of the stepwise discriminant analysis employing the values of these five tumor markers in the serum in cases of ovarian cancer was compared with that of CA125 measurements alone. Because the frequency of cases with an elevated serum CA125 level increased more specifically in the ovarian cancer group than those of other tumor makers in the serum, this parameter was considered to be more useful for the diagnosis of ovarian cancer than the levels of the other tumor markers. The frequencies of cases with the elevated serum CA125 levels, however, also increased in the groups of patients with endometriosis and at an early stage of normal pregnancy more than in the group of healthy nonpregnant females. In the ovarian cancer patients, the discriminant analysis employing the values of CA125 and four other tumor markers in sera was more useful for early diagnosis, differential diagnosis, early detection of recurrences, and the determination of complete remission after therapy than the measurement of the serum CA125 level alone.     

CA125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer

OBJECTIVES: The main objective of screening is to identify cases of ovarian cancer in early stages. However, screening of women in the general population is ineffective due to a failure of detecting early-stage disease and high false positive rates of CA125 and transvaginal ultrasound (TVU) monitoring. The purpose of this study is to evaluate ovarian cancer screening by means of pelvic examination, serum CA125 and TVU in a consecutive series of high-risk women. METHODS: Clinical data were collected from 132 BRCA1, 20 BRCA2 germ line mutation carriers, 72 members of hereditary breast and ovarian cancer (HBOC) families and 88 breast cancer patients from a hereditary breast cancer (HBC) family, seen between January 1996 and December 2002. RESULTS: Among 10 women with an elevated CA125 level and a positive TVU, three screening carcinomas (one FIGO stage IC, one stage IIIB and one stage IV) and one interval carcinoma (stage IV) were detected. Five occult ovarian/fallopian tube carcinomas (two stage IA, one stage IC, one stage IIIB and one stage IV) after bilateral prophylactic (salpingo-) oophorectomy (BP(S)O) have been found in 152 women. The sensitivity, specificity, positive and negative predictive values (PPV and NPV) of the combination of CA125 and TVU were the highest (40%, 99%, 40% and 99%) followed by CA125 alone (50%, 96%, 13% and 99%), pelvic exam (40%, 98%, 21% and 99%) and TVU, separately (40%, 90%, 6% and 99%). CONCLUSION: By combining CA125 with TVU results, a PPV of 40% was achieved. However, the diagnostic tools appear to be only sensitive in detecting ovarian cancer at an advanced stage, while three of four tumors with early-stage disease in this series had normal screening tests prior to the diagnosis.     

Elevated serum levels of macrophage colony-stimulating factor and OVX1, 11 months prior to the diagnosis of stage IC ovarian cancer

In published trials, CA125 has been utilized to trigger ultrasound examination for the early detection of ovarian cancer. Although serum CA125 levels can be elevated prior to clinical detection of ovarian cancer, only approximately half of patients with stage I disease will have an abnormal value. A combination of CA125, macrophage colony-stimulating factor (M-CSF) and the mucin marker OVX1 will detect> 95% of stage I patients, but it is not known whether the markers can be elevated prior to clinical detection of the disease. A postmenopausal patient was found to have small unilocular bilateral cystic adnexal lesions during an abdominal ultrasound examination. No pelvic abnormality could be palpated. Serum levels of the CA125 antigen were within the normal range. Progressive ultrasound changes prompted a laparotomy II months later, and the diagnosis of a stage IC serous cystadenocarcinoma of the ovary was established. A retrospective analysis of stored serum samples revealed that this patient had elevated serum levels of M-CSF and OVX1 at the time of the original ultrasound scan. Interpreted within the context of a potential screening strategy for ovarian cancer, these data illustrate that either or both of these tumor markers and/or ultrasound could have identified this ovarian cancer many months prior to the actual diagnosis, while the disease was at an early stage.     

Serum markers as prognostic factors in epithelial ovarian cancer: an overview

A comprehensive review of the literature and the authors' personal experience on serum determination of tumour markers in epithelial ovarian cancer can be summarised as follows: CA 125 is the most reliable marker for monitoring the course of epithelial ovarian cancer; CA 125 assay is not an adequate screening test for this malignancy but it can represent an useful adjunct to clinical examination and ultrasound in the differential diagnosis of ovarian masses in postmenopausal women; Serial measurements of CA 125 are useful in monitoring the response to chemotherapy and follow-up. In patients with preoperative positive CA 125 assay, the concomitant determination of other tumour markers does not add further information when compared to CA 125 alone. Conversely in patients with preoperative negative assay the measurement of one or more of other antigens could be of clinical relevance.     

Comparison of serum CA 125, clinical impression, and ultrasound in the preoperative evaluation of ovarian masses

The ability to differentiate a malignant from a benign ovarian mass was assessed for four diagnostic procedures: serum CA 125, clinical examination, original ultrasound, and reviewer ultrasound interpretation. When these tests were used individually, the sensitivity and specificity of CA 125 levels were equal to those of a review ultrasound. Overall, the sensitivity of clinical impression and original ultrasound was poor. Sensitivity and specificity were highest for CA 125 assays in postmenopausal patients, especially when these were used as the second diagnostic test. Positive and negative predictive values significantly increased among postmenopausal patients when CA 125 was added to any of the other diagnostic tests examined. In conjunction with such tests, measurement of serum CA 125 significantly increased diagnostic accuracy and may thus have an important role in the preoperative evaluation of women with ovarian masses.     

Ovarian cancer identified through screening with serum markers but not by pelvic imaging

Abstract. Woolas RP, Oram DH, Jeyarajah AR, Bast RC Jr, Jacobs IJ. Ovarian cancer identified through screening with serum markers but not by pelvic imaging.
This study evaluated the possible role of 3 additional tumor markers to CA 125 among postmenopausal volunteers participating in a sequential multimodal ovarian cancer screening study. In 82 asymptomatic women the finding of a serum CA 125 level of > 30 U/ml precipitated pelvic ultrasound examination. Levels of CA15–3, CA72–4 and CA19–9 were subsequently determined in sera stored from the time of the CA 125 assay. Following ultrasound 29 women underwent surgery for benign conditions. The remaining 53 women underwent 2 years of surveillance. In 5 of these women a diagnosis of ovarian cancer was established between 6 and 10 months after their initial investigation. Elevated levels of at least one of the 3 additional tumor markers were present in the serum, prior to ultrasound abnormalities being detected, in 4 (80%) of the women who developed cancer. At least one of this 3-marker panel was elevated in 29% of the 48 women who have not developed cancer and 14% of the 29 women undergoing surgery for benign conditions. Information complementary to pelvic ultrasound examination for the preclinical detection of ovarian cancer could be obtained through multiple marker assay. Coordinated elevated serum levels of tumor markers could increase the sensitivity of this sequential screening protocol.     

Evaluation of HE4 as an extrabiomarker to CA125 to improve detection of ovarian carcinoma: is it time for a step forward?

Purpose

To evaluate human epididymis protein 4 (HE4) as an extrabiomarker to cancer antigen 125 (CA125) to improve the detection of ovarian carcinoma.

Methods

Sixty patients with ovarian carcinoma, 50 patients with benign ovarian tumors and 30 healthy women were included in the present study. Serum concentration of HE4 was assayed using ELISA technique, while CA125 was assayed using chemiluminescent enzyme immunoassay.

Results

The median CA125 and HE4 serum values were significantly higher among ovarian cancer patients when compared with healthy control However, the median serum levels of CA125 but not HE4 were significantly higher among patients with benign ovarian tumors as compared to healthy women. Based on the receiver operator characteristics curve analysis, HE4 had higher sensitivities than CA125 for the detection of ovarian cancer at 90, 95 and 98 % specificities and the combination of both markers yielded a higher sensitivity than either alone. However, CA125 but not HE4 had higher sensitivities for the detection of benign ovarian tumors at the same specificities. In addition, a positive correlation was observed between HE4 and CA125 among patients with ovarian carcinoma.

Conclusion

HE4 is a valuable marker for ovarian cancer diagnosis and when combined with CA125, they had a higher sensitivity at a set specificity, thus providing a more accurate predictor of ovarian cancer than either alone.     

Doppler ultrasound assessment and serum cancer antigen 125 in the diagnosis of ovarian tumors.

OBJECTIVE: To differentiate benign from malignant ovarian tumors based on sonographic detection of a solid component. METHOD: Sixty-three women with ovarian masses were evaluated preoperatively by gray scale and power/color Doppler ultrasonographic examination, with specific predefined criteria for the solid component. Sensitivity, specificity, and positive and negative predictive values were calculated and assessed against the histopathologic outcome. The contribution of cancer antigen (CA) 125 levels to the diagnostic accuracy was also assessed. RESULT: Sensitivity, specificity, and positive and negative predictive values were 100%, 95.2%, 91.3% and 100%, respectively, with two false-positive results. Had an elevated CA 125 level (>35 U/mL) been included in the malignancy criteria, the false-positive results would have been eliminated, giving an accuracy of 100%. CONCLUSION: Sonographic evaluation with predefined specific criteria for the detection of a solid tumor component is an accurate method of preoperative discrimination between benign and malignant ovarian tumors. A serum CA 125 assay may assist in eliminating false-positive results.     

Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: discrimination of benign from malignant disease

CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels greater than 65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels greater than 65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels greater than 65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%.     

The significance of serum CA 125 elevation in malignant and nonmalignant diseases

OBJECTIVES: The aims of the study were to investigate whether an elevated CA 125 level signals malignancies other than ovarian cancer and to find the cause of death for 247 women with elevated values among the 5550 women screened in 1986-1988 in the Stockholm population. METHODS: The Swedish Regional Cancer Registry delivered malignancy diagnoses among the 5550 women screened. The Cause of Death Registry gave the cause of death among the women with elevated CA 125 values. RESULTS: Patients with ovarian cancer were excluded. In 44 women with elevated CA 125 values other malignancies were reported to the Cancer Registry. They represent 18% of the entire group with elevated values. Among the 5297 women with normal CA 125 values 13% developed various malignancies. The difference between incidence of malignant disease in women with elevated values and women with normal values is significant, P = 0.02. Especially during the test-related period, from 1 year before to 1 year after the test, malignancies were detected in 6.9% of the population with elevated values and in only 1.6% with normal values (P = < 0.001). Breast cancer and lung cancer were overrepresented among women with elevated CA 125 values (P = 0.015 and < 0.001, respectively). Of the total 5500 women screened, 358 women died with different diagnoses. Elevated CA 125 values had been noted earlier in 25 women, and of these 20 died of malignant diseases, predominantly ovarian, breast, and lung cancer. CONCLUSIONS: Asymptomatic postmenopausal women with elevated CA 125 levels in ovarian carcinoma screening trials should, if ovarian cancer is excluded, be investigated for possible breast or lung cancer. The findings also suggest that elevated CA 125 level is a risk factor for death from malignant disease.     

The value of CA 125 determination in the serum of patients with ovarian cancer

The circulating ovarian cancer associated antigen CA 125 was determined in serum of 63 patients with ovarian malignancies by radioimmunometric solid phase assay using the monoclonal antibody OC 125 as catcher and tracer. The results of 41 patients with 43 active tumour situations were compared with the CA 125 serum levels of 27 patients without recurrence after therapy of ovarian cancer and 49 benign ovarian tumours. Significant differences exist between these three groups (p less than 0.001) with elevated values (greater than 35 U/ml) in 84 per cent in ovarian carcinoma, 22 per cent in benign tumours and nought per cent in woman without recurrence in follow-up. The pre-operative sensitivity in ovarian cancer is 93 per cent (in epithelial carcinoma 96 per cent) with a distinct dependence of the CA 125 serum levels on the stage of the disease (stage III and IV versus stage I and II; p less than 0.01). A positive correlation of CA 125 values to clinical status was found in 82 per cent in follow-up. Increasing values of CA 125 can detect the recurrence any months earlier than the clinical examination. Decreasing serum levels in chemotherapy don't reflect the objective tumour remission in every case. Because of elevated values in benign and inflammatory adnexal tumours and the relative low sensitivity in borderline cases (three of seven patients greater than 35 U/ml) the CA 125 assay seems not be suitable for a screening method. However it is a substantial amplification in control of therapeutic success and an early detection of recurrence of ovarian cancer disease.     

Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening

Objective To assess the performance of ultrasonography in a multimodal ovarian cancer screening strategy.
Design Prospective ovarian cancer screening trial between December 1986 and June 1993.
Setting General practice, occupational health departments and an ovarian cancer screening clinic at a London teaching hospital.
Population Postmenopausal women, ≥ 45 years with a raised CA125.
Methods Volunteers with a CA125 ≥ 30 U/mL underwent a pelvic ultrasound. Scans were classified as normal, abnormal (ovarian volume ≥ 8.8 mL) or equivocal (normal volume with abnormal morphology). Abnormal ovarian morphology was subclassified as simple cyst (single, thin walled cyst with no septa or papillary projections) or complex (all other abnormalities). Volunteers with abnormal scans were referred for a gynaecological opinion. Follow up was via the cancer registry and postal questionnaires.
Main outcome measures Sensitivity, specificity and positive predictive value of different ultrasound criteria for detection of index cancer (e.g. primary invasive epithelial carcinoma of the ovary and fallopian tube).
Results Seven hundred and forty-one women underwent 1219 scans and 20 index cancers occurred during a median follow up of 6.8 years. The sensitivity for detection of ovarian cancer of different ultrasound criteria was 100% for abnormal morphology, 89.5% for abnormal volume and 84% for complex morphology. The highest specificity (97%) and positive predictive value (37.2%) was achieved using complex morphology.
Conclusion A variety of ultrasound criteria can achieve high sensitivity, specificity and positive predictive value for index cancers in postmenopausal women with an elevated CA125. Use of ovarian morphology to interpret ultrasound may increase sensitivity and use of complex ovarian morphology may increase the positive predictive value.     

New reference levels for CA125 in pre- and postmenopausal women

Objective: CA125 is a glycoprotein commonly produced by the endometrium. Serum CA125 is widely useful as a marker for ovarian cancer screening, with 35 U/mL the generally accepted upper limit of normal. Since CA125 is known to fluctuate with vaginal bleeding and menopausal status, the purpose of this study was to develop different reference ranges for normal women of differing physiologic states.Methods: We retrospectively analyzed 1,407 patients with serum CA125 levels taken at Cleveland Clinic Florida between 1992 and 1997. Patients with obvious elevation of CA125 from gynecologic cancers were excluded. Student t test was used to determine statistical significance.Results: Among 1,407 patients studied, 256 were premenopausal, 46 perimenopausal, 957 postmenopausal, and 148 excluded due to known gynecologic cancers. There was a significant difference between the mean CA125 values of premenopausal (19.3 ± 15.6) and postmenopausal women (11.7 ± 9.2) with P .7 × 10⁻⁶. Among premenopausal women, there was a statistically significant difference between CA125 levels during menses (21.4 ± 19.3) and luteal phase (14.0 ± 9.1) with P = .03. Among the subgroup of postmenopausal women with known bleeding history, the mean CA125 values for women with vaginal bleeding was 12.49 ± 11.5 compared to those without bleeding, 9.62 ± 4.6 (P = .017).Conclusions: For normal premenopausal women, the overall upper limit of CA125 should be 50 U/mL. However, if menstrual status is known, the upper normals should be: 62 during menses, 51 for proliferative phase, and 32 for luteal phase. For postmenopausal women, the CA125 levels should be no more than 35 for those with vaginal bleeding and 20 for those without bleeding. The stratified CA125 values may help provide more specific ovarian cancer screening.     

Ovarian cancer screening in women with a family history of breast or ovarian cancer

OBJECTIVE: To evaluate positive predictive values of CA 125 or transvaginal ultrasonography screening for ovarian cancer according to family history of breast or ovarian cancer. METHODS: In the screening arm of a randomized controlled trial of screening compared with usual care, 28,460 women with family history data received baseline and annual CA 125 and transvaginal ultrasonography examinations. We analyzed CA 125 and transvaginal ultrasonography results from the first four rounds of screening. We classified women as average (n=22,687), moderate (n=2,572), or high (n=2,163) risk based on family history, or high risk due to a personal history of breast cancer (n=1,038). Cancers were identified by active follow-up of women with abnormal screening results and annual questionnaires. We calculated positive predictive values for screening combinations. RESULTS: Similar proportions (4.8-5.0%) of women in each group had abnormal screening results. Higher-risk women were more likely than lower-risk women to undergo biopsy after a positive screen. Screening identified 43 invasive ovarian cancers. The positive predictive values for abnormal screening results were 0.7% in average-risk, 1.3% in moderate-risk, and 1.6% in high-risk groups; one ovarian cancer occurred among the breast cancer survivors. The positive predictive values for postbaseline abnormal screening results were also higher in the higher-risk groups. The positive predictive values did not significantly differ across risk groups. CONCLUSION: Probabilities of abnormal annual CA 125 and transvaginal ultrasonography screens were similar across groups based on family history of breast or ovarian cancer. However, ovarian cancer was more likely to be diagnosed after an abnormal screening result among women at higher family history-based risk than among women at lower risk. LEVEL OF EVIDENCE: I.     

CA125 expression at clinical diagnosis by ovarian carcinoma not detected through antecedent serum CA125 screening

At the time of clinical presentation with ovarian carcinoma, 85% of women have an elevated serum level of the CA125 antigen, but the duration of the preclinical phase of expression of CA125 is unknown. From the database of The Royal London Hospital ovarian cancer screening project, 19 women were identified who had a serum CA125 level <30 IU ml⁻¹, measured between 2 and 24 months prior to their clinical diagnosis of ovarian cancer. Histological sections of tumor removed from these women were reviewed. In 17 cases tumor tissue was immunocytochemically stained for CA125 expression. Tumor blocks of 40 women presenting clinically with ovarian cancer with known preoperative CA125 levels were also stained for CA125 expression. The serum CA125 level at the time of diagnosis was available in six of the 19 screening study cases, four of which had levels> 30 IU ml⁻¹. In five of the 13 cases with unknown serum CA125 levels, ovarian tumor tissue expressed CA125. Among the 40 controls, 24 tumors expressed CA125 and all 24 had a serum level greater than 47 IU ml⁻¹. An annual screening test using serum levels of CA125 at a cut-off of 30 IU ml⁻¹, cannot detect all cases of ovarian cancer that express the antigen at the time of clinical diagnosis. The development of a panel of complementary tumor markers will be necessary to provide a test with a higher sensitivity for the detection of preclinical ovarian cancer.     

Screening for ovarian cancer by transvaginal ultrasound and serum CA125 measurement in women with a familial predisposition: a prospective cohort study

OBJECTIVE: This study evaluates the accuracy of transvaginal ultrasound (TVUS) in combination with CA125 to detect ovarian cancer in women at hereditary risk for ovarian cancer. METHODS: A semi-annual surveillance protocol comprising CA125 measurement and TVUS was offered to 676 women including 85 BRCA mutation carriers. Surgical intervention was performed if TVUS revealed a suspicious cyst or if elevated CA125 levels or cystic lesions persisted in two consecutive examinations. RESULTS: Ten women underwent histological verification that revealed one serous cystadenocarcinoma stage Ic. No interval ovarian cancer occurred. The specificity of surgical intervention reached 98.7% (95% confidence interval (CI): 97.5% to 99.3%) and a positive predictive value (PPV) of 10% (95% CI: 1.8% to 40.4%). CONCLUSION: The low PPV is due to the unexpectedly low incidence of ovarian cancer. Large scale investigations including details on potential confounders and modifiers are needed to further evaluate accuracy and effectiveness of ovarian cancer screening for women at high risk.     

CA 125 measured before second-look laparotomy is an independent prognostic factor for survival in patients with epithelial ovarian cancer

The prognostic significance of serum CA 125 level measured in the week before second-look operation was evaluated in 208 patients with invasive epithelial ovarian cancer. Serum CA 125 level was greater than 35 U/ml in 44.7% of patients. All patients with pathological complete response (PCR) had a serum CA 125 level less than or equal to 35 U/ml except one who developed lung metastases 2 months later. The sensitivity of serum CA 125 for identifying residual tumor at second-look operations was 58%, the specificity was 98%, the predictive value of a positive test was 99%, and the predictive value of a negative test was 43%. By Cox regression analysis, tumor state of second look, serum CA 125 level, histologic type, FIGO stage, and tumor grade were identified as independent prognostic factors for survival. We conclude that measurement of serum CA 125 level after induction chemotherapy represents a noninvasive method to identify patients at high risk for subsequent death from ovarian cancer. As far as we know, this is the first report to identify serum CA 125 level as an independent prognostic factor at the time of second-look laparotomy.     

The concomitant determination of different serum tumor markers in epithelial ovarian cancer: relevance for monitoring the response to chemotherapy and follow-up of patients.

The levels of CA125, CA19.9, CA15.3 CA72.4, and TATI were serially measured during and after chemotherapy in 43 patients with epithelial ovarian cancer having elevated concentrations of one or more of the antigens before initial surgery. The value of 35 U/ml was chosen as cutoff level of CA125 for the monitoring of disease. Changes in the serum levels of CA125, CA19.9, CA15.3, CA72.4, and TATI correlated with the clinical course of disease in 87.4% of 215, 76.3% of 80, 71.3% of 122, 76.0% of 167, and 48.5% of 101 instances, respectively. After the sixth course of monthly primary chemotherapy, elevated antigen levels were strong predictors of persistent disease, while normal antigen values were associated with both positive and negative second-look findings. It is worth noting that antigen levels above the cut-off limits before the third course, but still in the normal range after the sixth course, seemed to be predictive of positive second-look findings. Among patients with elevated antigen levels at diagnosis, clinical detection of neoplastic progression after treatment was stopped was preceded by an elevation of serum CA125 in 93.3% of 15 patients, of serum CA19.9 in 80.0% of 5 patients, of serum CA15.3 in 66.7% of 9 patients, of serum CA72.4 in 81.8% of 11 patients, and of serum TATI in 40% of 10 patients. In patients with positive CA125 assay at diagnosis, the concomitant evaluation of the other antigens did not seem to be of additional benefit for monitoring epithelial ovarian cancer. However, the measurement of the other tumor markers could represent an interesting biochemical tool for the management of patients with negative CA125 assay. In particular the evaluation of serum CA19.9 or CA72.4 could be very useful in the monitoring of patients with mucinous ovarian cancer, which often fails to express CA125 antigen.     

Tumor marker CA 125 level and ovarian volume at different cycle day periods and in postmenopause

The value of using CA 125 for screening of ovarian carcinoma is still under debate. It is important to be aware of possible physiological variation in serum levels of this antigen. This study aimed at finding out whether there were any differences in CA 125 levels in serum at different cycle day periods of fertile women and postmenopausal women. In 106 women, CA 125 and ovarian volume were measured at different cycle day periods and in postmenopausal women. The highest levels were found in cycle day (CD) 1-9, i.e. 22 units/ml and the lowest in postmenopausal women i.e. 6.7 units/ml. No correlation could be found between the CA 125 levels and ovarian volume as measured by vaginal sonography.     

The role of CA 125 in the evaluation of palpable or enlarged postmenopausal ovaries

A serum CA 125 assay provided a method of more accurately identifying a postmenopausal woman at high risk for ovarian cancer when a screening ultrasound examination revealed a 2 X 3 cm ovary that could not be detected by palpation.