Maternal serum Ca125 and Ca15-3 antigen levels in normal and pathological pregnancy.

OBJECTIVE: To evaluate the value of maternal serum CA125 and CA15-3 concentrations for discriminating pathological from normal pregnancies. METHODS: Serum samples from 120 women, in whom pregnancy outcome was pathological, i.e. spontaneous abortion, fetal death, intrauterine growth retardation, chromosomal and structural abnormalities, and (pre)eclampsia, were assessed for CA125 and CA15-3 and compared with levels found in 350 women with a normal pregnancy outcome matched for age and duration of pregnancy. RESULTS: Maternal CA125 serum values were significantly higher in the first and the third trimester of pregnancy (median 23.0 and 21.0 U/ml; p < 0.00001 and p < 0.001, respectively), compared to those in the second trimester (median 14.0 U/ml), but not significantly different from those obtained in pathological pregnancies. Maternal serum CA15-3 values were significantly higher during the third trimester (median 26.0 U/ml) compared to the first and second trimester of pregnancy (median 14.0 and 15.0 U/ml; p < 0.0001); CA15-3 serum levels in normal and pathological pregnancies showed no significant difference. CONCLUSION: Maternal serum levels of CA125 are higher during the first and third trimester of pregnancy. CA15-3 maternal serum levels are higher during the third trimester compared to the first and second trimester. Maternal CA125 and CA15-3 serum levels showed no relation with a pathological outcome of pregnancy.

Quantification of MUC1 in breast cancer patients. A method comparison study.

OBJECTIVE: To compare the performance of four serum assays for the quantification of MUC1 in breast cancer patients. STUDY DESIGN: A total of 282 serum samples were evaluated with two automated (Boehringer Mannheim Enzymun-Test CA 15-3 and Chiron ACS BR) and two manual assays (Centocor CA 15-3 radioimmunoassay [RIA] and Biomira Truquant BR RIA). Sera were obtained from healthy controls (n=50), patients with benign (n=25) and malignant breast disease (n=77) and patients with other malignancies (n=69). In addition, sera from pregnant women (n=56) and patients with liver cirrhosis (n=5) were included. RESULTS: Intraassay coefficients of variation (C.V.s) were highest for the manual Centocor CA 15-3 assay (7.4% for values below 50 kU/l and 8.1% for values above 180 kU/l). Interassay C.Vs were highest for the manual Truquant BR assay (11.7% for the lower concentration values and 18.6% for the higher concentration values). False positive rates ranged between 0% for the Centocor CA 15-3 RIA and 14% for the ACS BR assay (cut-off: 30 kU/l). In monitoring breast cancer patients all four assays show similar patterns, although absolute MUC1 values found may differ up to 50%. CONCLUSION: For monitoring purposes all assays perform equally well, however, automated assays show lower inter- and intraassay variability, especially in the higher value range. Therefore we recommend the use of the same, automated, assay for quantification of MUC1 during the follow-up of breast cancer patients.

Fluctuations in CA 125 and CA 15-3 serum concentrations during spontaneous ovulatory cycles.

The aim of this study was to investigate cycle dependent changes of serum CA 125 and CA 15-3 concentrations during spontaneous ovulatory cycles. Twenty apparently healthy women with spontaneous menstrual cycles attending our infertility clinic were included. Of these women, 18 had occluded tubes as a result of sterilization. Ovulation was confirmed by luteinizing hormone test and ultrasonography and, to exclude endometriosis, a laparoscopy was performed. Serum samples for CA 125, CA 15-3, 17 beta-oestradiol and progesterone determinations were taken every second day starting on the 2nd day of the cycle until the 7th day of the next cycle. After correction for inter-individual variation in serum concentrations, highest CA 125 concentrations were found during the menstruation. During the follicular and peri-ovulatory phase CA 125 serum concentrations were lowest. For CA 15-3, serum concentrations were not statistically different throughout the cycle. CA 125 and oestradiol concentrations were negatively correlated, CA 15-3 and oestradiol concentrations were positively correlated. Absolute serum concentrations of both CA 125 and CA 15-3 vary among females. Within the female, fluctuations of CA 125 are phase related. In the population studied most of the patients had tubal obstruction and high CA 125 serum concentrations during menstruation, which revokes the theory that the menstrual rise of CA 125 is due only to retrograde menstruation.

Clinical and technical evaluation of ACS BR serum assay of MUC1 gene-derived glycoprotein in breast cancer, and comparison with CA 15-3 assays.

The mucin glycoprotein-detecting assay CA 15-3 is a valuable tool for monitoring the course of disease in breast cancer patients. Assays of CA 15-3 are based on the use of two MAbs to polymorphic epithelial mucin (PEM). We evaluated the technical and clinical performance of the Chiron ACS BR, an automated competitive chemiluminescence assay using a single MAb, B27.29, and compared the assay's results with those of the Centocor CA 15-3 RIA, the Abbott IMx CA 15-3, and the Boehringer Mannheim Enzymun-Test CA 15-3. The study population consisted of 253 healthy women, 66 patients with benign breast disease, 168 breast cancer patients, and 76 patients with other carcinomas. In the technical evaluation, we assessed the precision and linearity on dilution of the ACS BR assay. Cutoff values (upper limits of values seen in healthy subjects) were determined for all four assays. Agreement between the assays was studied by linear regression analysis. The ACS BR assay gave within- and between-assay CVs of 2.2% and 3.9%, respectively. Three samples from healthy women gave discordant values by ACS BR and were not included in the calculations. All four assays exhibit a highly similar pattern when monitoring breast cancer disease; the closest agreement of values was obtained between ACS BR and Centocor CA 15-3. We conclude that the ACS BR assay is a fast and reliable immunoassay for measuring PEM in serum. Although it detects a slightly different epitope on the PEM molecule than is targeted in other assays, for cancer serum samples it agreed better with the original Centocor CA 15-3 assay than did the other two CA 15-3 assays tested.

Mucin-like carcinoma-associated antigen serum levels in patients with adenocarcinomas originating from ovary, breast and colon.

The mucin-like carcinoma-associated antigen (MCA) enzyme immunoassay was tested in 962 healthy controls. MCA levels were compared with CA 125 in 70 patients with benign and 76 with malignant ovarian tumors. In addition MCA was compared with CA 15.3 in 58 patients with breast cancer and with CEA in 50 patients with colon carcinoma. In healthy controls the 95th percentile cutoff of 19.2 U/ml appeared to be higher than generally used. With the common cutoff value of 14 U/ml, a 38% sensitivity and 100% specificity was reached in malignant versus benign ovarian tumors. In colorectal cancer only 4% of patients had elevated MCA serum levels (CEA: 50%). In breast cancer patients the MCA assay performed better than CA 15.3 although only 17.2% showed elevated levels (CA 15.3: 7.4%). Thus MCA seems to be of limited value in the diagnosis and follow-up of adenocarcinomas of breast, ovary or colon.

Serum tumor marker immunoassays in gynecologic oncology: establishment of reference values.

OBJECTIVE: Our purpose was to establish reference values for six monoclonal antibody-based serum immunoassays applied in patients with carcinoma of the female genital tract. STUDY DESIGN: Sera from 938 healthy women (median age 48.0 years, range 37 to 76 years) were assayed for levels of CA 125, CA 15.3 (two methods), CA M29, CA M26, and mucin-like cancer antigen (MCA). RESULTS: Reference values, defined as those including 95% of healthy controls, were in women with unknown menopausal status as follows: CA 125, 37 U/ml; CA 15.3 (Centocor), 33 U/ml; CA 15.3 (Boehringer Mannheim), 28 U/ml; CA M26, 83 U/ml; CA M29, 13 U/ml; and MCA, 19 U/ml. Postmenopausal values were significantly lower for CA 125 and CA M26 and significantly higher for CA M29 and CA 15.3 (both methods). MCA serum levels were age independent. CONCLUSION: Reference values found were not in accord with those generally applied in gynecologic oncology. In addition, serum levels were influenced significantly by menopausal status (except with MCA).

Multicenter evaluation of the Abbott IMx CA 15-3 assay.

We describe a new fully automated procedure for the quantitative measurement of CA 15-3: the microparticle enzyme immunoassay (MEIA) technology developed by Abbott Labs. for the IMx automated immunoassay analyzer. The new IMx CA 15-3 test uses two mouse monoclonal antibodies, 115D8 and DF3. The test has a dynamic range to 250 kilounits/L and a minimal detectable dose of CA 15-3 < 0.2 kilounits/L. On dilution, linearity is excellent, with recoveries ranging from 94% to 101%. Studies were conducted at four sites to evaluate the performance characteristics of this assay. The intra- and interassay CVs were < 4.7% and < 5.6%, respectively, and showed a between-laboratory CV < 5.9%. Test results of the Abbott IMx CA 15-3 (y) were correlated with those obtained with the Centocor CA 15-3 RIA (x), a solid-phase heterologous RIA. Linear regression analysis on results for 1973 samples yielded: y = 0.97x - 2.09 (r = 0.9899, Sy/x = 22.2, range 1-4089 kilounits/L).

Evaluation of colorectal cancer-associated mucin CA M43 assay in serum.

The technical performance of a newly developed assay for CA M43, a serum marker for colorectal cancer, was evaluated and its preliminary clinical potential assessed. The heterologous double-determinant enzyme immunoassay for the detection of the tumor-associated mucin CA M43 utilizes two monoclonal antibodies (CT 43 and CT 66) selected for their binding capacity to two distinct epitopes present on mucins in the sera of patients with colorectal cancer. CT 66 recognizes both Lewis(a) and sialylated Lewis(a) antigen; CT 43 is directed toward a mucin epitope of an as-yet uncharacterized structure. Precision experiments revealed interassay CVs of 11.8%, 5.9%, and 4.9% at 9.3, 11.9, and 78.9 units/mL, respectively; intraassay precision was 2.0% at 95.1 units/mL. The upper normal value was set at 7.5 units/mL, which included 99% of the values found in healthy controls. In colorectal cancer patients, CA M43 showed a positivity rate equivalent to that of carcinoembryonic antigen (CEA) and superior to that of CA 19.9, with only one CA 19.9-positive serum being negative for CA M43. Interestingly, CA M43 appeared to be complementary to CEA, with CA M43 and CEA together reaching 87% positivity in metastatic disease.

CA 125 in gynecological pathology--a review.

The original CA 125 serum tumor marker test is a homologous double-determinant (OC 125 monoclonal antibody based) assay for the quantification of tumor associated mucin-like CA 125 molecules present in the serum. Commercial kits, now supplied by various manufacturers (and in different versions, e.g. IRMA, EIA, etc.) are currently widely applied in the following clinical situations: (i) Monitoring of disease. Doubling or halving of CA 125 serum values correlated (in 87% of all cases) with tumor progression or regression, respectively. (ii) Early prediction of outcome. Deviation from the ideal CA 125 regression curve predicts poor outcome within 3 months of cytostatic treatment. (iii) Tumor status after completion of therapy. Patients with CA 125 > 35 U/ml have (in 95% of all cases) still tumor present (at second look surgery). However, patients with CA 125 < 35 U/ml have in 50% (mostly minimal) residual disease. (iv) Early detection of recurrence. After a complete remission, a rise in CA 125 precedes tumor recurrence in 75% of all patients, with lead times up to more then 1 year, surpassing the CT-scan in cheapness and accuracy. (v) Diagnosis and differential diagnosis. Only when used in combination with other markers, do CA 125 determinations have a value as a diagnostic adjunct in the discrimination of ovarian cancer patients from those with benign ovarian tumors and from those with advanced colon cancer. Today, optimal management of ovarian cancer patients can only be provided using the CA 125 serum test.

Multicenter technical and clinical evaluation of a fully automated enzyme immunoassay for CA 125.

The technical performance and clinical usefulness of the newly developed Enzymun-Test CA 125 (Boehringer Mannheim) was evaluated in a multicenter study. Sera tested were obtained from healthy control subjects (n = 1003) and from patients with benign conditions (379), ovarian cancer (518), or other malignancies (479). Intra- and interassay variability was low at CA 125 concentrations greater than 100 units/mL. Intra- and interassay CVs were respectively less than or equal to 36% and 23% for the low CA 125 concentrations (less than or equal to 35 units/mL) and less than or equal to 15% and 14% for the medium CA 125 concentrations (36- less than or equal to 100 units/mL). Interlaboratory reproducibility of the Enzymun-Test CA 125 was excellent. A strong linear correlation was observed between Enzymun-Test CA 125 and three of four other commercially available assays of CA 125 in serum. Cutoff values of 35 units/mL in three of these other tests corresponded to Enzymun-Test CA 125 values ranging from 27.0 to 42.1 units/mL. In the fourth test, an enzyme immunoassay, a cutoff of 35 units/mL corresponded to Enzymun-Test values ranging from 64.1 to 77.0 units/mL. Discordant, as yet unexplained, results in which Enzymun-Test values were greater than 65 units/mL and Centocor CA 125 immunoradiometric assay results were less than 35 units/mL were found in 15 of 1003 samples (1.5%) of apparently healthy control subjects. Sensitivity and performance of the Enzymun-Test were very similar to those of the Centocor assay for sera from the patients with various benign disorders or malignant diseases. Given its excellent automated technical performance, this new CA 125 serum assay is feasible for monitoring ovarian cancer patients. Test results are interchangeable with those from other laboratories and, in general, with those obtained by most other CA 125 tests.

Use of serum tumor markers in the differential diagnosis between ovarian and colorectal adenocarcinomas.

In the search for a method to facilitate the preoperative discrimination of ovarian carcinomas from colorectal carcinomas serum levels of 6 tumor markers were measured in 47 patients presenting with ovarian cancer and compared to levels found in 24 female patients with advanced, untreated colorectal cancer. The markers studied were CA 125, CA 15.3, CA 19.9, CEA and two recently developed mucin markers, CA M29 and CA M26. Levels of CA 125, CA 15.3, CEA and CA M29 showed significant differences between both groups. In predicting ovarian cancer, sensitivity was highest for CA 125 at 94% (35 U/ml cutoff level). However, the specificity of CA 125 was at 71% low. Specificity increased significantly by using a combination of a CA 125-positive score (greater than 35 U/ml) and a simultaneous negative CEA score (less than or equal to 5 ng/ml) (specificity 100%, sensitivity 81%). A CA 125/CEA serum ratio greater than 25 resulted in the highest discriminative power with a specificity of 100% and a sensitivity of 91% resulting in an overall test accuracy of 94%. It is concluded that the serum tumor markers used, especially a combination of CA 125 and CEA, are helpful in the preoperative differential diagnosis between adenocarcinomas of ovarian and colorectal origin.

Carcinoma-associated mucin serum markers CA M26 and CA M29: efficacy in detecting and monitoring patients with cancer of the breast, colon, ovary, endometrium and cervix.

Two recently developed monoclonal antibody (MAb)-based anti-mucin assays, CA M26 and CA M29, were studied in 250 cancer patients and compared to 3 well-established marker tests, viz., CA 125, CA 15.3 and SCC, in order to assess their clinical usefulness as serum tumor markers. Pre-treatment sera were obtained from patients with predominantly low-stage epithelial malignancies comprising 200 adenocarcinomas (of the ovary, endometrium, breast and large intestine) and 50 squamous-cell carcinomas (of the uterine cervix). Pretreatment sera of 50 patients with benign ovarian tumors were included to evaluate levels in benign disease, CA M26 and CA M29 cut-off levels were established in 89 healthy controls. In patients with adenocarcinomas, overall positivity for CA M29 was 24%, ranging from 10% in breast cancer to 60% in ovarian cancer. Overall positivity was highest for CA 125 (30%) and lowest for CA M26 (18%) with CA M29 (24%) being similar to CA 15.3 (25%). In adenocarcinomas the combined CA M26-CA M29 assays equalled results obtained with the CA 125-CA 15.3 combination (33% vs. 36%). Elevation of 2 or more markers was highly indicative of advanced disease (p less than 0.025). A majority of positive patients showed either CA M26 or CA M29 elevations, indicating that both antibodies detect distinct epitopes. After adjustment for tumor site and stage, the profile of CA M26 as a single marker differed significantly from the profiles of CA 125 and of CA M29. CA M26 was frequently (32%) elevated in patients with squamous-cell carcinoma of the cervix and CA M26 levels were often independently elevated. CA M26 seems to be valuable as an additional marker in breast cancer and perhaps as a new marker in cervical cancer. CA M29 may be useful in ovarian cancer in addition to CA 125.