MUC1 epithelial mucins are produced by both normal and malignant epithelial cells. Serum proteins reactive with monoclonal antibodies against MUC1 mucins were studied using several techniques. Separation of proteins by native PAGE showed that anti-MUC1 core protein antibodies reacted with a high M(r) mucin but also with a 70-kD protein (p70) in normal women and women with ovarian cancer. After purification by gel filtration, p70 was not reactive in a double-determinant ELISA (CASA) and only weakly reactive in an inhibition assay. Serum CASA levels increased during pregnancy but p70 disappeared. Neuraminidase treatment of serum resulted in a greater increase in CASA in normal women and in ovarian cancer patients with low initial CASA than in ovarian cancer patients with high CASA and pregnant women (p < 0.05). These findings suggest that pregnancy and ovarian cancer-derived mucins are less heavily sialylated than mucin derived from normal tissues. An inhibition assay was developed which was more sensitive, but provided no diagnostic advantage over CASA. MUC1 is present in the serum of all women, reactivity in assays utilizing core protein antibodies is probably dependent not only on molar concentration but on the degree of exposure of peptide epitopes.

BACKGROUND:The new tumor-associated mucin assay, cancer-associated serum antigen (CASA), was assessed with the CA 125 assay for use in the management of patients with epithelial ovarian cancer.METHODS:CASA and CA 125 were assessed retrospectively for use in (1) monitoring 28 patients with Stage 3 or 4 ovarian carcinoma during therapy, (2) predicting the outcome of 41 second-look laparotomies (SLL), and (3) predicting the survival outcome by measuring these levels after surgery but before chemotherapy in 65 patients with Stage 3 disease.RESULTS:Of 20 patients with recurrence after an initial response, the presence of CASA levels detected recurrence in 65% before clinical detection; CA 125, 50%; and the combination of CASA and CA 125, 80%. Six patients whose disease was in long-term remission did not have elevations of either marker. When used to predict the results of SLL, the positive predictive values of CASA and CA 125 were 77% and 100%, respectively. The negative predictive values for CASA and CA 125 were 71% and 66%, respectively. CASA detected 50% of positive SLL where microscopic disease only was found; the CA 125 test did not. Multivariate analysis of survival rates using levels of CASA and CA 125, age, residual disease, tumor type and grade, or the presence or absence of cisplatin in the chemotherapeutic regimen found that postoperative CASA levels ranked above all prognostic factors except age. CASA levels may be more accurate than surgical reporting of residual disease or they may define a subset of patients with biologically more aggressive ovarian carcinoma.CONCLUSIONS:The CASA test is sensitive to ovarian carcinoma, and both CASA and CA 125 are more useful when used in conjunction.

BACKGROUND:The tumor markers CASA (cancer-associated serum antigen) and MSA (mammary serum antigen) have previously been shown to be useful in the clinical management of ovarian and breast carcinoma, respectively, but have not been assessed in other types of cancer. These assays were compared with carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) in a blind trial using sera from the Mayo Clinic-National Cancer Institute (NCI) Diagnostic Serum Bank.METHODS:CASA and MSA were assessed retrospectively in a blind trial using 465 serum samples from the Mayo Clinic-NCI Diagnostic Serum Bank representing malignant and benign disease of the breast, ovary, lung, pancreas, bladder, colon, and prostate and age-matched and gender-matched healthy control donors. CASA, MSA, and PSA levels were determined using commercially available kits, and CEA values and clinical details were later provided by the Mayo Clinic.RESULTS:CASA and MSA showed good reproducibility in 45 duplicate samples. CASA values were significantly elevated in the serum of patients with malignant tumors of the breast (44%), ovary (58%), lung (56%), prostate (48%), and bladder (54%), but not in those with benign conditions of these organs or pancreatic or colon cancer. MSA levels were only elevated significantly in cancers of the breast (52%) and ovary (58%). CASA showed significantly better sensitivity than either CEA (20%) or MSA (25%) in the detection of lung cancer, whereas CEA showed significantly superior detection of colon cancers (78%). CASA was not as sensitive as PSA in prostate cancer (48% versus 96%), but gave superior specificity in nonmalignant conditions of the prostate (93% versus 70%), although this was not statistically significant.CONCLUSIONS:The commercial CASA and MSA assays are reliable and reproducible tests for these tumor markers. In addition to ovarian cancer, CASA is also elevated significantly in many patients with breast, lung, prostate, and bladder cancer and has potential clinical use in patients with these tumors. The use of the MSA assay appears restricted to breast cancer.

This investigation was undertaken to establish a reference range for tumour-associated MUC1 mucins in the serum of healthy women of the ages at risk for adenocarcinoma of the ovary and breast. Blood samples and clinical information were obtained from 5,000 women attending a breast screening mammography clinic. Data from women diagnosed with breast carcinoma and those subsequently diagnosed with other cancers were omitted from the reference range. Mucin concentrations were measured using the CASA assay which detects the protein core of MUC1 encoded mucins. Multiple linear regression analysis showed no effect on CASA concentrations by non-malignant changes to the breast, menopausal status, presence/absence of the reproductive tract, parity or history of hormone use. However, CASA concentrations were significantly increased in smokers (P < 0.001) and progressively increased with age (P < 0.001). These data show that these factors must be given consideration when setting upper limits of normal using MUC1 protein core binding assays.

The use of the mucin-specific lectin from Sambucus sieboldiana (SSAM) in the detection of tumor-associated serum antigens produced by patients with ovarian, cervical, and uterine cancer was investigated. Two-site assays were developed which used either SSAM or the MUC1 core protein-specific monoclonal antibody (mab) BC2 as capture, and biotinylated SSAM to detect bound mucin (SSAM and BC2SSAM assays respectively). These new assays were compared to the CA125 assay, and another assay for MUC1 (CASA), which utilizes the core protein reactive mabs BC2 and BC3. Some asymptomatic women and patients with benign disease showed very high levels in the SSAM assay, while this was not the case in the other assays. When cutoff levels were set to exclude healthy women and patients with benign disease, the levels of detection in patients with ovarian cancer were 51% with CASA (>6.7 units/ml), 71% with CA125 (>250 units/ml), and 38% with BC2SSAM (>8.6 units/ml). The levels of detection in cervical and uterine cancer patients were 28% and 25% with CASA, 0% and 8% with CA125, and 28% and 25% with BC2SSAM respectively. Of particular interest was the very different spectrum of reactivity observed with the CASA and BC2SSAM assays which use the same capture mab, indicating that each assay detects different glycoforms of the MUC1 mucin. Indeed, when used in combination, the CASA and BC2SSAM assays gave 62% of ovarian cancer patients, and 50% of cervical or uterine cancer patients with elevated marker levels. The additional use of BC2SSAM gave no advantage over the combined use of the CASA and CA125 assays in ovarian cancer, with 80% of patients detected, but the CASA/BC2SSAM combination was particularly useful in the cervical and uterine cancers due to the low level of detection with CA125. In fact, the additional use of CA125 gave no advantage over the CASA/BC2SSAM combination in these patients. Furthermore, the BC2SSAM assay may also be useful in monitoring patients with high preoperative BC2SSAM levels (>10 units/ml), since this assay predicted recurrence in 5/5 cases, and was negative in all cases with no evidence of disease. Furthermore, the performance of this assay in monitoring these patients was equal or superior to CA125 and CASA.

OBJECTIVE:To compare mammary serum antigen (MSA) levels with mammography as a screening test for breast cancer. To determine the value of MSA testing to decrease the need for women to undergo mammography.DESIGN:A blind prospective comparison of MSA levels and mammography to detect breast cancer.SETTING:Royal Women's Hospital Breast Cancer Screening Clinic. Women were mainly self-referred.RESULTS:MSA levels had a wide range in normal women and women with mammography-detected breast cancer. Mean MSA levels in women with breast cancer reflected tumour volume, but a wide range was again seen. At 60% specificity, the sensitivity of an elevated MSA level for breast cancer was 63% for invasive cancer and zero for in-situ disease. MSA levels were modestly but significantly elevated in smokers over non-smokers.CONCLUSION:The MSA level is an insufficiently sensitive or specific marker to have a role in screening for breast cancer.

Serum levels of the tumor associated antigens CA125, CASA, OSA and MSA were determined preoperatively in a non-consecutive series of patients with: invasive epithelial ovarian cancer (OC, n = 87), ovarian tumors of low malignant potential (LMP, n = 9), benign adnexal masses (BAM, n = 48) and other peritoneal and pelvic malignancies (n = 48). In addition, serum levels of CASA, OSA, and MSA were determined in 3477 asymptomatic well women. Ninety-eight percent of the asymptomatic women had CASA levels < 6.0 U ml-1, OSA levels < 5.5 U ml-1 and MSA levels < 80.0 U ml-1. Serum CA125 levels were> 35 U ml-1 in 89% of OC, in 44% of LMP, and in 23% of BAM. Serum CASA levels were> 6.0 U ml-1 in 58% of OC, in 0% of LMP, and in 0% of BAM. Serum OSA levels were> 5.5 U ml-1 in 61% of OC in 0% of LMP and in 4% of BAM. Serum MSA levels were> 80.0 U ml-1 in 56% of OC, in 11% of LMP, and in 10% of BAM. When cut-off levels were set to exclude all patients with BAM, the best discrimination from OC using a single assay was achieved using CASA (58%). However, a combination of CASA and CA125 gave positive levels in 69% of OC at levels which precluded BAM. All markers were also elevated in some colon cancers, cervical cancers, uterine cancers and other peritoneal malignancies. A combination of CA125 and CASA levels, obtained preoperatively may assist the general gynecologist in avoiding potentially difficult oncologic surgery.