CA 15-3: a prognostic marker in breast cancer

CA 15-3 (also known as MUC1) is the most widely used serum marker in breast cancer. MUC1 is a large transmembrane glycoprotein which is frequently overexpressed and aberrantly glycosylated in cancer. Physiologically, MUC1 appears to play a role in cell adhesion and the high levels present in cancer may be causally involved in metastasis. At present the main uses of CA 15-3 are in preclinically detecting recurrent breast cancer and monitoring the treatment of patients with advanced breast cancer. In a prospective study of 368 patients we show that patients with high preoperative levels of CA 15-3 (>30.4 U/mL) had a worse outcome than patients with low levels of the marker. In multivariate analysis CA 15-3 as a prognostic marker was independent of both tumor size and nodal status. Furthermore, in multivariate analysis the prognostic impact of CA 15-3 was stronger than that of tumor size and at least as strong as nodal status. CA 15-3 may thus be the first independent prognostic serum marker in breast cancer.     

Correlation of biochemical tumor markers with conventional pathological features in primary breast cancer.

In this prospective study the correlation of pathological with biological prognostic factors and serum tumor markers has been investigated in 574 patients with primary invasive breast cancer. The p53 protein and Bax level correlated positively with tumor size, lymph node status and histological grade. The serum levels of CEA, CA 15.3, TPA-M and TK correlated with tumor extent. There was a significant difference between pre- and postmenopausal breast cancer patients in serum levels of TPA-M and cytosol levels of Bax. Whether these correlations can help in predicting the prognosis of breast cancer by providing additional information with respect to the conventional factors, will have to be investigated by several years of careful clinical follow-up.     

Study of lung cancer regulatory network that involves erbB4 and tumor marker gene

Our purpose is to screen out serum tumor markers closely correlated to the nature of solitary pulmonary nodule (SPN) and to draw a regulatory network containing genes correlated to lung cancer. Two hundred and sixty cases of SPN patients confirmed through pathological diagnosis were collected as subjects, factors closely correlated to the nature of SPN were screened out from eight tumor markers through Fisher discriminant method, and functional annotation and pathway analysis were conducted on erbB4 as well as its tumor marker genes by GO and KEGG databases. Four key tumor markers: CYFRA21-1, CA125, SCC-Ag and CA153 were successfully screened out and the first three proteins’ corresponding gene were KRT19, MUC16 and SERPINB3 while that of CA153 was not found. GO analysis on erbB4, KRT19, MUC16 and SERPINB3 showed that they covered three domains, cell components, molecular function and biological process; meanwhile, combined with KEGG database and based on signal pathway of erbB4, a regulatory network of lung cancer cells escaping from apoptosis was successfully made. This study indicates that serum tumor marker genes play an important role in the occurrence and development of lung cancer, besides, this study primarily discussed the molecular mechanism of these tumor markers in predicting tumor, which provides a basis for in-depth information about lung cancer.     

Evaluation of chromogranin A expression in serum and tissues of breast cancer patients

Human chromogranin A (CgA) is a member of the granin family and is widely distributed in large dense core granules of endocrine and neuroendocrine cells. A variety of non-neuroendocrine carcinomas arising in various tissues show patterns of neuroendocrine differentiation. Expression of CgA has been documented in epithelial cells of normal mammary gland as well as in breast cancers, and elevation of serum CgA has been detected in patients with breast cancer. Our study was undertaken to evaluate the relationship between serum CgA levels and neuroendocrine features in breast cancer. In addition, we evaluated the expression of serum CgA in patients affected by breast cancer compared to controls and the relationship between serum CgA and tumor histology, extent of disease, lymph node status, tumor stage and serum CA 15.3 levels. We enrolled 266 patients with infiltrating ductal or lobular breast carcinoma and a group of 100 age-matched healthy women serving as controls. Serum CgA and CA 15.3 were assayed by specific immunoradiometric methods. The overall sensitivity of CgA and CA 15.3 was 0.06 and 0.34, respectively (chi2 19.1, p<0.0005). No relationship was found between serum levels of CgA and tumor histology, extent of disease, lymph node status or tumor stage while serum levels of CA 15.3 were strongly correlated with all these variables but tumor histology. No relationship was found between serum levels of CgA and CA 15.3. Immunostaining against CgA, CgB, NSE and synaptophysin was performed on primary tumor tissue of 14 serum CgA-positive and 24 serum CgA-negative patients and was negative in all cases. We also evaluated eight cases of pathologically-proven neuroendocrine breast cancer: only four and two of these showed positive CgA immunostaining and increased serum CgA concentration, respectively. In conclusion, serum CgA assay offers no additional information regarding the presence, the extent and the histology of breast cancer compared to the CA 15.3 assay. Moreover, serum CgA was not an accurate marker to identify or exclude the rare neuroendocrine differentiation of breast cancer. We therefore conclude that CgA is not useful as a serum marker in breast cancer.     

Circulating CA 15.3 levels in breast cancer. Our present experience

CA 15.3 is an antigen expressed by human breast carcinoma cells, and defined by two monoclonal antibodies, 115D8 and DF3. We used IRMA to determine the circulating serum levels of CA 15.3 in 1178 subjects with breast cancer, non-breast malignancies, benign diseases and controls. A threshold level of 40 U/ml was established with 140 healthy controls and 650 patients with benign diseases (respectively 0% subjects and 1.5% patients had abnormal antigen levels). Elevated CA 15.3 was found in 12 of 184 patients with malignancies different from breast cancer (6.5%), either epithelial carcinomas with distant metastases, mainly in the liver, or primary liver tumors. Breast cancer patients (n = 204) were analysed by prior therapy, UICC stage and WHO response to therapy. Eight of 134 (5.9%) patients with stage II or III breast cancer at presentation and no evidence of disease (NED) had elevated CA 15.3. All of 22 patients with stage IV breast cancer not responding to therapy (SD and PD) had antigen levels greater than 40 U/ml, as did 10 of 34 (29.4%) stage IV patients in objective response (CR + PR). Three of 14 pretreatment patients had abnormal marker levels, and they later proved to have distant metastases. Serum CA 15.3 values were statistically different (p less than 0.01) in NED (20.6 +/- 11.2 U/ml), CR + PR (33.5 +/- 24.0 U/ml), stable disease (98.8 +/- 50.4 U/ml) and progressive disease (greater than 200 U/ml) breast cancer patients. Our results suggest that circulating CA 15.3 antigen levels agree with the stage of breast cancer and with the response to therapy.     

TPA and CA 15.3 measurements for breast cancer monitoring in a routine setting.

TPA and CA 15.3 concentrations were routinely determined in serum of patients treated for breast cancer during a 15-month period. ROC curves did not show differences in the ability to differentiate between NED and PD on the basis of matching tumor marker values. During monitoring of patients with NED, TPA levels showed fluctuations of more than 25% that were not disease related. We concluded that CA 15.3 is a more slowly reacting marker of tumor burden than TPA, which is an immediate indicator of cell turnover.     

Serum tumor markers may precede instrumental response to chemotherapy in patients with metastatic cancer

PURPOSE: Although serum tumor markers (STMs) are widely used in clinical practice, their predictive role for the response to anticancer treatment is still controversial. The correlation of CEA, CA 15.3, CA 19.9, CA 125 (only with peritoneal involvement) and NSE levels with imaging response and clinical benefit was investigated in 60 non-selected patients with metastatic epithelial cancers treated by single-agent docetaxel chemotherapy. METHODS: STM measurement was performed at baseline and subsequently every three to four weeks. We applied the WHO criteria to evaluate both STM and instrumental responses. Concordance analysis was performed by the Cohen Kw index, and the significance of the results was established using the Fleiss, Cohen & Everitt test. Qualitative interpretation of data was obtained with the Landis & Koch scale. Correlations of STM response with clinical benefit (PS or pain improvement) were evaluated by the chi-square test. RESULTS: The primary tumors included breast cancers (38 patients), gastrointestinal non-colorectal cancers (12 patients), and lung cancers (10 patients). An overall significant good degree of agreement was observed between STM and instrumental response (p < 0.0005). The degree of agreement for each marker was as follows: excellent for CEA (p < 0.0005) and CA 125 (p = 0.006), good for CA 15.3 (p < 0.0005) and CA 19.9 (p = 0.011). Restricted analysis for the correlation of each marker with primary tumor origin showed good prediction of radiological response for CA 15.3 and CEA in breast cancer patients (p<0.0005 for both), for CEA and CA 19.9 in gastrointestinal cancer patients (p = 0.01 and 0.04, respectively), and for CEA+NSE in lung cancer patients (p = 0.01). Conversely, STM response did not correlate significantly with the clinical benefit for the patients, both in terms of PS and pain improvement (p = 0.24 and p=0.42, respectively). CONCLUSION: This study showed STMs to be good predictors of tumor response. Although STMs cannot replace diagnostic imaging, in metastatic cancer they might be useful to optimize the timing of radiological re-evaluation in the palliative setting.     

Analytical and clinical evaluation of a new tumor marker in breast cancer: CA 27.29.

Evaluation of a radioimmunoassay for a new tumor marker, named CA 27.29, recently proposed for use in breast cancer patients, is reported in this study. After considering the analytical performance, the clinical study was directed to a control group of 66 apparently healthy subjects (Controls), a group of 25 women with benign breast disease (BBD) and a group of 164 breast cancer patients divided into primary before any treatment (M-), in follow-up with no evidence of disease (NED) and presence of metastases (M+). When compared to CA 15.3, our results showed similar sensitivity of both markers with a slightly lower specificity for CA 27.29. In some cases, however, CA 27.29 elevation appears earlier than CA 15.3 as a sign of metastases. We thus propose their associated use.     

Proteomic Profiling of a Mouse Model for Ovarian Granulosa Cell Tumor Identifies VCP as a Highly Sensitive Serum Tumor Marker in Several Human Cancers

The initial aim of this study was to identify novel serum diagnostic markers for the human ovarian granulosa cell tumor (GCT), a tumor that represents up to 5% of all ovarian cancers. To circumvent the paucity of human tissues available for analyses, we used the Ctnnb1(tm1Mmt/+);Pten(tm1Hwu/tmiHwu);Amhr2(tm3(cre)Bhr/+) transgenic mouse model, which features the constitutive activation of CTNNB1 signaling combined with the loss of Pten in granulosa cells and develops GCTs that mimic aggressive forms of the human disease. Proteomic profiling by mass spectrometry showed that vinculin, enolase 1, several heat shock proteins, and valosin containing protein (VCP) were more abundantly secreted by cultured mouse GCT cells compared to primary cultured GC. Among these proteins, only VCP was present in significantly increased levels in the preoperative serum of GCT cancer patients compared to normal subjects. To determine the specificity of VCP, serum levels were also measured in ovarian carcinoma, non-Hodgkin's lymphoma and breast, colon, pancreatic, lung, and prostate cancer patients. Increased serum VCP levels were observed in the majority of cancer cases, with the exception of patients with lung or prostate cancer. Moreover, serum VCP levels were increased in some GCT, ovarian carcinoma, breast cancer, and colon cancer patients who did not otherwise display increased levels of widely used serum tumor markers for their cancer type (e.g. inhibin A, inhibin B, CA125, CEA, or CA15.3). These results demonstrate the potential use of VCP as highly sensitive serum marker for GCT as well as several other human cancers.     

Soluble MUC1 and serum MUC1-specific antibodies are potential prognostic biomarkers for platinum-resistant ovarian cancer

MUC1 (CA15-3) and MUC16 (CA125) tumor-associated antigens are upregulated in ovarian cancer and can be detected in patients’ sera by standardized tests. We postulated that increased MUC1 and MUC16 antigens augment antibody responses in platinum-resistant ovarian cancer patients and that the frequency and intensity of these responses can be used as immune biomarkers of treatment response and disease outcome. We measured MUC1 and MUC16 tumor expression by immunohistochemistry (IHC), assessed serum antigenic levels and quantitated circulating antibodies by ELISA in a cohort of 28 ovarian cancer patients with platinum-resistant or platinum-refractory ovarian cancer, and treated with intraperitoneal (IP) interleukin-2 (IL-2). MUC1 and MUC16 were overexpressed in tumor samples and showed differential distribution profiles. Serum MUC1 (CA15-3) measurements were elevated in all patients and significantly correlated with increased risk of death (P = 0.003). MUC1-specific IgM and IgG anitbodies were found in 92 and 50% of cases, respectively. Patients with progressive disease had higher mean anti-MUC1 IgG than responders at both early (P = 0.025) and late (P = 0.022) time points during IP IL-2 treatment. Anti-MUC1 IgM antibodies inversely correlated with overall survival at both early (P = 0.052) and late (P = 0.009) time points. In contrast to MUC1, neither soluble MUC16 nor MUC16-specific antibodies were significantly associated with clinical response or overall survival in this study. Increased serum MUC1 and high anti-MUC1 antibody levels are prognostic for poor clinical response and reduced overall survival in platinum-resistant or platinum-refractory ovarian cancer.     

Clinical significance of blood-based miRNAs as diagnostic and prognostic nucleic acid markers in breast cancer: Comparative to conventional tumor markers

microRNAs (miRNAs) are implicated in carcinogenesis and their expression in biological fluids offer great potential as nucleic acid markers for cancer detection and progression. Authors investigated the expression level of miRNAs (miRNA-21, miRNA-126, and miRNA-155) to evaluate their role as diagnostic and prognostic markers for breast cancer compared with other commonly used protein-based markers (CEA and CA15-3). Serum samples from patients with breast cancer (n = 96), patients with benign breast lesion (n = 47), and healthy individuals (n = 39) were enrolled for detection of miRNA expression levels and protein-based tumor markers using fluorescent real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Correlation among investigated markers with clinicopathological factors and clinical outcomes were determined. Expression of miRNA-21 and miRNA-155 revealed significant increases in patients with breast cancer compared with both benign and control groups, the same result was reported for tumor markers; on the other hand, miRNA-126 was significantly decreased in breast cancer group as compared with the other two groups. miRNA frequencies were significantly related to clinical staging and histological grading as compared with tumor markers. Patients with breast cancer with increased miRNA-21 and miRNA-155 and decreased miRNA-126 expressions had significantly worse disease-free survival, while only miRNA-21 and miRNA-126 showed poor OS (P< 0.005). In conclusion, investigated miRNAs were superior over tumor markers for the early stage of breast cancer especially those with high-risk factor and their assessment in blood facilitates their role as a potential prognostic molecular marker.     

The role of blood tumor marker measurement (using a biochemical index score and c-erbB2) in directing chemotherapy in metastatic breast cancer

The role of blood tumor markers in monitoring response in advanced breast cancer is established in endocrine therapy and standard chemotherapy. This study examines marker levels in patients receiving new chemotherapy regimens. Thirty patients were recruited into two multicenter trials in which docetaxel-based regimens were used in 15 patients. The other 15 received doxorubicin-based regimens. Biochemical response calculated from a score using CA15.3, CEA and ESR was compared with UICC response. Marker changes at 2, 4 and 5 months correlated with UICC response at 3, 4(1/2) and 6 months, respectively (p < 0.03). Eleven patients achieved both clinical/radiological and biochemical response at the end of treatment; markers had not yet returned to below cutoffs in seven, suggesting a possible advantage to continue chemotherapy. No patient showed a biochemical response whilst judged clinically/radiologically progressive. Nineteen patients had progressed either clinically/radiologically or biochemically at six months; of these, eight showed progression assessed earlier by markers so that a median of four cycles of chemotherapy could have been saved. Measurements of serum c-erbB2 showed a correlation with tissue c-erbB2 staining in the primary tumor (p < 0.003). Among the patients with positive tissue staining, sequential changes in serum c-erbB2 completely paralleled initial response.     

Cellular and humoral immune responses to MUC1 mucin and tandem-repeat peptides in ovarian cancer patients and controls

The objective of this study was to demonstrate the presence of proliferative T cell responses to human polymorphic epithelial mucin (MUC1) and its tandem-repeat peptides in peripheral blood mononuclear cells (PBMC) from ovarian cancer patients and from controls and to correlate these cellular responses to a humoral response to MUC1. PBMC were obtained from 6 healthy women, from 13 women in the third trimester of pregnancy and from 21 ovarian cancer patients. Only 1 of the 6 healthy women showed a weak primary proliferative response (stimulation index, SI<2) to a 20-mer MUC1 tandem-repeat peptide in the presence of interleukin-2 (IL-2). In PBMC from 5/13 pregnant women (38%) a weak response could be induced by the 20-mer and/or 60-mer tandem-repeat peptides (SI ≤ 3.0) and in PBMC from 8/15 ovarian cancer patients (53%) 20-mer and/or 60-mer MUC1 tandem-repeat peptides induced primary responses (SI ≤ 5.4). MUC1 mucin purified from a breast tumor cell line and/or from urine of a healthy donor had a relatively strong stimulating effect (SI ≤ 19) on PBMC from 4 of 16 ovarian cancer patients (25%). In contrast, in PBMC of 9 ovarian cancer patients stimulated by the addition of a Candida albicans extract, MUC1 mucin strongly inhibited proliferation. This inhibition could partially be abrogated by the addition of IL-2. MUC1 (CA 15.3 assay) and free circulating MUC1 IgG and IgM antibodies (PEM.CIg assay) were determined in the plasma of all subjects. The MUC1 and the free circulating MUC1 IgG antibody plasma levels were significantly higher in the ovarian cancer patients than in the healthy women. Although no significant correlations were found between MUC1 mucin, MUC1 Ab plasma levels and the individual proliferative responses to the MUC1 antigens, an association may exist between them, since all three are significantly higher in the ovarian cancer patients than in the healthy women. Received: 27 August 1998 / Accepted: 10 December 1998     

MUC3 and MCA serum levels and steroid receptor content in breast cancer

Mucins are an important class of complex glycoproteins expressed by many epithelial cells and their malignant counterparts. The aim of this study was to determine the serum levels of MUC3 and mucin-like carcinoma-associated antigen (MCA) in patients with primary breast cancer and to analyze the possible relationships between these two mucins and the steroid receptor status. The preoperative basal serum levels of MUC3 (ELISA assay with monoclonal antibody 1143/B7) and MCA (EIA assay with anti-MCA mouse monoclonal antibody b-12) were determined in 44 patients with breast cancer while estrogen receptor (ER) and progesterone receptor (PgR) levels were measured by the dextran-coated charcoal method in the cytosol of neoplastic tissue. MUC3 was expressed in 43/44 serum samples while high MCA serum levels were found in 16/44 only; the mean values of both markers did not correlate with menopausal status, tumor size, nodal involvement or ER. The only significant difference observed was a lower median value of MCA in patients with small tumors (T1-T2). No statistically significant correlation between MUC3 and MCA, MUC3 and ER or MCA and ER was observed; a statistically significant direct correlation between MUC3 and PgR+ status and a statistically significant inverse correlation between MCA and PgR+ were observed. Our results suggest that further investigations are necessary to establish whether progesterone can modulate MUC3 and MCA expression in breast cancer.     

Carcinoembryonic antigen and breast carcinoma antigen (CA 15.3) in preoperative staging and postoperative monitoring of patients with carcinoma of the breast

Serum levels of carcinoembryonic antigen (CEA) and breast carcinoma antigen (CA 15.3) were determined in patients with breast carcinoma: in 129 before initial surgical or nonsurgical treatment and in 134 afterwards. Before any initial treatment, CEA was elevated in 15% of patients with Stage IV disease and CA 15.3 was high in 11% with Stage III and 48% with Stage IV. While monitoring management active disease was associated with elevated serum CEA in 66% of the patients, with elevated CA 15.3 in 73% and with at least one of the markers elevated in 86%. Both tests had high specificity (93% and 98%). The rise in serum CEA and, even more so, of serum CA 15.3 roughly paralleled the increase in bulk of the tumor: from locoregional disease through metastases to the lungs, bones, lungs with bones, and liver. Decreases in the levels of serum CEA and CA 15.3 reflected response to therapy, increases in the level of at least one marker-treatment failure, and levels fluctuating above the normal range indicated stationary disease. During follow-up, the predictive value of a negative test (levels within the normal range), suggesting that the patient might be free of disease, was 61% for CEA alone, 67% for CA 15.3 alone, and 80% for the two tests combined. We conclude that an elevated serum level of only one of the markers was useful for staging, implying advanced disease. Determination of both markers jointly was useful for monitoring the effectiveness of the therapy and for follow-up aimed at detection of relapse.     

c-myc oncogene gene dosage, serum CEA and CA-15.3 antigen levels, and cellular DNA values in relation to ex vivo chemosensitivity of primary human breast cancer

A pilot study on relationships of selected molecular factors (c-myc oncogene average gene copy numbers (AGCN); serum CEA and CA 15.3 antigen levels; tumor cells' DNA values), to the ex vivo chemosensitivity of primary female human breast cancer in a modified adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA), was performed. Four drug combinations were tested. A group of 75 cases of female primary breast cancer was assessed. Numerous correlations were found among molecular factors tested but none, with the exception of tumor grading, of these reflected ex vivo chemosensitivity of tumors tested. The results suggest that the parameters tested may not be important factors related to adjuvant chemoresponsiveness of primary human breast cancer to tested drug combinations.     

Possible utility of serum determinations of CA 125 and CA 27.29 in breast cancer management

The utility of measurement of serum levels of the tumor associated antigens CA 125 and CA 27.29 in detecting the presence of disease and in monitoring changes in disease status was examined in 63 patients with breast cancer. In patients with clinically detectable disease the CA 125 level was elevated in 59%, the CA 27.29 level in 59.5% and one or both markers in 84.6%. Specificity for presence of disease was 83.6% for CA 125, 88% for CA 27.29, and 69.1% for the two markers combined. Changes in marker levels of more than 50% correlated with clinical changes in disease status in 58% of cases for either CA 125 or CA 27.29 alone. In 87.5% of cases with clinically progressive disease one or both marker levels increased by more than 50% from the previous levels. In no case with greater than 50% increase in a marker level was there regression of disease. Thus, the use of these markers in combination might have utility in cases where diagnosis of recurrent disease is difficult or where monitoring of response to treatment is hampered by lack of measurable disease.     

Prognostic significance of CA 15.3 in metastatic breast cancer

We have investigated the possible relation between serum levels of CA 15.3 and disease status in 110 patients after radical mastectomy for breast cancer, with metastatic diffusion. Its persistent elevation was usually related to a very poor prognosis. In patients who died within 18 months the marker was always elevated. In case of progression of the disease, the marker level appeared to be consistently correlated with the general clinical condition. In healthy patients with stable disease the marker remained near the normal range.     

CA 15.3 and CEA plasma level monitoring in patients with breast cancer

CA 15.3 and CEA were determined in the serum of 217 patients with early and advanced breast carcinoma. CA 15.3 was high (greater than 30 U/ml) in 1/6 (17%) patients with stage I-II primary tumor, in 4/77 (5%) patients without clinical signs of disease after mastectomy, in 67/102 (65%) patients with advanced disease in progression, and in 13/32 (41%) patients with advanced disease not in progression and undergoing therapy. The corresponding incidences of pathological CEA values (greater than 2.5 ng/ml) were 33, 8, 55 and 14%. The combination of the two markers brings about a certain improvement in the sensitivity for recognising patients with advanced disease in progression (79/102 = 77%). The presence of high values of CA 15.3 is statistically correlated to the prevalent site of metastases (bone and viscera greater than soft tissues). Monitoring the two markers during antitumor therapy in 36 patients showed good accordance (56%) between CA 15.3 changes and response to therapy. The decrease of the marker in patients who achieved partial remission was statistically significant. In conclusion, CA 15.3 is more sensitive than CEA in recognising patients with advanced disease in progression and gives better accordance with the response to therapy. The simultaneous use of the two markers may be useful in the follow-up of operated patients and in monitoring the disease during treatment.