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.     

OVX1 and CEA in patients with colon carcinoma, colon polyps and benign colon disorders

The OVX1 tumor marker promises to complement CA125 for detection of early stage ovarian carcinoma. OVX1 has also been shown to be elevated in colon cancer patients. This study is designed to assess serum OVX1 levels in patients with specific stages of colon cancer, colon polyps or other GI disorders. Serum OVX1 and CEA were measured by radioimmunoassay or enzyme immunoassay for 206 patients at the time of colonoscopy or staging for colon carcinoma. In patients with stage I, II, III, or IV colon carcinoma, serum OVX1 was positive in 37%, 48%, 74% and 63%, respectively. Fifty-three percent of patients with colon polyps had elevated OVX1 levels, while OVX1 levels were positive in only 7% of healthy controls. If both OVX1 and CEA were considered, at least one of these markers was elevated in 36%, 60%, 79% or 89% of patients with stage I, II, III or IV colon carcinoma, respectively. The majority of patients with inflammatory bowel disease or diverticulosis also had elevated OVX1 levels. Both markers were positive in 27% of patients with colon carcinoma, and not in any patients with a normal colonoscopy or with a diagnosis of diverticulosis or hemorrhoids. In conclusion, serum OVX1 improves the sensitivity of CEA for detecting colon polyps and colon cancer; however, the use of OVX1 in this setting is hindered by its elevation in non-malignant colonic processes.     

Comparison of CA 15-3 and CEA in diagnosis and monitoring of breast cancer

In order to assess the utility of the tumor-associated antigen CA15-3 in the diagnosis of breast cancer, this new tumor marker was measured pre-operatively in 1342 patients. This group comprised 509 patients with malignant disease (134 with breast cancer and 375 with other malignancies not involving the breast) and 833 patients with benign surgical diseases (95 patients with fibroadenoma of the breast, 738 with other benign diseases). The results were compared with those for carcino-embryonic antigen (CEA) in the diagnosis of breast cancer. CA15-3 was above the normal limits of 25 U/ml in 31% of the patients with breast cancer, in 22% of patients with other malignancies, and in 9% of patients with benign diseases. CEA was elevated in 26% of patients with breast cancer (greater than 3 ng/ml). CA15-3 levels were above 50 U/ml in 13% of the breast cancer patients, in 6% of patients with other malignancies, and in 0.2% of the patients with benign diseases. There was a good correlation between CA15-3 level and tumor stage in breast cancer. CA15-3 serum levels were over 50 U/ml in respectively 0%, 2%, 13%, and 73% of the patients with stages I, II, III, and IV. CA15-3 and CEA were also determined in 671 patients who had received initial curative surgery of breast cancer, and who regularly attended our follow-up clinic. CA15-3 was found to be more sensitive than CEA in detecting recurrences of breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preoperative and longitudinal serum levels of CA 125 and CA 15.3 in patients with breast cancer

Serum levels of ovarian carcinoma antigen (CA 125) and breast carcinoma antigen (CA 15.3) were determined in 237 patients with breast carcinoma, 121 before any therapy and 116 after initial treatment, during uneventful follow-up or at the time of relapse. The aim was to assess how often the CA 125 test failed, i.e., was false-negative in patients in whom the CA 15.3 test was true-positive and, more important, whether it gave diagnostic information in patients in whom the CA 15.3 test failed. Before surgery or other initial therapy, serum CA 125 and CA 15.3 gave similar information in 85.1 percent of the patients: true-positive in 4.1 percent and false negative in 81.0 percent: CA 125 gave less information in 13.2 percent; and more information in only 1.7 percent. During follow-up, serum CA 125 and CA 15.3 gave similar information in 73.3 percent of the patients: true-positive (i.e., rising persistently from a nadir or elevated above 65 U/ml) in 23.3 percent, true-negative in 36.2 percent, and false-negative in 13.8 percent; CA 125 gave less information in 25.0 percent: false negative in 22.4 percent and false-positive in 2.6 percent; and more information in only 1.7 percent. Therefore, the CA 125 test appears useless for staging and is redundant when the CA 15.3 test is employed, for management of patients with breast cancer.     

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.     

Serum levels of carcinoembryonic antigen, gastrointestinal cancer-associated antigen and alphafetoprotein in staging and management of patients with advanced carcinoma of the stomach

Serum levels of carcinoembryonic antigen (CEA), gastrointestinal cancer-associated antigen (GICA or CA 19-9), and alphafetoprotein (AFP) were concurrently determined in patients with carcinoma of the stomach: in 84 preoperatively, and in 67 serially postoperatively. Before surgery, serum CEA gave information about the tumor load analogous to serum GICA in 69% of the patients: true-positive in 25% and false-negative in 43%; less information in 18% and more in 14%. The sensitivity of the test tended to be better in the more advanced stages, and was higher for CEA with GICA than for CEA alone or GICA alone. During follow-up, serum CEA gave information about the presence or absence of active disease analogous to serum GICA in 78% of the patients: true-positive in 30%, true-negative in 36% and false-negative in 12%; less information in 9% and more in 13%. Neither test gave any false-positive indications. Sensitivity of the test rose from 67% for CEA alone and 60% for GICA alone to 81% for CEA with GICA. Serum AFP was elevated only preoperatively in 2% of patients. We conclude that joint application of CEA and GICA tests gave only slightly better preoperative sensitivity than CEA alone or GICA alone but proved fairly sensitive for postoperative follow-up of the patients. AFP was of little value for either purpose.     

CA 15.3 as a tumour marker in breast cancer

CA 15.3 is an antigenic determinant associated with human mammary carcinomas. Two murine monoclonal antibodies have been raised against the determinants, and an immunoradiometric assay (IRMA-Kit, Centocor, USA) has been developed to determine the antigen levels in plasma of cancer patients. Based on the 99% confidence limit of healthy women, plasma values above 30 U/ml are considered abnormal. Plasma samples from 357 women were examined in the present study. Healthy females (n = 84) ranged below the cut-off level between less than 10 and 29 U/ml. Higher values were found in 12.5% of benign breast diseases and in 23.6% of breast cancer patients, including all stages. Depending on the stage of the disease, there were elevated levels in 11% of operable breast cancer patients preoperatively, in 7% of the cases with no evidence of disease after primary treatment and in 63.5% of patients with disseminated mammary carcinoma. In metastasized breast cancer the frequency and the degree of abnormal titers were closely related to the extent of the metastatic disease. Follow-up examinations of 63 patients under cytotoxic therapy showed CA 15.3 changes correlating well with the clinical course in up to 90% of the antigen positive cases. The present data indicate that CA 15.3 may be useful in the surveillance of breast cancer patients. However in our study one third of the patients with metastatic breast cancer did not show any increase in CA 15.3 and must be regarded as antigen negative.     

Carcinoembryonic antigen, ferritin, tissue polypeptide antigen, and CA15/3 in breast cancer: relationship between carcinoma and normal breast tissue

The study of tumor markers in breast cancer tissue may supply information on the tumor's biological features and its clinical behaviour. Forty-nine primary breast cancer patients are evaluable to date. CEA, ferritin, TPA and CA15/3 were measured with radioimmunometric methods in the cytosol of carcinoma and normal tissue from the same breast. The concentrations of the four markers were higher in the tumor than in normal tissue in 42/49 cases for CEA, 47/49 for ferritin, 42/49 for TPA and in 24/29 for CA15/3. However, an overlap was found between carcinoma and normal tissue levels, particularly for CEA and TPA. We can conclude that the four substances studied may be markers of malignancy in breast carcinoma when non-malignant breast tissue from the same patient is determined at the same time, whereas assays within a single, unknown breast tissue sample may be useful only in the case of ferritin and, partly, CA15/3.     

Tumor markers in patients with chronic renal failure.

In order to evaluate the specificity of tumor markers in chronic renal failure, we have determined serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA 19.9), carbohydrate antigen 50 (CA 50), alphafetoprotein (AFP), neuron-specific enolase (NSE), prostatic acid phosphatase (PAP), prostatic specific antigen (PSA), squamous cell carcinoma antigen (SCC), carbohydrate antigen 15.3 (CA 15.3) and carbohydrate antigen 125 (CA 125) in 30 patients with chronic renal failure and in 36 hemodialyzed patients without clinical evidence of neoplasia. CEA, CA 50, NSE and SCC frequently show increased serum levels, suggesting a renal metabolism, while others remain, generally, within the normal levels.     

Preliminary study on serum levels of mucinous like cancer antigen (MCA) in patients with breast disease: comparison with CEA

MCA (mucinous-like cancer antigen) can be measured in the biological fluids of patients by means of a solid phase enzyme immunoassay. This study describes the results of MCA determination in sera of 230 patients with benign (99) and malignant (131) breast diseases. MCA levels were significantly higher in breast cancer patients than in non cancer patients and in healthy subjects (p less than 0.001). MCA concentrations tended to increase as the stage of the disease advanced. The 95th percentile of MCA value distribution in normal subjects showed a diagnostic sensitivity in breast cancer patients of 16.3% at stage I, 26.2% at stages II-III and 52% at stage IV. In a group of 118 cancer patients, MCA and CEA were tested simultaneously. The diagnostic sensitivity and specificity of MCA and CEA assays was very similar; nevertheless the association of the two tests showed 11 cases with high levels of MCA and low levels of CEA and 9 patients with high levels of CEA and low levels of MCA. Seventy-four out of 118 patients were negative for both markers and in 22 out of 118 patients markers were positive. The new marker MCA appeared to correlate with breast cancer and gave different information complementary to CEA.     

Tumor markers in squamous cell carcinoma of esophagus: immunometric assay in cytosol and membrane fraction

Carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), ferritin, and the monoclonal antibody-detected tumor-associated antigens CA19.9 and CA50 were measured by radioimmunoassay in tissue fractions of carcinoma and normal esophageal mucosa from 59 patients with untreated primary squamous cell carcinoma of the esophagus. Tumor markers were measured in cytosol (118 samples) and in a membrane-enriched fraction (32 samples). CEA, TPA and ferritin were detected in almost all the cytosol samples evaluated, CA19.9 and CA50 in 66% and 50% of cases respectively. Ferritin was significantly higher in carcinoma than in normal mucosa. The cytosol concentrations of CEA, TPA, CA19.9 and CA50 were not significantly different in carcinoma and normal tissue. Concentrations of CEA, CA19.9 and CA50 in the membrane fraction tended to be higher in normal tissue than in carcinoma, whereas the cytosol-to-membrane ratio was significantly higher in carcinoma. For CEA, CA19.9 and CA50, the phenotypic pattern of the malignant transformation seems to involve a different intracellular distribution rather than a quantitative change. No correlations were found between tissue and serum concentrations of the tumor markers, the former being related to the phenotypic characteristics of the tumor, the latter to the tumor burden.     

Comparison between CEA, TPA, CA 15/3 and hydroxyproline, alkaline phosphatase, whole body retention of 99mTc MDP in the follow-up of bone metastases in breast cancer

The development of bone metastases in cancer can be monitored easily using three markers: 24 h urinary hydroxyproline excretion (HOP) (an index of osteoclastic activity), serum alkaline phosphatase (Alk.Ph.) (an index of osteoblastic activity) and 24 h whole body retention of 99mTc-methylene diphosphonate (WBR%) (an index of bone turnover). To evaluate the effectiveness of this group of bone tumor markers in breast cancer we compared it with the following group of three markers which are commonly used in the monitoring of breast cancer and in the follow-up of advanced disease with or without bone metastases: carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA) and breast carcinoma antigen (CA 15/3). In 48 patients with bone metastases CEA, TPA and CA 15/3 were shown to be sensitive (79%, 85%, 90% respectively), while HOP, Alk.Ph. and WBR%, which are commonly accepted as reliable markers of bone activity, showed a lower sensitivity (67%, 46%, 75% respectively). These results may be explained by the lack of osteoclastic or osteoblastic (or both) activity at the time of diagnosis. This explanation is supported by the fact that the bone markers HOP, Alk.Ph. and WBR% were found to be more sensitive than the others in the subsequent follow-up study. We conclude that in our study, CEA, TPA and CA 15/3 are at first more sensitive than Alk.Ph., HOP and WBR% but during the follow-up Alk.Ph., HOP and WBR% are possibly both more specific and more sensitive.     

MCA in patients with breast cancer: correlation with CEA and CA15-3

MCA serum levels were determined in 27 healthy subjects, 136 with benign pathology (42 breast) and in 289 patients with cancer (247 active). The last group includes 223 patients with breast cancer (96 without metastases, 89 with metastases and 38 no-evidence of disease). CEA and CA15-3 serum levels were determined in all the patients with breast diseases. The mean levels of MCA were 4.7 + 2.4 U/ml in the control group, considering less than 11 U/ml as normal. MCA values were abnormal in 15.4% of patients with benign pathology, mainly in those with liver cirrhosis (8/20) and lung diseases (4/20). In the majority of these cases, the rise was only moderate, lower than 15 U/ml in 97.5% of patients. In malignant diseases, important increments were found in breast cancer (19.8% Mo, 77.5% M1) and ovarian cancer stages III-IV (44.4%). When we compared MCA serum levels with CA15-3 and CEA in breast pathology, a similar specificity was observed: 92.3%, 92.3% and 100% in cases with benign pathology and 92.1%, 94.7%, and 97.4% in NED patients, respectively. MCA and CA15-3 sensitivity was similar in breast cancer without metastases (19.8%) and lower for CEA (16.7%). In patients with breast cancer without metastases, we found a relation between positivity of these tumor markers and prognostic factors (tumor size, nodal involvement). The disease free interval in patients with locoregional breast cancer was shorter in cases with abnormal presurgical levels of some of the tumor markers, but only the difference from MCA was significant (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Colorectal carcinoma: nucleosomes,carcinoembryonic antigen and ca 19-9 as apoptotic markers; a comparative study

Background  

Colorectal carcinoma is a common and often fatal disease in which methods of early detection and monitoring are essential. The present study was conducted for measuring serum levels of nucleosomes, carcinoembryonic antigen (CEA) and CA 19-9 in patients newly diagnosed with colorectal carcinoma and confirmed by clinicopathological study.     

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.     

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.     

Clinical evaluation of the simultaneous determination of CA 15-3, CA 125 and sHER2 in breast cancer

Objective We investigated serum levels of CA 15-3, sHER2 and CA 125, and their usefulness in the detection of metastatic disease in breast cancer patients.

Methods The levels of CA 15-3, sHER2 and CA 125 tumour markers were determined in 60 patients, 40 with localized and 20 with metastatic breast carcinoma. The control group consisted of 10 healthy women.

Results We found that, at the time of diagnosis, serum levels of all three tumour markers were elevated in patients with distant metastases, but of minute importance in the detection of any breast cancer. When the data for the individual markers were combined the overall sensitivity of metastases detection with all three markers improved. In this regard, 90% of patients with distant metastases had an increase in serum level of at least one of tested tumour markers. Similar results were obtained using receiver operating characteristic curve (ROC). Moreover, using ROC we defined cut-off values for metastasis detection for each of the tested markers.

Conclusion Our findings indicate that measurement of CA 15-3 serum values in conjunction with sHER2 and CA 15-3 can increase sensitivity in metastasis detection.     

Clinical evaluation of the simultaneous determination of CA 15-3, CA 125 and sHER2 in breast cancer

Objective We investigated serum levels of CA 15-3, sHER2 and CA 125, and their usefulness in the detection of metastatic disease in breast cancer patients.

Methods The levels of CA 15-3, sHER2 and CA 125 tumour markers were determined in 60 patients, 40 with localized and 20 with metastatic breast carcinoma. The control group consisted of 10 healthy women.

Results We found that, at the time of diagnosis, serum levels of all three tumour markers were elevated in patients with distant metastases, but of minute importance in the detection of any breast cancer. When the data for the individual markers were combined the overall sensitivity of metastases detection with all three markers improved. In this regard, 90% of patients with distant metastases had an increase in serum level of at least one of tested tumour markers. Similar results were obtained using receiver operating characteristic curve (ROC). Moreover, using ROC we defined cut-off values for metastasis detection for each of the tested markers.

Conclusion Our findings indicate that measurement of CA 15-3 serum values in conjunction with sHER2 and CA 15-3 can increase sensitivity in metastasis detection.     

Diagnosis of bone and liver metastases in breast cancer comparing tumor markers and imaging techniques

One hundred and forty-seven patients were examined by bone scintigraphy, ultrasonography and scintigraphic scan of the liver, at different times after surgical removal of a breast cancer, to rule out skeletal and hepatic metastases. At the same time as imaging procedures, serum levels of tumor markers (CEA, TPA and CA 15-3) were determined using radioimmunometric methods. One or more markers were elevated in all 13 patients with hepatic metastases; 9 out of 46 patients with bone metastases had all serum markers normal, with a sensitivity of 80%. Combined assay of the markers proved useful, TPA and CA 15-3 showing the best sensitivity in bone metastases, and all three markers in liver metastases.