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.     

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.     

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.     

Clinical evaluation of CA 15.3 in the post-operative follow-up of breast cancer patients

In 265 patients operated for breast carcinoma the monoclonal antibody serum test CA 15.3 was predictive of metastatic diffusion of the disease. Its level increased in cases of distant metastasis with no significant difference between multiple and single sites (p = 0.014). The concentration of the marker was higher in 21 (23.8%) patients without nodal involvement and in 19 (27.5%) with nodal involvement (p = 0.193). Our study suggests that CA 15.3 may be an aid in the follow-up of patients with metastatic diffusion of breast cancer.     

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)     

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.     

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)     

Prognostic value of CA 15.3 kinetics for metastatic breast cancer

Up to 80% of breast cancer patients developing metastases have high levels of CA 15.3. We studied the prognostic implications of CA 15.3 kinetics in 119 patients before and at first metastasis by univariate and multivariate statistics. At first metastasis, CA 15.3 was elevated in 82.4% of patients, with a lead time (median 162 days) in 42.0% of them. Kaplan-Meier analysis showed overall survival (median 1477 days) to be significantly related to estrogen receptor (ER) and progesterone receptor (PgR) status (p=0.0001) and tumor size (p=0.025). The interval between diagnosis and first abnormal CA 15.3 (p=0.0001), the CA 15.3 concentration (p=0.013), and the presence or absence of a lead time (p=0.001) also had prognostic value. ER and PgR status (p=0.0005 and p=0.0103, respectively), metastasis-free interval (p=0.0003), existence of a CA 15.3 lead time (p=0.0028), and days from diagnosis to first abnormal CA 15.3 (p=0.0055) entered in the Cox model. After first metastasis (median survival 573 days), ER and PgR status (p=0.0001 and p=0.0004, respectively), existence of a lead time for CA 15.3 (p=0.0138), and the concentration of first abnormal CA 15.3 (p=0.0145) had individual prognostic value. In the Cox model ER status (p=0.0001), nodal status (p=0.0191), existence of a lead time for CA 15.3 (p=0.0033), days from diagnosis to first abnormal CA 15.3 (p=0.0132), and concentration of first abnormal CA 15.3 (p=0.0320) were found to be independent prognostic variables. Compared to a matched historical control group that was not monitored by CA 15.3 assaying (n=140), the study group had a significantly longer survival after the first metastasis (p=0.0005). In conclusion, the kinetics of CA 15.3 before the first metastasis is of prognostic value. When associated with 18-fluorodeoxyglucose imaging, serial CA 15.3 assays may help to implement early treatment of metastases.     

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.     

Tumour associated antigens CA 15.3 and CA 125 in ovarian cancer

CA 125 and CA 15.3 antigens were determined by enzyme immunoassay in 78 patients with ovarian cancer for a total of 540 determinations. The antigens were also investigated in sera from 100 women with other gynaecological diseases, 82 lung cancer patients and in 39 pleural fluids of varying origin. CA 15.3 reference values were evaluated in 91 healthy women (cut-off: 25 U/ml). CA 15.3 sensitivity at diagnosis (60%) and for detecting relapse (44%) was lower than that of CA 125 (90% and 64.7%, respectively). However, CA 15.3 does not increase with aspecific mesothelial cell reaction and thus it is more specific than CA 125. Combined use of the markers during follow-up improves early detection of relapse (at least one of the two was positive in 79% of cases). Therefore both CA 15.3 and CA 125 should be routinely determined for the detection and monitoring of ovarian cancer.     

Significance of CA72.4 in patients with colorectal cancer. Comparison with CEA and CA19.9.

CA72.4 is a new tumor-associated antigen identified by monoclonal antibodies cc49 and B72.3. Serum levels of CA72.4 were measured in patients with benign and malignant diseases. The cut-off used was 4 U/mL. CA72.4 is a highly specific marker since only 3% of 162 patients with benign diseases had elevated levels of antigen. Forty-four percent of 89 patients with colorectal cancer had elevated CA72.4 levels. Compared with CEA and CA19.9, we have found that CEA (75%) is the most sensitive marker (p less than 0.001). The simultaneous use of two or three markers did not further contribute to the evaluation of patients with colorectal cancer.     

Preoperative carbohydrate antigen 195 (CA195) and CEA serum levels as prognostic factors in patients with colorectal cancer

We evaluated in 214 patients with primary colorectal cancer the prognostic value of the preoperative serum levels of CEA and CA195. For CEA these levels were above the cutoff of 6 ng/ml in 31.3% of patients, whereas for CA195 they were higher than 12 U/ml in 35.9% of patients. The simultaneous use of both antigens increased the sensitivity to 49%, which was significantly higher than that of CEA (p < 0.001) and CA195 (p < 0.01) taken singly. The mean preoperative CEA levels were significantly (p < 0.001) correlated with Dukes' stage only, while there was a significant correlation between preoperative serum levels of CA195 and Dukes' stage (p < 0.001), grade of differentiation (p < 0.01) and tumor location (p < 0.05). The results indicated that high preoperative serum levels of CEA and CA195 were associated with a shorter overall survival (p < 0.0001). In addition, separate Cox multivariate analysis showed that preoperative CA195 was, after Dukes' stage, the strongest factor to predict overall survival (p < 0.0001).     

CA 15-3 in human breast cancer. Comparison with tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA)

CEA, TPA, CA 15-3 were assayed in 238 patients in follow-up for breast cancer after surgery. CA 15-3 showed the best sensitivity and specificity; the predictive value of a positive CA 15-3 test was three times higher than CEA and TPA. No association was found between marker positivity and the number of organs involved by metastases. CA 15-3 positivity was significantly associated with visceral rather than soft tissue recurrences; no significant similar association was observed for CEA and TPA. CA 15-3 serum levels were early predictors of relapse in four out of nine patients within a 6-12 month follow-up period.     

A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients

Mitotane (o,p'-DDD or (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane, DDD) is the drug of choice for non-resectable and metastatic adrenocortical carcinomas (ACC). Measurement of mitotane and metabolites, o,p'-DDE (1,1-dichloro-2-[p-chlorophenyl]-2-[o-chlorophenyl]ethene, DDE) and o,p'-DDA (1,1-[o,p'-dichlorodiphenyl] acetic acid, DDA) provides a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed a simple, robust and efficient high performance liquid chromatography (HPLC) method to measure mitotane and its two main metabolites, DDE and DDA. The method involves a single ethanol extraction of mitotane, DDE, DDA, and an internal standard (int std) p,p'-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) with an extraction efficiency of 77-88%. All compounds are measured simultaneously using a reversed-phase phenyl HPLC column with an isocratic elution of mobile phase at a flow rate of 0.6 ml/min followed by UV detection at λ 226 nm. Inter and intra-day validation demonstrates good reproducibility and accuracy. Limits of quantitation are 0.2 μg/ml for mitotane and DDE, and 0.5 μg/ml for DDA. The method has been evaluated in plasma from 23 patients on mitotane therapy, revealing DDA concentrations 1-18 times higher than the parent compound.