Judith Jo

c-erbB-2 oncoprotein, CEA, and CA 15.3 in patients with breast cancer: prognostic value.

The diagnostic value of a new tumor marker, c-erbB-2, was studied in the sera of 50 healthy subjects, 58 patients with benign breast diseases, and 413 patients with breast cancer (186 locoregional, 185 with advanced disease, and 42 with no evidence of disease). Using 15 U/ml as the cut-off, no healthy subjects or patients with benign diseases and only 2.4% of no evidence of disease patients had elevated serum levels. Abnormal c-erbB-2 levels were found in 29% (101/370) of the patients with breast carcinoma (locoregional 9%, metastases 45.4%). CEA (cut-off 5 U/ml) and CA 15.3 (cut-off 35 U/ml) sensitivity was 18% and 16% in patients with locoregional disease and 61% and 70% in those patients with advanced disease, respectively. A trend toward higher serum levels of all three tumor markers in patients with nodal involvement or greater tumor size was found, but was statistically significant only with CEA (p < 0.01). By contrast, c-erbB-2 was related to steroid receptors, in both locoregional and metastatic tumors. When the prognostic value of these markers was evaluated, patients with abnormally high presurgical CEA and c-erbB-2 had a worse prognosis than those patients with normal values, in both node-negative (p < 0.05 and p < 0.001, respectively) and node-positive patients (p < 0.556 and p < 0.001, respectively). By contrast, no relationship was found between CA 15.3 values and prognosis. Multivariate analysis showed that CEA and c-erbB-2 were also prognostic factors. The correlation between serum and tissue levels of c-erbB-2 was studied in the tumors of 161 patients. Significantly higher c-erbB-2 serum levels were found in patients with overexpression in tissue by immunohistochemistry, in both locoregional and advanced disease (p=0.0001). Serum concentrations in patients with advanced disease were related to the site of recurrence, with significantly higher values in patients with metastases (mainly in those with liver metastases) than in those with locoregional recurrence. In summary, c-erbB-2 serum levels seem to be a useful tumor marker in the prognosis of patients with breast cancer. Using all three tumor markers, sensitivity was 35% in patients with locoregional breast cancer and 88% in patients with recurrence.

Use of serial carcinoembryonic antigen and CA 15.3 assays in detecting relapses in breast cancer patients

SummaryTo evaluate the utility of CEA and CA 15.3 for early diagnosis of recurrence, serial serum determinations of both antigens were performed in 1023 patients (follow-up: 1–10 years, mean 6.2 years) with primary breast cancer (CA 15.3 in 533 cases) and no evidence of residual disease (NED) after radical treatment (radical mastectomy or simple mastectomy and radiotherapy). 246 patients developed metastases during follow-up.Results: CEA and CA 15.3 were elevated (> 10 ng/ml or > 60 U/ml, respectively) prior to diagnosis in 40% (98/246) and 41% (37/91) of the patients with recurrence, with a lead time of 4.9 ± 2.2 and 4.2 ± 2.3 months, respectively. When patients with locoregional recurrences were excluded, sensitivity improved to 46% (CEA) and 54% (CA 15.3), and to 64% with both tumor markers (CEA and/or CA 15.3). Higher levels of both CEA and CA 15.3 at diagnosis of recurrence, higher sensitivity in early diagnosis of relapse, and a higher lead time were found in ER+ (CEA) or PgR+ patients (CA 15.3) than in those that were negative for these receptors in the primary tumor (p < 0.001). Specificity of the tumor markers was 99% for both CEA (777 NED patients) and for CA 15.3 (444 NED patients), respectively. In conclusion, CEA and CA 15.3 are useful tools for early diagnosis of metastases, mainly in those patients with ER+ or PR+ tumors.

Carcinoembryonic antigen in staging and follow-up of patients with solid tumors.

The presence of a tumor antigen in human colonic carcinomas and their metastases was described about 25 years ago. This antigen, called carcinoembryonic antigen (CEA), is one of the first known tumor markers. Since then, many more have been described, but CEA, determined alone or in combination with others, is still one of the most used. CEA is not organ specific and abnormal values may be found in a wide range of carcinomas, especially those with gastrointestinal involvement. CEA assay should not be used for cancer diagnosis because its sensitivity in patients without cancer metastases is low. In addition, abnormal CEA values may be found in patients with benign diseases. However, the probability of malignancy increases directly with CEA concentration. Its main clinical applications are prognosis, early diagnosis of recurrence and follow-up of patients with carcinomas. In a wide range of malignancies, CEA serum levels are clearly related to tumor stage. Presurgical CEA serum levels are a well-established prognostic factor in colorectal, breast and lung cancer. Patients presenting with increased preoperative CEA serum levels have both a shorter disease-free interval and lower survival than those with normal CEA levels. In the early diagnosis of recurrence, CEA also plays an important role: in about 70-85% of patients with colorectal tumors and in 40-50% with breast cancer, CEA serial increase is the first sign of tumor recurrence. In patients with disseminated tumors, serial determinations are also a useful tool for therapy monitoring: CEA values decrease with effective treatment while stable or increasing values are observed when treatment is not effective.

Serum Levels of C-erbB-2 (HER-2/neu) in Patients with Malignant and Non-Malignant Diseases

The diagnostic value of a new tumor marker, c-erbB-2, was studied in the sera of 50 controls, 112 patients with benign diseases and 534 patients with malignancies. Using 15 U/ml as the cutoff, no healthy subjects, patients with benign diseases (excluding liver cirrhosis) or patients with no evidence of disease (45 patients) had serum levels higher than this limit. Abnormal c-erbB-2 levels were found in 38.5% (10 of 26) of the patients with liver cirrhosis and in 26.7% (8 of 30) of those patients with primary liver cancer. No differences were found between the c-erbB-2 serum concentrations in liver cirrhosis or primary liver cancer, suggesting the possible catabolism of this antigen in the liver. Abnormal levels of this antigen were found in 20% (56 of 278) of the patients with breast carcinoma (locoregional 7%, metastases 41.5%), in 21% (6 of 28) of ovarian carcinomas (stage I-II 0%, stage III-IV 42.8%), in 21% (3 of 14) of the colorectal tumors (locoregional 0%, metastases 30%), and in 13.3% (11 of 83) of the patients with lung cancer (locoregional 11.5%, metastases 16%). C-erbB-2 sensitivity in other patients with advanced disease was: 25% (9 of 36) in prostatic cancer, 22% (2 of 9) in gastric cancer, and 11% (1 of 9) in vesical tumors. When patients with liver metastases were excluded abnormal c-erbB-2 serum levels were only found in breast, lung, prostatic and ovarian carcinomas. C-erbB-2 sensitivity in patients with lung cancer was related to tumor histology with significantly higher value in non-small cell lung cancer (mainly adenocarcinomas) than in patients with small cell lung cancer (p < 0.013). C-erbB-2 concentrations in patients with breast cancer were significantly higher in patients with recurrence (mainly bone and liver metastases) and in patients with progesterone receptor-negative (< 15 fmol/mg) tumors (p < 0.01). In conclusion, c-erbB-2 is not a specific tumor marker and abnormal serum levels may be found in patients with liver pathologies. Its sensitivity suggests its possible application as a tumor marker in breast, ovarian, lung (mainly adenocarcinomas) and prostatic tumors.

Study of a new tumor marker, CYFRA 21-1, in malignant and nonmalignant diseases

The diagnostic value of a new tumor marker, CYFRA 21-1, was studied in the sera of 50 controls, 206 patients with benign diseases and 469 patients with malignancies. Fifty controls showed mean serum concentrations of 1.2 +/- 0.5 ng/ml. Using 3.3 ng/ml as the cutoff, abnormal CYFRA levels were found in 13.1% of patients with benign diseases, mainly in those with liver cirrhosis (29.4%) or renal failure (20.8%), and in 44.4% (180/405) of patients with active cancer. Neither healthy subjects nor no evidence of disease (64 cases) patients had serum levels higher than this limit. CYFRA 21-1 results were significantly higher in patients with active cancer than in those with benign diseases or without active tumors (p < 0.0001). CYFRA serum levels were significantly higher in patients with metastases (59.5%) than in those with locoregional disease (33.7%; p < 0.001). CYFRA 21-1 sensitivity in patients with lung cancer was related to tumor histology with abnormal levels in 65.6% of patients with non-small cell lung cancer and in 25% of patients with small cell lung cancer (p < 0.0001). In breast cancer, CYFRA 21-1 concentrations were significantly higher in patients with metastases and in patients with primary tumors but with nodal involvement (p < 0.001).

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), alfafetoprotein (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 cronic 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.

CYFRA 21-1 in lung cancer: comparison with CEA, CA 125, SCC and NSE serum levels

CYFRA 21–1, CEA, CA 125, SCC and NSE serum levels were determined in 50 healthy subjects and in 189 patients with primary lung cancer (101 with locoregional disease, 68 with recurrence and 20 patients with no evidence of residual disease (NED). Abnormal CYFRA 21–1 serum levels were found in 53.6% (90/168) of the patients with active cancer. Neither healthy subjects nor NED patients had abnormal serum levels. CYFRa 21–1 serum concentrations were significantly higher in patients with active cancer than in healthy subjects or in NED patients (p < 0.0001). CYFRA 21–1 sensitivity was related to tumor histology with abnormal levels in 64.7% of patients with NSCLC and in 30% of patients with SCLC (P <0.0001). In NSCLC, serum CYFRA 21–1 concentrations were also related to histological type, the highest values being found in squamous cell carcinomas and LCLC and the lowest in adenocarcinomas (p < 0.04). There was also a clear relationship between CYFRA 21–1 and tumor extension, with significantly higher values in patients with metastases than in those without metastases (p < 0.0001). Abnormal CEA values were found in 49.1%, CA 125 in 39%, SCC in 27.8% and NSE in 21.3% of the patients with active cancer. With respect to histological type, CYFRA was elevated in 68.3% of squamous cell carcinomas (CEA: 46.7%, SCC: 50%, CA 125:31.7%, NSE: 11.7%), in 54.8% of adenocarcinomas (CEA: 62%, SCC: 26.2%, CA 125: 59.5%, NSE: 9.5%), in 78.6% of LCLC (CEA: 64.3%, SCC: 28.6%, CA 125: 78.6%, NSE: 7.1%) and in 30% of SCLC (CEA: 37.7%, SCC: 3.8%, CA 125:20.8%, NSE: 45.3%). In summary, CYFRA 21–1 is the most sensitive tumor marker in patients with lung cancer, especially in NSCLC patients.

CA 125 in biological fluids.

CA 125 is not a specific tumor marker, and is synthesized by normal and malignant cells of different origin (mainly in tissues derived from the müllerian epithelia) in a similar proportion. Abnormal CA 125 levels may be found in fluids of different origin (ascites, pleura, pericardium, amniotic fluid, cyst fluid, bronchoalveolar fluid, etc.) and in serum from patients with these fluids. Differences in serum CA 125 found in malignant or benign diseases may be related to the number of cells that synthesize the marker, and are highly dependent on the access to serum, where the marker is normally determined. Moreover, CA 125 is a very good tumor marker in ovarian and lung cancer. The sensitivity of CA 125 in ovarian cancer is related to stage (40–95%), histological type (lower levels in mucinous adenocarcinoma), and the marker is useful in the early detection of recurrence (sensitivity 80%) and in therapy monitoring. Its sensitivity in lung cancer is lower than in ovarian cancer, 39% in locoregional malignancies and 69% in metastastatic disease, but clearly related to stage and histology (mainly in adenocarcinomas and large cell lung cancer) and it is useful in prognosis and disease monitoring.

Prognostic Significance of SCC Antigen in the Serum of Patients with Head and Neck Cancer

SCC antigen (Ag) is a tumor-associated Ag (TAA) obtained from squamous cell carcinoma of the uterine cervix. This study reports the evaluation of this TAA in patients with head and neck malignant diseases and its possible prognostic value. Serum samples from 28 patients with benign head and neck diseases from 399 patients with cancer were obtained prior to treatment. SCC Ag serum levels were determined by radioimmunoassay using 2.5 ng/ml as the upper limit of normality. Elevated SCC Ag serum levels were found in 14% of 28 patients with benign diseases, in 29% of 217 patients with primary tumors, in 48% of 46 patients with recurrence (43% in locoregional, 64% in metastases) and in 4% of 136 patients with no evidence of disease. In patients with primary tumors, SCC Ag serum levels were related to nodal involvement and tumor location with significantly higher levels in node-positive patients (p = 0.001) and in tumors located in the nasopharynx and piriform sinus (p = 0.02). Presurgical SCC Ag serum levels in patients with primary tumors had prognostic value with shorter disease-free survival in those patients with abnormal values of this TAA (p < 0.001), in both, node-negative and node-positive patients (p < 0.01). Multivariate analyses showed that SCC Ag is a significant independent predictor of disease-free survival even when other prognostic factors are considered. In conclusion, pretreatment SCC Ag serum levels are an independent prognostic indicator in patients with head and neck malignancies.

A prospective study of tumor markers CA 125 and CA 19.9 in patients with epithelial ovarian carcinomas.

In a prospective study, CA 125 and CA 19.9 serum levels were measured in 229 patients with ovarian cancer [121 with active disease, 108 in complete remission (CR)], and in 20 patients with other malignancies. Abnormal levels of CA 125 were found in 90% of patients with active ovarian cancer, in 1.8% of those in CR and in 38% of cases with other malignancies. Abnormal CA 19.9 serum levels were found in 36, 9 and 48% of these groups, respectively. Serum levels of both tumor markers were related to tumor stage and histological type. The highest levels of CA 125 were found in serous adenocarcinoma and the lowest in the mucinous type (p < 0.0001). In contrast, significantly higher CA 19.9 values were found in mucinous carcinoma than in other histologies (p < 0.0001). CA 125 and CA 19.9 were useful for monitoring disease activity in 88.3 and 32%, respectively, while one or other tumor marker was useful in 92% of patients. At the time of the second-look operation, abnormal CA 125 serum levels were found in 32% (6/19) of patients with active disease and in none of those with CR (0/38). CA 125 sensitivity was 83% (5/6) in those patients with residual tumor > 2 cm and in 8% (1/13) in those with tumor < 2 cm. CA 19.9 values were abnormally high in 16% of cases with persistent disease and in 11% of CR patients. In conclusion, our results confirm that CA 125 is a useful marker in ovarian carcinoma. CA 19.9 improves the results obtained with CA 125 alone only in mucinous adenocarcinomas.