Serum HCG beta,CA 72-4 and CEA are independent prognostic factors in colorectal cancer

In colorectal cancer, stage is considered to be the strongest prognostic factor, but also serum tumour markers have been reported to be of prognostic value. The aim of our study was to investigate the prognostic value of serum carcinoembryonic antigen (CEA), CA 19-9, CA 242, CA 72-4 and free beta subunit of human chorionic gonadotropin (hCG beta) in colorectal cancer. Preoperative serum samples were obtained from 204 colorectal cancer patients, including 31 patients with Dukes' A, 70 with Dukes' B, 49 with Dukes' C and 54 with Dukes' D cancer. The serum levels of CEA, CA 19-9, CA 242 and CA 72-4 were measured with commercial kits with cut-off values of 5 microg/L for CEA, 37 kU/L for CA 19-9, 20 kU/L for CA 242 and 6 kU/L for CA 72-4. The serum hCG beta was quantitated by an immunofluorometric assay (IFMA) with 2 pmol/L as a cut-off value. Survival analyses were performed with Kaplan-Meier life tables, log-rank test and Cox proportional hazards model. The sensitivity was 44% for CEA, 26% for CA 19-9, 36% for CA 242, 27% for CA 72-4 and 16% for hCG beta. The overall 5-year survival was 55%, and in Dukes' A, B, C and D cancers the survival was 89%, 77%, 52% and 3%, respectively. Elevated serum values of all markers correlated with worse survival (p < 0.001). In Cox multivariate analysis, the strongest prognostic factor was Dukes' stage (p < 0.001), followed by tumour location (p = 0.002) and preoperative serum markers hCG beta (p = 0.002), CA 72-4 (p = 0.003) and CEA (p = 0.005). In conclusion, elevated CEA, CA 19-9, CA 242, CA 72-4 and hCG beta relate to poor outcome in colorectal cancer. In multivariate analysis, independent prognostic significance was observed with hCG beta, CA 72-4 and CEA.     

Carcinoembryonic antigen (CEA): comparison of the Farr and solid-phase methods for detection of CEA

Carcinoembryonic antigen (CEA) was detected in 180 preoperative malignant serum samples, or from the first benign serum sample if more than one sample was taken by the Farr assay using reagents provided by the Montreal laboratory of Gold and Freedman and in 148 plasma and 178 serum samples by a solid-phase assay using reagents provided by the Cancer Diagnostic Laboratory of Hoffmann-La Roche, Inc. Disposable, polystyrene tubes were coated with anti-CEAγG in the solid-phase assay. These were then used along with ¹²⁵I-CEA to construct an antibody dilution curve, standard inhibition curve and to test plasma or serum samples directly for CEA. In general, levels of CEA were higher for all diagnostic categories by the Farr assay than by the solid-phase assay. For CEA levels greater than 10 ng/ml, samples from colorectal cancer patients were clearly separable from other samples by both techniques. Thus, levels greater than 10 ng/ml were found by the Farr and solid-phase assays done on serum and by the solid-phase assay done on plasma respectively in 39%, 23% and 13% of patients with colorectal cancer, and in 14%, 4.5% and 1% of patients with other diseases. Aliquots from 123 blood samples were tested by both the Farr and the solid-phase assays. Serum was studied in all 123 by the Farr assay. Fifty-seven of the solid-phase assays were done on serum and the remaining 66 were done on plasma. The results showed good agreement (77% overall) for the two assays when serum results were considered, but lesser agreement (59% overall) when serum results by the Farr assay were compared with plasma results by solid-phase. The serum/plasma disagreement noted between the Farr and solid-phase assays was largely found in samples from patients with colorectal cancer (45% agreement), and appeared to be due mainly to samples from patients with Duke's A or B colonic cancer. Antibody dilution and standard inhibition curves done using reagents from the two laboratories in both the Farr and solid-phase assays indicated that the CEA from Montreal detects antibody sites on both anti-CEA preparations which are not available to the CEA from Roche. Further, the unlabelled CEA from Roche appears to be more similar antigenically to the Montreal ¹²⁵I-CEA than unlabelled Montreal CEA itself. This suggests that iodination of CEA may have altered the anti-genie character of the molecule. It is suggested that this alteration, as well as the use of CEA preparations of higher specific activity than those used initially, might account, at least in part, for the apparent loss of specificity of recent “CEA tests” for colorectal cancer as compared to the earlier report from Thomson and colleagues.     

Usefulness of preoperative CEA levels in the assessment of colorectal cancer patient stage

In order to demonstrate a prognostic value of preoperative CEA levels, we have tried to define a correlation between CEA and histologic stage of tumor in 124 patients with colorectal carcinoma. CEA concentration has been evaluated by radioimmunologic assay and the histologic stage following Dukes' classification. The results show a 25.0% positivity rate for patients in stage A, 48.2% for stage B, 61.1% for stage C, and 85.7% for stage D. The mean CEA values are 7.8 ng/ml in the first group, 30.3 ng/ml in the second, 58.1 ng/ml in the third, and 134.3 ng/ml in the last group. Furthermore, we have tried to relate the histopathologic grade of the tumor (G) with CEA levels in 54 patients of the 124. We conclude that preoperative CEA has a prognostic value, and it is useful in the staging of colorectal cancer patients. A low concentration indicates an early stage of the tumor, while a high concentration indicates a wide spread of disease; on the other hand, there are not significant correlations with cancer grading.     

The clinical information value of an immunoenzyme study of the tumor markers CA-19-9, CEA and AFP in cancer of the stomach, pancreas, colon and rectum]

Blood levels of CEA, CA 19-9 and AFP were assayed by immunoenzyme technique in 60 cases of gastric cancer, 15 patients with pancreatic cancer and 30 patients with colorectal cancer. CEA and CA 19-9 levels were found to depend upon stage and degree of tumor differentiation. Changes in the antigen levels in the course of treatment reflected the degree of its radicality. In application of the immunoenzyme assay, CA 19-9 level appeared most clinically relevant in gastric, pancreatic and colorectal cancers. CEA concentration can serve as an indicator of liver metastases. CA 19-9 and CEA levels can be used for monitoring and objective evaluation of treatment for gastric, pancreatic and colorectal cancer as well as for predicting response.     

Detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT-PCR for CEA and CK20 mRNAS

The purpose of our study was to develop specific, sensitive, objective assays for early detection of disseminated tumour cells in patients with colorectal cancer (CRC). Carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) were chosen as markers because they are selectively expressed in epithelial cells with maintained expression in CRC. Real-time quantitative RT-PCR assays with RNA copy standards were constructed. Regional lymph nodes were collected from patients with CRC (n = 51) and benign intestinal disease (n = 10). Results were compared to routine histopathology and anti-CEA immunohistochemistry. Lymph node levels of CEA and CK20 mRNA correlated strongly (p < 0.0001, r = 0.8). Lymph nodes from non-CRC patients had <0.01 CEA and <0.001 CK20 mRNA copies/18S rRNA unit. Lymph nodes from 3/6 Dukes' A, 17/26 Dukes' B, 10/10 Dukes' C and 7/9 Dukes' D patients had CEA mRNA levels above cut-off. Corresponding figures for CK20 mRNA were 3/6, 10/26, 9/10 and 5/9, respectively. CEA mRNA levels varied from 0.001 to 100 copies/18S rRNA unit in Dukes' A and B, and 50% of the Dukes' B patients had CEA mRNA levels within the range of Dukes' C patients. Three Dukes' B patients have died from CRC or developed distant metastases. All 3 had high CEA and CK20 mRNA levels. Determination of mRNA was superior to immunohistochemistry in showing CEA expression in lymph nodes. The present qRT-PCR assay for CEA mRNA seems to be a superior tool to identify individuals with disseminated tumour cells. Future extended studies will establish the clinically most relevant cut-off level.     

肿瘤相关抗原LEA与CEA在大肠癌表达的对比研究

目的：探讨ＬＥＡ对大肠癌的诊断价值。方法：用免疫组织化学方法（Ｓ－Ｐ法）检测１１７例大肠癌组织呼９９例大肠非癌变组织ＬＥＡ（Ｌａｒｇｅ Ｅｘｔｅｋｍａｌ Ａｎｔｉｇｅｎ）与ＣＥＡ的表达状况。结果：ＬＥＡ在组织学上诊断大肠癌的灵敏度为８６．３％,特异度为５３．５％,与ＣＥＡ相比,灵敏度与ＣＥＡ相似（Ｐ〉０．０５）,特异度要强于ＣＥＡ（Ｐ〈０．０５）。两种抗原联合应用并不比ＬＥＡ单独应用的诊断价值高。     

大肠癌患者术前测定血清CEA、CA_(50)和CA_(242)的临床意义

目的：了解大肠癌患者血清CEA，CA50和CA242的临床意义。方法：采用放射免疫分析测定106例大肠癌患者术前血清中CEA，CA50和CA242。结果：CEA，CA50和CA242的阳性表达与患者性别、年龄、肿瘤部位及大小无明显关系（P＞0．05）；肿瘤发生淋巴结转移时血清CEA明显升高；CA50仅在晚期肿瘤出现升高（P＜0．05）；有淋巴结转移或肿瘤细胞分化较差的（低分化、未分化）血清CA242显著高于无淋巴结转移或细胞分化程度较好的（高分化、中分化）（P＜0．01）。结论：CA242测定有助于术前判断肿瘤分期；CEA和CA242显著升高提示淋巴结转移的存在，作为大肠癌辅助诊断指标具有一定临床价值。     

Ki-67 and CEA expression as prognostic markers in Dukes' C colorectal cancer

This study investigated the relationship between clinicopathological or immunohistochemical factors and postoperative prognosis for Dukes' C colorectal cancer. Short-term survivors died from cancer within 2 years of surgery, whereas long-term survivors were disease-free for over 10 years. The groups differed in Ki-67 antigen and CEA expression in colon cancer, and CEA expression in rectal cancer that was limited to the metastatic lymph nodes. The immunohistochemical scores were higher in short-term survivors. Our data suggest that the characteristics of metastatic lymph nodes are important as a predictor of the aggressiveness of tumor behavior and that the expression of Ki-67 antigen or CEA there may be a useful indicators of patients' survival in Dukes' C colorectal cancer.     

Serum tumor markers in colorectal cancer staging,grading, and follow-up

Early diagnosis of colorectal cancer, a frequent neoplasia in industrialized countries, permits curative surgery. In this study we assessed the clinical role of serum tumor markers determination in diagnosing, staging, and grading colorectal cancer; the role of carcinoembryonic antigen (CEA), CA 19-9, tissue polypeptide antigen (TPA) and CA 72-4 in colorectal cancer follow-up was also assessed. In 114 patients with colorectal cancer, the oncofetal antigen CEA was compared with the membrane-associated glycoproteins CA 19-9, CA 242, and CA 72-4 and with the cytokeratins TPA, tissue polypeptide-specific antigen (TPS) and tissue polypeptide monoclonal antigen (TPM). Overall, the most sensitive indices were TPA and TPS (67% and 70%, respectively). Tumor stage influenced the levels of CEA, CA 19-9, and TPA, but not those of TPS, while tumor grade influenced CEA and TPS, but not CA 72-4, TPA, and TPM. TPA was the most sensitive index in identifying early or well-differentiated colorectal cancers. The sensitivity was enhanced when this marker was determined in combination with CEA, in diagnosing both advanced and early colorectal tumors. Seventy-seven patients were followed up after therapy for at least 18 months. CEA was the most sensitive index of recurrence (58%); however, this sensitivity is too low to consider tumor markers useful in colorectal cancer follow-up. © 1996 Wiley-Liss, Inc.     

CEA in tumors of other than colorectal origin

Carcinoembryonic antigen has been demonstrated to be a valuable clinical aid in the management of patients with colorectal carcinoma. Its elevation in the serum prior to evidence of clinical recurrence in up to 80% of patients highlights its utility. CEA has also been found to be elevated in the serum of patients with other epithelial malignancies, but these have not been as well studied as has colorectal carcinoma. In patients with breast cancer CEA elevations may be found in 40-73% of patients presenting with disease in stages I-IV. In addition, 80% of patients will have a CEA elevation 3-10 months prior to clinical symptoms of recurrence. Seventy-seven percent of patients with bronchogenic lung cancer will have an elevated preoperative value. However, cigarette smoking also causes an increase in the CEA assay level and, thus, differentiation between benign and malignant conditions is more difficult. In small cell carcinoma of the lung, CEA assay levels above 10 ng/ml correlate highly with metastatic disease, while values less than 2.5 ng/ml correlate with localized disease. Pancreatic and gastric malignancies demonstrate CEA level elevations in just over 50% of cases. But these, however, have not been clinically useful. Epithelial neoplasms of the female reproductive tract (cervix, uterus, and ovary) also produce CEA in 47-75% of cases and may correlate with stage of disease at diagnosis and level of cellular differentiation. CEA assay levels are elevated in a variety of tumors and correlate with tumor stage, degree of differentiation, and effectiveness of therapy; they may also be the earliest marker of recurrence.     

The preoperative carcinoembryonic antigen test in the diagnosis, staging, and prognosis of colorectal cancer

A study of preoperative carcinoembryonic antigen (CEA) levels was conducted in 319 patients with surgically treated colorectal cancer, 272 of whom had disease resectable with curative intent. Only three patients could not be completely followed. All of the remaining 316 patients have been followed for a minimum of 5 years or until death. From the standpoint of diagnosis, the CEA test was more frequently positive (greater than 5 ng/ml) in patients with advanced stage disease, with larger primary tumors, and with more differentiated histopathologic characteristics. It was grossly insensitive in diagnosis of resectable cancer (26%) and was only reasonably reliable (72%) in patients with unresectable and metastatic disease. In relationship to surgical pathology of colorectal cancer, CEA levels were significantly correlated with stage of disease and with size of the primary tumor in Dukes' B lesions, but not with extent of nodal metastasis in Dukes' C lesions. In advanced stage lesions, CEA was inversely correlated with degree of anaplasia. In the overall patient group, and also among resectable patients, the preoperative CEA level was strongly associated with survival after adjustment for the effects of a number of other prognostic factors. Within stages of resectable disease, however, CEA was not significantly associated with survival among patients with Dukes' A and B lesions or Dukes' C lesions with one to three nodes involved. CEA was found to be a significant and independent prognostic determinant only in patients with Dukes' C lesions who had four or more metastatically involved lymph nodes. Under these circumstances, a preoperative CEA level could perhaps be of some value for stratification of Dukes' C patients in randomized colorectal cancer surgical adjuvant trials. The value of this test as a prognostic guide in clinical practice, however, would seem to be limited because of a lack of sensitivity in identifying individual poor prognosis patients.     

Differences in messenger RNA expression of carcinoembryonic antigen in surgical specimens of colorectal carcinoma.

Carcinoembryonic antigen (CEA) is the most widely used tumor marker for colorectal cancer. Plasma CEA levels have been variably associated with prognosis. Since plasma CEA level is multifactorial, CEA gene expression in tumors may provide one precise mechanism to evaluate its functional role. This study evaluated CEA expression at the messenger RNA (mRNA) level in 22 human colorectal carcinomas and their adjacent normal mucosae by Northern blot hybridization using a 32P-labeled CEA probe (a loop-domain specific cDNA, LV7). Both tumor and normal mucosa displayed three mRNA species of 4.0, 3.6, and 3.0 kb in length. The expression of 3.6-kb mRNA which encodes for CEA was dominant and it was correlated with another 4.0-kb CEA mRNA expression. The expression of 3.0-kb mRNA which encodes for nonspecific cross-reacting antigen was weak and not detectable in 8 of 22 colon tumors and 12 of 22 normal colon mucosae. In only one tumor, a 4.5-kb mRNA (which might encode for a new family member of CEA) was expressed. A two- to fourfold higher expression of CEA mRNA (3.6 kb) was observed in 11 of 22 colorectal tumors (2 of 9 proximal colon tumors and 9 of 14 rectosigmoid tumors) when compared with morphologically normal adjacent mucosae. Preoperative plasma CEA levels and Dukes' staging had no correlation with this CEA mRNA expression. CEA mRNA did not appear to correlate with metastasis because its expression in the primary colon cancers with metastases (Dukes' stage D tumor) was not always increased. These data also imply that factors other than mRNA expression in tumor might be important in regulating plasma CEA levels.     

Clinical use of carcinoembryonic antigen (CEA) determination]

The carcinoembryonic antigen (CEA) is a tumor marker defined by specific heterologous antisera. Elevated levels of circulating CEA have been detected by radioimmunoassay in 20-90 per cent of cases of colorectal carcinomas depending on the degree of tumor spread. The fact that elevation of CEA level can also be observed in other types of carcinomas and in several non malignant conditions greatly limit the value of the CEA test for the early diagnosis of colorectal carcinoma. Thus, the CEA assay should not be used as a screening test for cancer. Repeated CEA measurements, however, appear to be of importance for the evaluation of tumor resection and the detection of tumor recurrence. The only localized tumors known to produce elevation of CEA above the levels observed in non malignant diseases are carcinomas of the large bowel and the pancreas. In carcinomas derived from other organs a marked increase of CEA level is always associated with the presence of distant metastasis. Therefore at the present time the clinical applications of the CEA radioimmunoassay should be limited to the differential diagnosis of patients with suspicion of primary colorectal or pancreatic carcinoma, to the detection of distant metastasis in other types of carcinomas and to the post operative follow up of patients who had elevated levels of CEA before surgery. Well-controlled studies are still needed to determine if therapeutic decisions based on CEA results can lead to improved survival.     

消化道肿瘤患者血清CA199和CEA水平测定

目的探讨糖类抗原199（CA199）、癌胚抗原（CEA）在消化道肿瘤中的水平及临床意义。方法采用ELISA法测定245例经病理学确诊的消化道肿瘤患者血清中CA199、CEA水平,并计算阳性率。结果CA199、CEA在胰腺癌（54.8%、29.0%）中阳性率最高,其次分别为肝癌（28.2%、10.3%）、结直肠癌（18.1%、26.0%）、胃癌（16.0%、12.0%）,在食管癌中表达最低（8.7%、8.7%）。结论消化道肿瘤患者的血清CA199、CEA存在一定水平的高表达。     

Expression of carcinoembryonic antigen (CEA) and nonspecific crossreacting antigen (NCA) in gastrointestinal cancer; the correlation with degree of differentiation.

In spite of its reputation as a tumour marker, little is known about the function of carcinoembryonic antigen (CEA). We examined the mRNA expression of CEA and NCA in 26 gastric and 14 colorectal cancers together with adjacent morphologically normal mucosae. There was no significant difference between the CEA mRNA levels of colorectal cancer and adjacent mucosa, whereas the CEA mRNA levels were significantly elevated in gastric cancer compared with normal gastric mucosa. The expression of NCA, on the other hand, was more cancer-specific and was significantly up-regulated in both gastric and colorectal cancers compared with the corresponding normal mucosae. No correlation was found between the mRNA level and plasma CEA value. No significant up-regulation was recognised in the node positive cancer, cancer with distant metastasis, or the metastatic tissues themselves. Marked diversity in the degree of differentiation in gastric cancer tissues, however, resulted in varied expression of the CEA gene family, compared with the constantly high expression found in colorectal cancer. Further analysis revealed significant up-regulation of NCA in well and moderately differentiated gastric cancers over poorly differentiated cancers, suggesting that NCA might have roles in differentiation.     

Immunostaining of colorectal cancer with monoclonal anti-CEA antibodies compared to serum and tumor CEA content

Carcinoembryonic antigen was measured in serum and in extracts from 37 colorectal tumors and we found a poor correlation between circulating and tumor CEA. Monoclonal antiCEA antibodies were used in indirect immunoperoxidase staining of the corresponding formalin fixed tissue sections. We found that serum CEA measurement had a sensitivity of only 41.9% as compared to 90.3% for the immunohistochemical staining. The positive and negative predictive values for immunostaining were respectively 96.6% and 72.7%. Immunohistochemical staining of tissue sections with monoclonal anti CEA coupled to other biochemical or immunological assays could be a useful adjunct for the diagnosis of premalignant or slightly modified tissues.     

Comparison of circulating MAM-6 and CEA levels and correlation with the estrogen receptor in patients with breast cancer

MAM-6 and CEA serum levels of 136 staged breast cancer patients were determined concomitantly. The sensitivities of the MAM-6 assay using monoclonal antibody (MAb) 115D8 and a polyclonal CEA assay were equally low and only a limited number of patients with early stages of breast cancer showed elevated antigen levels. However, the sensitivity rose to 75% for MAM-6 and to 60% for CEA in stage-IV patients. The levels of both antigens correlated well in the sera of these patients, although MAM-6 serum levels were elevated more frequently, while only in a few cases were MAM-6-negative sera CEA-positive. A group of stage-II breast cancer patients who eventually developed distant metastases was followed in a longitudinal study. Tumor progression or regression was clinically determined and compared with the MAM-6 and CEA serum levels in order to establish the value of each assay for the monitoring of breast cancer. The course of the disease correlated significantly better with changes in MAM-6 antigen levels than with changes in CEA levels (p less than 0.05), being 79% and 42% respectively. The lower correlation of CEA levels with the course of the disease was mainly due to a lower sensitivity of the CEA assay for advanced breast cancer. The specificity of changing MAM-6 and CEA levels was not significantly different. The main advantage of the MAM-6 assay over the CEA assay is the higher sensitivity of the former. In a preliminary study among stage-IV patients a correlation was found between elevated MAM-6 levels and the presence of the estrogen receptor in the primary tumor.     

Comparison of CA 19-9 and carcinoembryonic antigen (CEA) levels in the serum of patients with colorectal diseases

The serum levels of CA 19-9 and carcinoembryonic antigen (CEA) were determined in 37 patients with benign colorectal diseases and in 111 patients with newly discovered colorectal carcinomas or clinically verified relapses. In cancer patients, the CA 19-9 level ranged from normal (0-37 U ml-1) to 77,500 U ml-1 whereas all samples but one from patients with benign colorectal diseases had a normal value. CA 19-9 was increased in 46% and 45% of patients with an advanced (Dukes C or D) carcinoma or a verified recidive, respectively. Only one out of 26 patients (4%) with a localized (Dukes A or B) carcinoma displayed an elevated CA 19-9 level (greater than 37 U ml-1). No clear correlation was found between the CA 19-9 and CEA levels. The sensitivity of the CA 19-9 test (36%) was poorer than that of the CEA assay (69%), but the new test was markedly more specific (97% vs 70%) than the CEA assay.     

Carcinoembryonic antigen in serum and the tissue of patients with colon cancer

Carcinoembryonic antigen (CEA) levels in the serum and colon tissue were evaluated in 83 patients with colon cancer. The mean concentration of serum CEA increased in parallel with Dukes' stages. CEA concentrations in the cancerous and normal colon overlapped. In the same patient, however, CEA of cancerous colon tissue was always higher than that of normal colon tissue. There was no difference in CEA concentrations in colon cancer between Dukes' A and B. However, in patients with Dukes' C stage, the concentration was higher than in those with Dukes' A and B. The detection of tissue CEA concentration as well as serum CEA is a useful marker for monitoring patients with colon cancer.