Carcinoembryionic antigen (CEA) a glycoprotein extracted from colonic cancer
tissue (P-globulin electrophoretic mobility, sedimentation coefficient 7 to 8S, and mol wt -200,000) can be detected and measured by radioimmunoassay. Clinical evaluations of CEA determination have given the following results: In health: (1) Serum CEA level is not influenced by sex, age, blood type, time of blood sampling, or family history of cancer; (2) serum CEA level is influenced by a his- tory of smoking or inflammatory disease of the bowel, lung, pancreas, and other organs (occasionally, a CEA level as high as 10 ng/ml is noted); and (3) currently, CEA positivity is defined as >2.5 ngiml, however, 5 ng/ml may be more realistic. I n cancer: (1) CEA level may be increased in primary cancer of the gastroin- testinal (GI) tract as well as in non-GI neoplasia; (2) the CEA test is not recom- mended for screening to detect early cancer; (3) serum CEA level depends on the stage of the neoplasia and usually is not influenced by the grade of differen- tiation; and (4) markedly increased (>25 ng/ml) serum CEA values are highly suggestive of metastatic cancer, particularly hepatic metastasis. I n biological fluid: The CEA or CEA-like activity can be measured in gastrointestinal secre- tions. Quantitative studies of CEA levels in such fluids may yield more informa- tion than is obtainable from studies of serum. However, this possibility needs more study at present. Therefore, the currently available CEA tests cannot re- place any of the now standard diagnostic methods for cancer detection. This use for assessment of therapy in selected patients or for following those known to be at high risk for cancer appears promising in preliminary studies, but clinical value, if any, remains to be determined. Cancer 37:562-566, 1976.
I N1965, GOLDA N D FREEDMAN REPORTED THAT
carcinomas of the colon contained an anti- gen that was absent from normal adult intesti- nosis of colonic cancer. Subsequently, immu- nochemicnl tests showed that this material could be detected in the serum of patients nal mucosa but was present in primitive ento- with gastrointestinal or nongastrointestinal derm.1g.2" T h e authors named this material malignancy, in extracts from gastrointestinal carcinoembryonic antigen (CEA) of the diges- a n d nongastrointestinal tumors, and in tissue tive system. In 1969, Thomson et al. described extract? of the fetal gastrointestinal t r a ~ t . ~ J ~ $ a radioimmunoassay for CEA in serumBoand ~ 1 4 4 Recently several laboratories have re-
reported positive findings in 97yo of a series ported CEA immunoreactivity in urine,7,13.21
of patients with cancer of the colon. So CEA stool,l2 14 and intestinal secretionsl~l"~'~3"45of was acclaimed in the medical and lay litera- cancer patients and of normals. ture as a tumor-specific antigen whose detec- T w o coopeiative trials of the CEA test in tion in the serum may be helpful in the diag- blood have been carried out in a number of centers in the United States and Canada. T h e Presented at the meeting of the ACS-NCI National National Cancer Institute of Canada and the Conference on Advances in Cancel Management, Part 11: Detection and Diagnosis, Denver, CO, May 1-3, American Cancer Society sponsored a col- 1975. laborative study of CEA tests employinq the From the Gastroenteiology Unit, Mayo Clinic and Thomson technique,25 while the Hoffmann- Mayo Foundation, Rochester, Minnesota. LaRoche Company organized a trial utilizing Supported by research giant CB 23854 from the National Cancer Institute, National Institutes of tlie Hansen technique.22 Through a contract Health. awarded by the National Cancer Institute, we Address for reprints: V. L. MI. Go, MD, Mayo Clinic, have carried out a prospective evaluation of Rochester, M N 55901. CEA test5 in a clinical setting, using reagents 562 10970142, 1976, S1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197601)37:1+<562::AID-CNCR2820370721>3.0.CO;2-0 by Nat Prov Indonesia, Wiley Online Library on [04/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License No. 1 CARCINOEMBRYONIC ANTIGEN - Go 563 kindly supplied by Dr. Hans Hansen, Hoff- or serum and their ways of separating free mann-LaRoche Company. Over the last 30 from antibody-bound antigen. Some tech- months, 6,700 patients have been entered into niques use either serum or plasma and some the study. From our experience and that of use inta.ct serum o r plasma (direct assay), others in such studies and in applying the whereas for others the test serum must be ex- CEA test to b10od3.2"30.31,~~.*3,~~and to gastro- tracted first with perchloric acid (indirect as- iritestinal1,15,17.",4~and urinary secretions,13.21 say). T h e reliability and comparability of the I shall review the present status of this test. various methodologies were demonstrated in a study organized by the National Cancer In- stitute in which CEA levels of 94 blood speci- PHYSICOCHEMICAL PROPERTIES OF CEA mens ohtained from different patients were tested simultaneously by different 1a.borato- Recent progress in elucidation of the physi- ries, including those of Das, Go, Gold, Han- cal and chemical properties of purified CEA sen, LoCerfo, Mach, Martin, Reynoso, Todd, has been reviewed extensively by Terry et al.38 and Zarncheck:"4 Correlations of 82 to 907; CEA is a glycoprotein, extracted, and purified from primary adenocarcinoma of the colon o r were obtained. from colonic carcinoma metastasized to the liver. Purified CEA has a molecular weight of CEA LEVELI N HEALTH CIRCULATING AND about 200,000, sedimentation coefficient of 7.0 BENIGNDISORDERS to 8.OS, and beta-globulin electrophoretic mo- T h e normal values for the different assays hili ty. Electron microscopy has shown the vary among laboratories. T h e Thomson assay molecule to be of uniform size with a complex and the CEA-Roche assay used the cut-off secondary structure.6 It is soluble in I hl point of 2.5 ng/ml; the Egan-Todd assay is perchloric acid and in half-saturated ammo- approximately 12.5 ng/ml; and other labora- nium sulfate. tories, including Mach and our laboratory, Chemical analysis of purified CEA shows use a cut-off point of 5 ng/ml. Therefore, the approximately 50 to 65y0 carbohydrate, the CEA result obtained by each laboratory remainder being protein. T h e carbohydrate should always be interpreted in comparison portion of CEA contained fucose, mannose, with tlie value obtained from normal controls galactose, N-acetyl-glucosamine, sialic acid, and tracer of N-acetyl-galactosamine. T h e charge using the same assay procedure. heterogeneity of various CEA preparations T h e serum or plasma CEA level is influ- enced by the history of cigarette smoking, have been attributed, in part, to variations in sialic acid content of the molecule. Amino tending to he higher in heavy smokers than in acid sequencing of the protein backbone of nonsmokers.2') Elevated 'CEA levels between CEA is not yet complete. However, the first 24 2.6 and 10 ng/ml and occasionally as high as residues from the N-terminal of purified CEA, 10 ng/ml occur in many patients with a va- obtained from liver metastasis or isolated riety of benign conditions including bron- from serum of patients with advanced meta- chitis, inflammatory bowel disease, pancrea- static colonic cancer, are identical.*' titis, cirrhosis, and pulmonary empliysetna.2~~~ x,21.2*.33.37 CEA positivity defined as greater than 2.5 ng/ml is not helpful in the diagnosis CE,\ RADIOIMMLINOASSAY METHOD of cancer, particularly if there is a history of heavy smoking or any of the listed underlying Several techniques for radioimmunoassay henign diseases. to measure CEA have been described. The We have found that other factors-sex, age, m a y measures inhibition of the binding of time of the clay when tlie blood sample was known amounts of radiolabeled purified CEA drawn, and the presence or absence of family to the specific antibody. T h e techniques used history of cancer-do not influence the CEA most often are those originally described by level."; Thornson et al.,5O by Hansen,31 and by Egan.11 Several modifications of these methods have CEA IN MALIGNANT DISEASES been validated.30e34~42 To date, the CEA-Roche test is the only one approved by the FDA for CEA tests have limited sensitivity and speci- clinical use. T h e assay techniques differ mostly ficity for cancer. T h e initial studies utilized in their ways of extracting CEA from plasma cases of frank gastrointestinal cancer, many 10970142, 1976, S1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197601)37:1+<562::AID-CNCR2820370721>3.0.CO;2-0 by Nat Prov Indonesia, Wiley Online Library on [04/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 564 Janirory Supplement 197G CANCER 1'01. 97 with metastasis; the CEA levels were higher Gerfo et al.,31J2 Reynoso et al.,23s43 Laurence than 2.5 ng/ml in more than 75% of them. et > I I . , ~ O Mach et al.,3-' and Khoo and Macky.41 Subsequent prospective evaluations of CEA However, a drop of the CEA level to normal tests in gastrointestinal malignancy, particu- after surgery does not always provide a good larly in cancer of the colon, have shown that index of completeness of surgical excision, for the CEA level varies with the stage of the can- in some cases the cancer recurs. I n a small cer. Large proportions of patients with early number of cases the CEA level has fallen to surgical and resectable colonic cancer have normal after surgical therapy but risen again normal concentrations of circulating CEA. As during recurrence, perhaps before there was the cancer spreads to adjacent organs or me- clinical evidence of recurrence. O u r experi- tastasi7es distantly, the amount of circulating ence showed that during recurrence after 110- CEA and the incidence of CEA positivity in- tentially curative resection the level of CEA crease. Greatly increased serum CEA values depends o n the stage of the recurrent disease. (> 25 ng/ml) are highly suggestive of meta- T h e CEA level is normal in localized recur- static cancer, and particularly hepatic metas- rent disease, and a n elevated CEA level sug- tasis. Similar patterns have been observed in gests regional and distant metastasis. Our data cancer of the pancreas, stomach, lung, breast, suggest that serial determinations of serum prostate, and other solid tumors. Therefore, CEA could indicate advances of recurrent can- the use of CEA test alone for screening pur- cer in long-term follow-up of patients who had poses is not recommended. At present, CEA undergone curative surgery and who have a tests are useful as a diagnostic adjunct when normal postoperative CEA. However, i t must cancer is suspected, but they cannot replace be made clear that i n those cases where CEA any of the currently standard methods for can- increased, the tumor recurrence was readily cer detection. A normal CEA level does not detectable by other means.42 preclude the presence of primary, metastatic, Serial CEA assays have been used for moni- or recurrent cancer. toring cancer chemotherapy in patients with Comparison of concentrations of circulating cancer of the colon, pancreas, stomach, biliary CEA and other enzymes such as serum alkaline tract,*4-.J"4G breast,5?48 cervix, body of the phosphatase, gamma-glutamyl transpeptidase, uterus, ovary,"fi.2' and lung,51 and in patients lactate dehydrogenase, and other serum en- with neuroblastoma.4~ These studies have zymes suggest that measurements of CEA and shown a fair correlation between effectiveness enzyme concentrations were complementary to of cancer chemotherapy and serum CEA con- each other in patients with primary and meta- centration, and our findings seem to confirm static m a l i g n a n ~ i e s . l 8 . ~Similar 0 ~ ~ ~ findings were these general results. However, serial determi- obtained from simultaneous measurements of nations of serum CEA must be interpreted in CEA and other tumor-associated antigens such the clinical context, for we have noted that as alpha-fetoprotein. I n our experience, when preterminally the CEA concentration may fall alpha-fetoprotein and CEA were measured si- rather than rise and that patients whose orig- multaneously, 54y0 of patients with gastric inal cancer produced no CEA may deteriorate carcinoma had elevations of one or both, without producing any. Furthermore, various whereas only 27% had elevated alplia-fetopro- cancer chemotherapy agents may alter the syn- tein alone and 2 2 7 , had elevated CEA al0ne.3~ thesis and secretion of CEA without affecting This suggests the possibility that measure- the progression of the neoplasia. It is in this ments of CEA and other tumor-associated an- area of research that CEA assay as a biologic tigens such as alpha-fetoprotein, human cho- marker for following cancer chemotherapy rionic gonadotropin, or Regan isoenzymes may prove fruitful. and other enzymes might increase significantly our ability to detect advanced gastrointestinal CEA-LIKEACTIVITY I N SECRETIONS cancer. CEA or CEA-like activities have been de- CEA AS MARKERFOR CANCER BIOLOGIC tected by various immunologic tests in saliva, THERAPY gastrointestinal secretion, feces, urine, bron- chial washings, and other biologic fluids and Thomson, Gold et al. first reported five secretions of different organ sy~tems.l,7.1"1~,~~. cases of colonic cancer with elevated CEA 1 5 ~ 7 . 2 1 . 3 5 . 3 6 ~ 4With 5 use of several intestinal per- levels that declined to normal in three cases fusion techniques, we recently have quantified after complete resection of the cancer. Such the secretion of CEA-like activity in the gastro- a response was confirmed by Dhar et al.,'" L o intestinal tract of healthy human subjects. 10970142, 1976, S1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197601)37:1+<562::AID-CNCR2820370721>3.0.CO;2-0 by Nat Prov Indonesia, Wiley Online Library on [04/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License No. 1 CARCINOEMBRYONIC ANTIGEN - Go 565 T h e secretory rate was highest in colonic se- end.5' I n pancreatic secretion, we found that cretion, arid next highest in pancreatico-biliary CEA output does not differentiate patients secretion.17 T h e CEA-like material extracted with pancreatic disease from healthy persons; from normal human saliva, normal gastroin- yet one-third of patients with pancreatic can- testinal secretion, and feces has chromato- cer and 20% of those with chronic pancreatitis graphic and immunologic properties similar had increased outputs of CEA in response to to those of purified CEA extracted from liver cholecystokinin stimulation.9 Hall and co- tissue containing metastatic cancer of the workers found abnormal urinary CEA values colon. Whether this immunoreactive CEA ma- in two-thirds of their patients with active terial is chemically the same as purified CEA bladder cancer.tl We have confirmed their ob- needs further study. servations and further noted that the fre- It has been suggested that studies of CEA- quency of abnormal CEA values correlated like activity in fluid secreted by hollow vis- with the extent and grade of the tumor. How- cera such as the gastrointestinal tract, lung, and urinary bladder might lead to improve- ever, urinary tract infection can produce ab- ment in early detection of cancer. Winawer normal CEA values in patients without can- found that the CEA concentration in colonic cer. lavage specimens from 38 patients ranged These and 0therf5-36,~gvarious preliminary from 0 to 4450 ng/mg protein.5' Patients with results suggest that measurement of CEA-like cancer and polyps were at the higher end of activities may have some diagnostic value. the range, patients with ulcerative colitis in- However, its ultimate clinical application re- termediate, and normal subjects at the lower mains to be determined. REFERENCES 1. Bhargava, .4. K., Chen, J. F.,Vincent, R. G., and 12. Elias, E. G., Holyoke, E. D., and Chu, T. M.: Chu, T. M.: Characterization of a glycoprotein from Carcinoemhryonic antigen (CEA) in feces and plasma ascites of pancreatic carcinoma and its comparisons of normal subjects and patients with colorectal car- with colonic carcinoembryonic antigen (CFA). Pro- cinoma. Dis. Colon Rectum 17:38:41, 1974. ceedings of the American Association for Cancer R e - 13. 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M.: Carcinoemhry- check, H.: Identification of carcinoemhryonic (CEA) onic antigen in patients with carcinoma of the lung. activity in the pancreatic juice of patients with car- J. Thornc. Cordiovnsc. S w g . 66:320-328, 1973. cinoma of the pancrras. Fed. Proc. 33:637, 1974. 52. Winawer, S. J.: Detection of early colon cancer. 37. Moore, T. L., Dhar, P., Zamcheck. N.. Keeley, A.. Nationnl 1.arge Bowel Cancer Project Newsletter 3:7-9, Gottlieh. L.. and Kupchik, H. 2.: Carcinoemhryonic an- 1975. tigen(s) in liver disease. Gastroenterology 63:88-94, 53. Zamcheck, N.: Carcinocmhryonic antigen-@an- 1972. titative variations in circulating levels in benign and 38. Moore, 1’. L., Kupchik, H. Z.,Marcon, N., and malignant digestive tract diseases. I n Advances in In- %amcheck,N.: Carcinoemhryonic antigen assay in can- ternal Medicine, vol. 19. Chicago, Year Rook Medical, cer of the colon and pancreas and other digestive tract 1974; pp. 413--433.