Tumor markers in cancer diagnosis and prognosis - Wiley Online Library

Tumor Markers in Cancer Diagnosis and Prognosis Mohamed A. Virji, MD Donald W. Mercer, PhD Ronald B. Herberman, MD

Introduction A tumor marker is a biochemical indicator for the presence of a tumor. In clinical usage, the term usually refers to a molecule that can be detected in plasma or other body fluids. Table I summarizes the major concep tual developments in the history of tumor markers. Bence Jones proteins in urine and the serum levels of acid phosphatase have been employed for many years as indica tors for multiple myeloma and prostatic adenocarcinoma, respectively. Although efforts were made in the early decades of this century to identify tumor-specific anti gens, the number of markers in clinical use remained limited, and almost none were available for the more common cancers.

markers. The search has yielded an ever increasing variety of tumor markers with differing tissue specificity and sensitivity. These discoveries have been made in com bination with several developments, most notably those of rapid, highly sensitive, immunoassay techniques to provide reli able quantitation; hybridoma technology for an unlimited supply of monoclonal an tibodies with defined specificities; recom binant DNA methodology for molecular genetic analysis of genomic alteration and expression in cancer cells; and refinements in protein purification and sequencing methods. This overview discusses the currently available tumor markers in cancer diagno sis and prognosis.

The discovery of alpha-feto@@t@Th' (AFP) as a marker for hepatomas, and car cinoembryonic antigen2 (CEA) as a marker for colon carcinoma, provided a fresh im petus for the search for specific tumor Dr. Virji is Director of the Tumor Marker Lab oratory at the Pittsburgh Cancer Institute, Uni versity of Pittsburgh School of Medicine, in Pittsburgh, Pennsylvania. Dr. Mercer is Clinical Associate Director of the Tumor Marker Laboratory at the Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, in Pittsburgh, Pennsylva nia. Dr. Herberman is Director of the Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, in Pittsburgh, Pennsylva nia. 104

Defining a Tumor Marker An ideal tumor marker would be expected to have high sensitivity and specificity for cancer and fulfill certain criteria.3 It would be produced and released primarily by transformed cells or by other tissues in re sponse to the tumor, at levels proportional to the state of differentiation and the mass of tumor cells. A therapeutic response or alteration in the state of the neoplastic tis sue would be reflected in a change in the production of the marker such that tumor ablation or recrudescence would result in an appropriate change in the level of the marker. Furthermore, elevated marker lev els would be seen in patients with small CA-A CANCERJOURNALFORCLINICIANS

amounts of tumor present, so that residual primary or recurrent tumors could be de tected at times appreciably earlier than would be possible by conventional diag nostic procedures. Most of the tumor markers currently

available for clinical use do not fulfill these criteria. The only constant abnormality ex pressed in a cancer cell is that of growth inconsistent with the physiologic needs of the tissue where the tumor originates. This heritable alteration in growth is not accom panied by other consistent expression of eithera singlebiochemicalfactoror a groupofmoleculesthatcouldbe usedasan imprint to distinguish a neoplastic from a normal cell.4 The detection of a molecular marker to serve as an indicator specific for a tumor depends upon the constantproductionof that molecule by the tumor, but not at all, or not above a background level, by non tumor cells. However, the production of the molecule may vary not only between similar tumors from the same organ, but also from the same tumor, since there is cellular heterogeneity within the same tu mor represented by differences in the rate of growth, the stage of differentiation, and, therefore, the expressionof biochemical features that could potentially be consid ered as markers for malignancy.5 The pro duction of such marker molecules may also be increased from normal tissues in re sponse to certain physiologic stimuli, thus further confounding the utility of a mole cule as a specific tumor marker. In practice, therefore, a tumor marker can be defined as a biochemical indicator that is usually found in abnormal concen tration in the presence of a neoplasm. Vir tually no tumor marker, however, has been shown to be specific or sensitive enough to use in the detection of tumors in the general population.

Categories of Tumor Markers Tumor markers can be divided into two broad categories—tumor-derived, mole cules produced by the neoplastic cells: and tumor-associated (or host-response), met abolic and immunologic products of nor VOL 38. NO 2 MARCH/APRIL1988

mal tissues produced in response to the presence of the neoplastic tissue. Both these groups include different types of molecules (Table 2). Tumor-Derived

Markers

Tumor-derived markers that are products of the cancer cell include differentiation antigens (lymphocyte surface markers);' oncofetal antigens (CEA, AFP); isoen zymes (neuron-specific enolase [NSE]; prostatic acid phosphatase [PAP]); hor mones (human chorionic gonadotropin

[HCG]; adrenocorticotropic hormone IACTHI); tissue-specific proteins (alpha

Virtually no tumor marker has been shown to be specific or sensitive enough to use in the detection of tumors in the general population.

lactalbumin, prostate-specific antigen); on cogenes and their products: and mucins and other glycoproteins or glycolipids. Until recently, it was believed that tu mor cells, by virtue of transformation, could acquire the ability to elaborate novel molecules not found in normal cells, and the search for such products was actively pursued in certain cancers. Apparently, uniquemoleculesforvarioushuman tu mors were initially thought to be identified, but rigorous studies revealed that these molecules were present in normal cells at certain stages of development or at low levels of expression.6 Transformed cells may produce sub stances that are not present in the normal differentiated tissues in which the tumor arose (ectopic molecules, ACTH, vaso pressin production by small cell carcino mas of lung), or that are characteristic of normalembryonicdevelopment(oncofetal antigens). 105

Oncofetal antigens are produced by neoplastic cells that are usually derived

antibody

Not only are these molecules not tissue specific, but they are also increased in cer tain benign conditions and are not present

roglobulin, C-reactive acute-phase reactants.

in all the tumors derived from the same

Tumor Markers in Clinical Use

response

to an altered

antigen

originating from the tumor tissue with sub from tissuesin which theseantigensare sequent antigen-antibody complex forma tion. Attempts have been made to isolate expressed normally during fetal develop ment, but they also occur in tumors arising the antigens from immune complexes and from unrelated tissue.78 Thus. AFP pro identify their possible use as tumor duced by hepatoma cells is elaborated by markers.2° the fetal hepatocytes. but it is also produced Other such markers include isoen by lung, testicular, and intestinal cancers.9 zymes. beta2-microglobulin. alpha@-mac

tissue.'°― AFP levels increase in cirrhosis

when cellular regeneration occurs. and in creased serum levels are observed in only

protein,

and other

tumor to therapy; a decline in serum levels follows tumor ablation, and increasing lev

The main function ot' tumor markers in clinical medicine has been as laboratory tests to confirm the diagnosis of a cancer serum or urine electrophoresis to identify a monoclonal peak for the myeloma proteins in multiple myeloma. CEA determination in colon cancer, and serum PAP levels in prostate cancer21.23 Tumor markers are also increasingly being used to determine

els denote failure of therapy or recurrence

the response to therapy and as an indication

up to 70 percent of all hepatomas.'2

These features limit the usefulness of the markers as screening

tests. They can.

however, confirm a diagnosis of cancer and are helpful in following

the response of a

of the disease. In this regard, HCG has proven to be a useful indicator for guiding

of relapse during the follow-up period.24'26 Experience with a range of markers has therapyinchoriocarcinoma and forindicat increased the awareness that both sensitiv ing progno5is.@3To a lesser extent, PAP for ity and specificity of an individual marker prostate cancerand CEA forbreastcancer are important in determining the role of a have providedsimilar information.'4'5 marker for a particular use. Studies designed to provide informa tion for a marker should address several issues: the presence of a pathologic level of Tumor-Associated(Host-Response) the marker as a biochemical indicator ac Markers companying a neoplastic process versus its Tumor-associated markers have been used absence in health: the relationship of the with tumor-derived markers to provide ad marker to benign tumors and other disease ditional information about certain cancers, processes of the same tissue: the relation to determine or confirm the extent of the ship of the marker to different tumor stages disease or its prognosis. and to therefore and histologic variants; the effect of the tumor burden on the concentration of the aid in therapeutic management. Serum fer ritin levels in neuroblastoma, determined marker and the rapidity of a decline or rise together with NSE levels, have been shown in the levels with a decrease or increase in to correlate with both disease stage and tumor mass: and the relationship of the therapeutic response. 16While the elevation marker to other markers of relevance. Al of serum levels of femtin, an acute-phase though such multistep studies could neces reactant producedmainlyintheliver, could sitate a concerted effort for every new tu reflect a response to tumor burden, it could mor marker identified, markers that have also be produced by tumor cells.'7―8 the potential to provide information for Immune complexes are found in the clinical decisions could be readily evalu serum of many patients with cancer, as ated through this process. well as in patients with other diseases.'9 Of the markers available, serum 1-ICG Theirpresenceincancermay indicate an provides information most useful for detec 106

CA-A CANCER JOURNAL FOR CLINICIANS

Year

Investigator(s)

concept

Observation

1846

Bence-Jones

Specific Proteins

Proteins inurine asmarkers for multiple myeloma (immunoglobulin light chains)

1928

Brown

Ectopic Hormones

Ectopic production ofhormones bytumors

1930

Zondek

Humanchorionicgonadotropin

1932

Gushing

Adrenocorticotropic hormone

1933

Gutmanet al

1959

Markert

lsoenzymes

Prostaticacidphosphatase in prostaticcancer lsoenzymesin tissue

differentiation 1960

Newell

1963

Abelev1

Ghromosomal Aberrations

Philadelphia chromosome

Oncofetal

Alpha-fetoprotein in livercarcinoma

Antigens

1965

Garcinoembryonic antigenin coloncancer

Gold and

Freedman2

1969

Huebnerand Todaro1@

Oncogenes

Oncogenes astransforming factors

1975

Kohler and Milstein

Monoclonal Antibodies

Monoclonal production of antibodies ofdefined specificities

VOL.38.NO.2 MARCH/APRIL 1988

107

tion, choice of therapy, and determination of the course of choriocarcinoma.27'28 In familial medullary thyroid carcinoma (MIC), serum calcitonin levels are sensi tive indicators for the presence of the can cer, which is otherwise undetectable by radioisotope scans or palpation; the serum levels of the hormone also correlate with the extent of disease. In individuals at high risk for MIC, regular screening with serum calcitonin is performed for early detection, and then subsequent to therapy, for moni toring response.29 Measurements of serum HCG and AFP in patients with germ cell tumors of the testis have been shown to correlate with the extent of disease. Serial measurements are valuable in following the

prove diagnostic accuracy, as has been at tempted in the diagnosis of ascites due to ovariancancer.4° A special use of immunohistologic techniques for tumor markers is in the diag nosis and classification of leukemias. B and I lymphocytes express cell surface differ entiation antigens during normal matura tion, characteristic of the cell lineage.4'

The disordered or arrested maturation of malignancy is marked by the presence of specific cell surface antigens for which probes in the form of monoclonal antibod ies have been developed.42 In a still evolv ing process, these probes are used for char acterization of leukemias and lymphomas

for cell lineage, maturation state, and alter

response to therapy and in the detection of residual disease and tumor recurrence.3° Other markers, such as CEA, have not ful filled the initial expectations of specificity

ations induced by treatment.43 It has been shown, therefore, that acute lymphoblastic leukemia is heterogeneous, and subgroups consisting of different I- and B-cell matur for colon carcinoma or sensitivity for de ation steps have been defined. tection of early stages of the disease;3―32 Through the use of DNA probes for information from clinical studies, how immunoglobulingenesortheI-cellrecep ever, has shown CEA's utility as a marker tor gene, it has also been shown that both in post-therapy management of patients B-cell and I-cell cancers represent mono withcolonand breast cancers.2233'35 clonal expansion of transformed cells.44 The histopathologic diagnosis of can This has resulted in a correlation between cer has been refined by the introduction of the cancer's cell type and the therapeutic immunochemistry techniques for the detec response observed. With the use of flow tion of tumor markers in tissue biopsies.36 cytometry techniques and monoclonal an The array of monoclonal antibodies of de tibodies, itis now possible to confirm mono fined specificities has aided in the definitive clonalproliferation incaseof relapseand diagnosis of tumors that are otherwise dif to determine appropriate therapeutic strate ficult to diagnose, and has also revealed the gies. This use of cell surface markers is heterogeneity in the distribution of a based on the presence of cellular matura marker within the tumor, indicating the tion and differentiation antigens. A similar nonuniformity of the antigen production in concept has been the basis for attempts at different areasofthesame tumor.37 Mono identifying maturation/differentiation anti clonal antibodies to different epitopes on a gens in other tissues, but has not yet re molecule, as for CEA, have also shown sulted in clinically applicable uses. expression of specific antigenic forms in In the field of radioimmunoimaging, certain tissues.38 The tissue expression of tagged antibodies have found initial appli an antigen determined immunohistologi cations in locating and mapping metastases cally—for example, CEA in colon can or delivering lethal irradiation locally to the cer—does not always correlate with the tumor.45 Although several antibodies have levels found in serum; this is probably due proved useful for imaging small, otherwise to a difference in the functional secretory occult metastatic lesions, the sensitivity mass of the tumor and the total tumor mass limitation remains at about one gm of tu containing the antigen.39 Histopathologic mor, and many radiolabeled antibodies are identification by immunochemistry and tu taken up in considerable amounts in some mor marker levels in serum or other body normal tissues, particularly in the liver or fluids could be used in combination to im spleen. In experimental studies, toxin 108

CA-A CANCERJOURNALFORCLINICIANS

Human chorionic gonadotropin Antidiuretic hormone Parathyroidhormone Calcitonin Insulin-like growth factors Catecholamines and metabolites

Aipha-fetoprotein carcinoembryonic antigen

Prostaticacid phosphatase Neuron-specificenolase Regan ALP isoenzyme LDH.1

ImmunoglobulinsProstate-specific antigenAipha-lactalbuminBeta2-microglobulin

CA-i 25CA-19-9CA-i 5-3,-,c@srcN-mycH-ras

Polyamines

Sialic acid Glycolipids

Ferritin Immunecomplexes Enzymes (LDH, GDH, CK-BB) Acute phase proteins Key:LDH = Lacticdehydrogenase CK-BB= Creatine kinase, BB isoenzyme

VOL.38,NO 2 MARCH/APRIL 1988

GDH = Glutamate dehydrogenase ALP = Alkalinephosphatase

109

tagged

antibodies

against

specific tumor

markers have been found to deliver the toxin at the site of a tumor and result in a decrease in tumor mass upon activation of the toxin.46 These applications are not yet part of routine clinical use, but they do demonstrate the potential for innovative approaches to targeted therapy using tumor markers.

Serum Tumor Markers in Diagnosis and Prognosis Only a few of the tumor markers for which tests have become available are in routine clinical use (Table 3). The most frequent use is as a confirmatory test at the time of initial diagnosis of cancer, together with a batteryof other diagnosticprocedures. Such use, however, if restricted to the time of diagnosis when histopathologic findings are already known, may be inappro

priate.3'47 The tumor markers are most use

@

ful if utilized not only as confirmatory tests, but also as a part of routine follow-up. The sequential estimation of a tumor marker level during the follow-up period and the chronology of the pattern obtained could thenbe correlated withtheresponseinthe patient to tumor therapy or as an indicator of recurrence. In only a few tumors are serum tumor markerlevels currently utilized asa partof routine clinical follow-up studies or as a regular guide to therapeutic decisions. In addition, the markers are usually followed individually rather than used as a selected panel of tumor-derived and tumor-associ

ated markers. The pattern of current tumor marker use is related to the empirical infor mation about a marker, the perceived ease of interpretation of the laboratory result in the clinical setting, and a reliance on other factors tojudgethecourseofthedisease.

trations in the serum and is also present in the semen. The immunochemical methods (counterimmunoelectrophoresis and ra dioimmunoassay [RIA]) are more sensitive analytically than the older enzymatic method, but do not have a greater sensitiv ity for detection of prostate cancer. 23.5ii@52 In adult males, the upper limit of serum concentration of PAP that can be detected with most of the RIA kits available is five ng/ml. Although serum PAP levels become elevated with extracapsular growth of pros tate cancer in 24 to 71 percent of patients. in most patients with early disease the serum concentration is within the normal range, thereby precluding use of the assay

in screening high-risk individuals.3'53'54 The serum levels correlate with the pres ence of metastatic disease, and PAP in bone biopsy samples has been employed for confirming bone-marrow metas tasis.'4'55 PAP, however, is not a sensitive indicator for the response to therapy, be cause only about one half of patients show a correlation between a decrease in serum enzyme concentration and reduction in tu mor mass, and in a small percentage of

patients serum levels do not increase as the disease worsens. 4.23,24.56 A new protein marker for prostate can cer, serum prostate-specific antigen (PSA), has recently become available: its clinical

utility, however, remains to be further evaluated

Human Chorionic Gonadotropin The placental hormone HCG comes closest to being an ideal tumor marker, since it fulfills most of the needed criteria. Its use in both gestational and germ-cell-derived choriocarcinomas

is well established

for

diagnosis of the tumor and estimation of its size and response to treatment, and during follow-up.

Prostatic Acid Phosphatase The prostatic isoenzyme of acid phospha tase is assayed by enzymatic methods or @

immunochemically The low pH, phosphoric monoester hydrolase from ly sosomes is normally found in low concen 110

HCG is produced by syncytiotropho blasts in the placenta during normal gesta tion and forms the basis for pregnancy tests for urine or serum samples; it is first de tected in plasma at five days and reaches a peak at eight to 10 weeks.6° l-ICG is a glycoprotein hormone of 45.000 molecular CA-A CANCER JOURNAL FOR CLINICIANS

Alpha-Fetoprotein

Liver, Testis

Carcinoembryonic Antigen

Colon, Lung, Breast

Human Chorionic Gonadotropin

Trophoblastic Tumors, Germ Cell Tumors of Testis

Calcitonin

Medullary Cancer of Thyroid

Prostatic Acid Phosphatase

Prostate

CA-i25

Ovary

Immunoglobulins

Multiple Myeloma

weight, is composed of two peptide sub units, and is structurally similar to thyroid stimulating hormone (TSH), follicle-stim ulating hormone (FSH), and luteinizing hormone (LH) from the anterior pituitary. The alpha-subunits of the hormones have structural homology, but the beta-subunits have unique carboxyl terminals.6163 Anti bodies directed against the beta-subunits have replaced the older immunoassays for laboratory determination of HCG, since these antibodies detect only HCG and should have no significant cross-reactivity with the other related hormones. To deter mine the analytic specificity for HCG, however, it is nonetheless important to de termine the information about cross-reac tivity of a new antibody. Using the beta subunit specific assays, the normal serum concentration of HCG in the nonpregnant state is less than one ng/ml. The half-life of

HCG is approximately 24 hours.26'@°'62 HCG is produced by all tumors contain ing syncytiotrophoblastic tissue, as well as by several other cancers—carcinomas of VOL.38.NO.2 MARCH/APRIL 1988

the lung, gastrointestinal tract, breast, and ovary; melanoma; and lymphoproliferative disorders.M67 Unlike the situation in preg nancy, tumor production of HCG is accom panied by varying degrees of release of free subunits.59'62'63 Less than 30 percent of the nontrophoblastic tumors produce HCG, and these tumors usually produce smaller amounts of the hormone. HCG levels are also increased in some non-neoplastic dis eases.62 There is a linear relationship between the trophoblastic tumor mass and the serum HCG level,68 and serial HCG measure ments are used in high-risk patients with hydatidiform mole to identify those whose disease has progressed to cancer. 3,26,69 HCG's value in screening for nonsemi nomatous testicular tumors, however, is limited by a lower sensitivity of detection for early disease.70'7' Persistent high or ris ing levels of serum HCG following re moval of a hydatidiform mole indicate a need for further therapeutic interven tion.26,27 111

The serum levels of HCG usually fall rapidly following successful treatment, and a plateauing at high levels or increases dur ing therapy may indicate drug resistance with a need for reevaluation of the treat ment regimen. Some patients with chorio

carcinoma may show a paradoxical rise of HCG initially

following

treatment and clin

ical response.27-72 This is believed to be due to the differentiation of some previ ously nonproductive tumor cells to hor mone-producing cells and may also be due to cell lysis with release of the hormone; it does not necessarily reflect treatment fail ure. Serial measurements of HCG are therefore important in determining re sponse 27.28 Serum levels of HCG are also of prog nostic value. Circulating levels above 8,000 ng/ml are usually associated with a poor prognosis unless the patient receives intensive therapy.3.26.27.73

seen in approximately two thirds of patients with hepatomas and germ cell tumors of the testis.9'@2-77Cholangiocarcinomas do not

show any increase in serum AFP, and ele vations occur in less than 25 percent of patients with gastrointestinal, pancreatic, and lung cancers.77'8°Non-neoplastic dis eases of the liver—cirrhosis, hepatocellu lar necrosis, and hepatitis—can also cause increased levels ofAFP, and some patients with metastatic liver disease also show in creased serum levels. 10.81.82 AFP levels decline rapidly following surgical resection of hepatocellular carci nomas or treatment of testicular germ cell

tumors. Serial measurements are of value in determining the presence of residual dis ease or relapse.77-82'83 AFP is measured se rially together with HCG in patients with testicular germ cell tumors to provide a sensitive index of response to therapy and disease recurrence 30

Alpha-Fetoprotein

Carcinoembryonic

The discoveryin 1963by Abelevand col leagues of a novel protein in the sera of adult mice bearing hepatomas led to re newed interest in the identification of tumor markers.―74 The protein, AFP, is normally present in fetal mice. Initial studies using a relatively insensitive immunodiffusion technique showed the presence of AFP in most of the patients with clinically apparent hepatocellular carcinomas 75,76 AFP is a single-chain glycoprotein of 70,000 molecular weight.77 It has sequence homology with albumin and is the major plasma protein in the fetus.78 AFP is pro duced in the yolk sac, liver, and gastroin testinal tract of the fetus and reaches a peak serum concentration of three ng/ml at 12 weeks of gestation. The levels decline after birth and reach the adult levels of one to 25 ng/ml by age one.9-77'78 AFP's plasma half life is approximately six days. Although increases in serum AFP are found in patients with hepatomas, the use of AFP determinations with sensitive ana lytic techniques to screen for hepatomas in high-risk patients provides only a relatively low yield of early, treatable tumors.'2'79 AFP increases (greater than 40 ng/ml) are

CEA,

112

a cell

Antigen surface

glycoprotein

of

200,000 molecular weight,@ was identified in 1965 by Gold and Freedman by immu nizing rabbits with an extract of human colon carcinoma.2'85 CEA is present in em bryonic tissues in the gastrointestinal tract, pancreas, and liver during the first two trimesters of gestation. Adult tissues were initially thought to be devoid of the anti gen, but very sensitive assays utilizing an tibodies to specific epitopes on the mole cule have shown expression of the antigen

on cells of normal colonic mucosa, as well as on other tissues. 38.86-88The diversity of epitopes to which the antibodies are di rected also makes it difficult to compare the serum concentrations determined by differ ent antibodies or to switch between kit methods, although the commonly used RIAs set the upper limit at 2.5 ng/ml.89 The half-life of the molecule is variable, but following removal of a tumor source of CEA, the levels should return to normal in six weeks.9° Increases in serum CEA levels also oc cur in many benign diseases—inflamma tory bowel disease, benign liver diseases, renal disease, pulmonary inflammatory CA-ACANCER JOURNAL FORCLINICIANS

disease,and collagendisorders—and in heavy smokers.31'3The levelsin these situations are usually below 10 ng/ml.91'92 CEA elevations are associated with many cancers, including carcinomasofthe liver, lung, breast, and pancreas.93'@ Pa tients with colorectal polyps have a 20 per cent incidence of increased levels.3' Pre

operative CEA levels have a bearing on prognosis,

since they correlate

with the

Dukes' grading of colon cancer, with stages progressing from A2 to D showing increases in 25 to 80 percent of pa tients.22'97 Well-differentiated colon can cers produce CEA, but poorly differen tiated tumors lack CEA. Screening for

colon cancer with CEA is not useful be cause of the low sensitivity for early dis ease and the association of increased levels with nonmalignant diseases.3133 In pa tients with recurrent colonic polyps, how ever, serial determinations of CEA are used in clinical follow-up in conjunction with

other investigations.

clinical use. Some of these new markers are discussed below.

Prostate-Specific Antigen PSA is@a biochemically and' immunologi cally distinct molecule isolated in 1979 from the prostate gland.'°3 It has a molec ular weight of 33,000 and is a glycosylated single-chain peptide.'°3―°5 Itsfunctionin

the normal gland is unknown. Although the molecule is prostate specific. it is not pros tate tumor specific. In adult males, the nor mal serum levels measured with an enzy matic immunoassay are less than four

ng/ml.'°6 Investigations haveshown thatpatients with benign prostatic hyperplasia or stage A malignant disease have similar slight ele vations (mean of 4.8 ng/ml), but patients with stage B and more widespread disease have levels more than twice the upper limit of normal.'03 A combination of PAP ‘¿and PSA determination has been reported to improve the sensitivity for detecting the disease. 03107 It appears, however, that

In patients with CEA-positive colorec talcancers, post-therapy serial serumCEA determinations are indicative of residual PSA could be most useful in monitoring diseaseifthelevelsdo notdeclineby six therapy and disease progressions. 03. OR

weeks.25'39'9° Recurrence is also indicated

Lower pretreatment levels of PSA are also

by a rising CEA level, with the tumor marker increases preceding clinically de tectable disease, sometimes by months.98 False-positive elevations due to inflamma

correlated with a better prognosis. 103

tory disease are also seen, however, as are false negatives in .a few cases of recurrence

Neuron-Specific

Enolase

NSE is the brain neuronal form of the gly

enolase. It is present in or nonresponse to therapy. peripheral and central neuroendocrine CEA levelsin breastcancercorrelate cells.'°'@ Increases in serum levels have with thetumor stageand with metastatic been found in 69 percent of .94 newly diag disease; most patients have increased levels nosed patients with small cell carcinoma of

(greater than five ng/ml).'5'@ Following re section of the tumor and successful chemo therapy, CEA levels fall in breast cancer patients.34'35 The serial follow-up of CEA

level has been useful as an indicator of tumor recurrence. IS.OO@ 02

colytic enzyme

the lung, and it may be useful in monitoring treatment.@°―@ NSE levels in neuroblas toma, a childhood tumor arising in the sym pathetic ganglia or adrenal medulla, show a correlation with the stage of the disease and also provide a prognostic and therapeu

tic guide. 16.112114Very high levels are cor New Tumor Markers for Specific Cancers Many new tumor markers, primarily tu mor-derived, have recently become avail able (Table 4). Most of these have yet to be fully evaluated and introduced into routine VOL.38,NO 2 MARCH/APRIL 1988

related with advanced stage and poor prog nosis. In stages III and IV neuroblastoma,

both serum NSE and femtin are markedly increased) 12.115There is experimental evi dence that the ferritin in neuroblastoma

may be derived from the neoplastic cells. 18.116 113

Prostate-Specific Antigen

Prostate

Tumor-Associated Antigen (TA-4)

Uterine Cervix

CA-i9-9

Pancreas, Colon

CA-i5-3

Breast

NSE

Small Cell Carcinoma of the Lung, Neuroblastoma

CK-BB

Lung, Breast, Prostate

LD-1

Testis

Key: NSE = Neuron-specificenolase CK-BB= Creatine kinase, BB isoenzyme

CA-125 CA-l25 is a cell-surface glycoprotein as sociated with cells of ovarian carcinoma. but is not found in normal adult ovarian cells.''7 Serum CA-l25 levels in healthy adults are less than 65 U/I. Serum CEA levels are increased in less than 25 percent of patients with ovarian carcinomas. CA-125. however. may provide the sensi tivity needed: according to the results of one study. 75 percent of patients with ovar ian cancers were reported to have elevated levels of CA-l25.''@ Increases in serum CA-l25 also occur during menstruation and pregnancy. with values up to 140 U/mI 114

LD-1 = Lactate dehydrogenase-1

during the first and second trimesters. I 9 Serum CA-125 may also be elevated (greater than 4(X) U/ml) in patients with liver cirrhosis. When used together with serum CEA assay. CA- 125 improves the positive identification of ovarian carcino mas. The half-life of the marker in plasma is about six days. In a recent report, CA-125 determina tion in malignant effusions and ascites was used with cytologic findings to diagnose ovarian cancer.4―20 The utility of CA- 125 for monitoring therapy and prognosis is not fully determined, but initial studies suggest that the levels correlate with tumor size and recurrence. CA-A CANCER JOURNAL FOR CLINICIANS

CA- 125 is present in normal fallopian tubes, in the endometrium, and in ovarian surface epithelium involved in the inflam matory process. The mesothelium and res piratory epithelium also show the presence of the antigen.

New Tumor-Associated (Host-Response) Markers The presence of neoplastic cells triggers

varying degreesofhostresponse, including the activation of the immune system, with participation of lymphocytes and macro phages. A number of molecules produced by these cells have recently been identified. CA 19-9 These molecules—lymphokines and cyto CA 19-9isa glycolipid antigen, probably kines—modulate the immune response. the Lewisa blood group hapten, originally

isolated from a human colorectal carci noma cell line.'2' Although CA 19-9 serum levels have a concordance with CEA con centration, some gastrointestinal tumors

that are positive for CEA do not have de tectable levels of CA 19-9. The marker's value in colorectal cancer, when used in conjunction with CEA, remains to be deter mined, but increases in CA 19-9 in inflam matory bowel disease and biliary disease

may limit its use. In recent studies, CA 199 has been shown to be useful in the diag nosis of pancreatic cancer, since blood lev

els can help differentiate pancreatitis from cancer. 122.123In this group

of patients,

however, other inflammatory bowel dis ease needs to be ruled out as the cause of

abnormal levels.

Tumor-Associated

lnterleukin-2

Receptors

Interleukin-2 (IL-2 or T-cell growth factor) is a 15,000 molecular weight glycoprotein

secreted by activated T cells that exerts its effects on other T cells by binding to spe cific cell surface receptors.43 These recep tors are also induced by cell activation and

have been identified as a 55,000 molecular weightglycoprotein. The receptor protein is shed by the cells into circulation and can be detected by an immunoassay tech

nique.'28 The levels of soluble receptor in plasma could potentially be used as an in dicator of the host response to tumors and be helpful in monitoring therapy. IL-2 re ceptors are also found on activated B cells, and their presence on the cell surface has been used for immunocytochemical identi fication of hairy cell leukemia.

Antigen

Tumor-associated antigen (TA-4) was pur ified by Kato et al from human uterine

Tumor Necrosis Factor

cervical mucosa in 1977, and preliminary

Tumor necrosis factor (TNF), or cachectin,

studies indicate that the serum levels cor

is produced by endotoxin or gamma-inter

relate with the stage of cervical squamous

feron-activated macrophages. TNF is a 17,000 molecular weight polypeptide cy tokine that binds to specific cell receptors. TNF induces hemorrhagic necrosis of tu mors and has many other effects, both sys temic and immunoregulatory. It appears to

carcinoma.'24―25In a follow-up study, ele vated post-therapy serum levels were found in patients with short survival.'26

An immunoassay for a subfraction of the TA-4 antigen, called squamous cell car cinoma-associated antigen (SCC-antigen), has also been developed. In a study of pa tients with head and neck squamous cell carcinoma, TA-4 was found to be elevated in 45 percent of the patients before treat ment. Following treatment, disease recur rence was associated with elevated levels in 92 percent of the patients with initially abnormal values.'27 VOL.38, NO.2 MARCH/APRIL 1988

be a mediatorofgeneral inflammation, and recombinant TNF hasbeenusedinclinical trials toaugmentthehostimmune response in cancer patients.'29-'3° Sensitive assays for serum TNF levels are only now becom ing available for investigational use, and

the role of TNF as a marker for host re sponse in cancer patients remains to be established. 115

Neoptenn

Neopterin is a metabolite formed in macro phages and lymphocytes, from guanosine triphosphate.

Activated and rapidly prolif

erating cells produce increased amounts of neopterin, which can be detected in plasma and urine. It has been suggested that neop tern levels could be used as an additional marker for the immunologic response in the host to the tumor, but its clinical utility has

not been fully evaluated.'3' IL-2 receptors (soluble), TNF, and neopterin are all indicators of immune (lymphocyte and macrophage) activation. Since the activation may be in response to a tumor or a nontumorigenic stimulus, these indicators are not specific for re sponse to cancer. Tumor Markers of General Applicability Periodically, reports have appeared pur porting to show that a biochemical deter mination

is indicative

of the presence of

cancer, regardless of the type of tumor and clinical stage.'32'35 In some cases, the data are inadequate to fully evaluate the value of such a marker, but considering the tissue heterogeneity of tumors, the extent of clin ical stage, and the variation in individual responses to the presence of a cancer, such tests would have to overcome several hur dles. Many of these tests have been shown in rigorous

studies to lack the specificity

that would allow their use as general tumor markers. Tests of recent interest in this category are outlined below. Information

on other tests has appeared in a review by Klavins. 132 Nuclear Magnetic Resonance Plasma Lipids

of

Fossel et al recently described the applica tion of the technique of water-suppressed proton nuclear magnetic resonance (NMR) spectroscopy for the analysis of spectral patterns of plasma samples from patients with malignant and benign tumors, from normal controls, from patients without tu mors, and from women with normal preg 116

nancies.'36 This technique was selected on the basis of previous reports that cancer patients have changes in plasma lipid pro files. 137.138 The NMR spectra obtained in the study group were analyzed for lipopro tein line widths.

The data obtained in the study showed that healthy controls and patients with be nign tumors and non-neoplastic diseases had similar spectral line widths that were different from those obtained from plasma samples from patients with untreated can cers, including breast, gastrointestinal, genitourinary, hematologic, and lung can cers, and lymphomas. However, plasma from pregnant subjects and samples from patients with benign prostatic hyperplasia had NMR spectral features similar to those found in the group with cancer. In a sepa rate group of patients who had already undergone treatment for cancer, the line width data had a wide scatter. The reported NMR spectral informa tion is tantalizing and needs to be pursued further to answer the questions about the biochemical basis for the observations, the effect of therapy on the spectral changes, the findings in chronic inflammatory dis ease, and the replicability of the findings by other investigators. This technique of identifying “¿oncolipids― may have other limitations due to the highly sophisticated and expensive means of analysis; these lim itations could possibly be overcome by identification of the molecular basis for the

observed differences between the groups and by developing a biochemical tech nique, if feasible. Oncogenes and Their Products Oncogenes are viral genes that have the potential to induce neoplastic transforma tion in cells. The existence of oncogenes was initially postulated by Huebner and Todaro to explain the mechanism of viral transformation of cells.'39 Viral oncogenes of RNA-containing retroviruses cause neo plastic transformation in susceptible host cells.'39 It is believed that the retroviruses may have acquired these genetic elements from mammalian cells originally, during viral infection and replication, where these CA-A CANCERJOURNALFORCLINICIANS

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VOL. 38, NO.2

MARCH/APRIL1988

117

Oncogene

Product FunctIon

Cancer

sis

Growth Factor'

SimianSarcoma

erb-B

CellSurface Receptors'*

ChickenErythroblastosis

neu

Rat Neuroblastoma

mos

MouseMaloneySarcoma

HER-2/neu

HumanBreast Cancer

src

ProteinKinase

ChickenRousCarcinoma HumanCML Lymphosarcoma

abi

MouseAbelson Leukemia

yes

ChickenSarcoma

H-rae

GTPBinding

Rat,Harvey Sarcoma HumanCarcinoma Sarcoma

K-ras myc

HumanLeukemia Lymphoma DNABinding

ChickenMyelomatosis HumanCarcinoma,Sarcoma, Leukemia

N-myc

HumanNeuroblastoma

myb

ChickenMyelomatosis

cit-A

Undefined

Chicken Erythroblastoma

B Iym-1

HumanLymphoma

met

Human Osteosarcoma

Oncogenes are given a three-letter, lower-case designation indicatingthe tumor and/or species in which they were initiallyidentified.An upper-case preceding letter is a modifierto distinguishsimilarlydesignated but differentoncogenes.

•¿ Homologous to platelet-derived growth factor. •¿ ‘¿The oncogene product is similar to the intracellular-activated portion of the cell surface receptor for epidermal growth factor.

CML = Chronic myelogenous leukemia

118

GTP

Guanosine 5'-triphosphate

CA-ACANCER JOURNAL FORCLINICIANS

Cancer/Site

MarkerS'

Breast

CEA, CA 15-3, Alpha-Lactalbumin,

Colorectal

CEA, CA 19-9, Beta-HCG

Lung (Small Cell)

AFP, CEA, NSE, Antidiuretic Hormone,ACTH

Neuroblastoma

NSE, HVA, VMA (Urine), Plasma-Catecholamines

Prostate

PAP, PSA, Gamma-Seminoprotein

Regan ALP lsoenzyme

‘¿Only tumor-derived markers are indicated. Selected tumor-associated (host-response) markers (ferritin, immune complexes, and acute phase proteins) could also be included in the panels.

ACTH = Adrenocorticotropichormone

HVA = Homovallinicacid

AFP ALP CEA CK-BB

NSE PAP PSA VMA

= = = =

Alpha-fetoprotein Alkaline phosphatase Carcinoembryonic antigen Creatine kinase, BB isoenzyme

genes served regulatory functions in the cellular genome. ‘¿@‘ Genetic elements sim ilar to viral oncogenes have been identified in eukaryotic cells. This plausible mecha nism of evolutionary acquisition of regula tory mammalian genes is therefi@re sup ported by the observations that the oncogenes bear a close similarity to certain mammalian genes, that they code for prod ucts that are regulatory cellular compo nents, and that the oncogenes in the retro viruses are in some cases incomplete copies of similar cellular genes or are incorporated in the middle of other genetic compo nents. 41.142 The cellular counterparts of

VOL 38, NO 2

MARCH/APRIL 1988

= = = =

Neuron-specific enolase Prostatic acid phosphatase Prostate-specific antigen Vanillylmandelic acid

the viral oncogenes are known as proto oncogenes. These are believed to be ac tivated in cancers due to mutational or chromosomal rearrangement events (see figure). Table 5 summarizes information about many of the oncogenes that have been iden tified to date. Oncogene activation has been detected in some cancers. and their proba ble products have also been identified.'4@ The oncogenes are not specific for a partic ular cancer. Tests have been developed to detect oncogenes in human cancer tissues and for some of their products in body fluids. 43 u Panels composed of such tests 119

fordetection of theoncogeneproductsin

plasma or other body fluids may be poten tially useful for the detection of oncogene associated cancers in high-risk groups. Strategies for Use of Serum Tumor Markers

@

The clinical usesofindividual serumtumor markers available' in routine laboratory use are well established and fall into the follow ing categories: confirmation of clinical diagnosis, indication of response to ther

apy, .early or confirmatory indication of tumor recurrence as part of follow-up as sessment,

and assessment

of prognosis.

Screening in high-risk groups for tumors using tumor-derived markers like CEA has been shown to be unproductive.

Tumor Marker Test Panels Tumor marker test panels have been de vised, composed of tumor-derived and tu mor-associated markers; statistical criteria have been formulated for interpretation of the combination used and to guide the se lection most appropriate for a particular cancer. 145-147Such an approach is effort

intensiveiind although it is notwidely ac cepted, there are indications that it can be useful, as has been shown in studies on patients with lung and prostate can Experience is necessary, how ever, to determine if such an approach is clinically useful in patients being prospec

tively ‘¿followed for the more common forms of cancer. Such panelsforspecific cancersmight be composed of primary, tumor-derived markersas wellas selected tumor-associ

ated markers (Table 6). The individual panels could be evaluated for the selected tumor, at the time of diagnosis, before ther apeutic intervention, in comparison with benign and nonmalignant

conditions,

and

in different tumor stages. A panel tested in this preliminary setting could then be fur ther evaluated for changes attributable to

therapeutic response, prognostic value, The use ofThesemarkersinscreening for and disease recurrence, as well as for fac specific tumors,even inhigh-risk groups, tors not primarily related to the cancer being'studiecl, but -which could affect the is limited due to a lack of appropriate speci ficity and sensitivity. The newer tumor test result.

markers that are becoming available are for tumors for which markers were either pre viously unavailable or considered inade quate in some regard. In the latter case, such as for PAP in prostate cancer, there

Better Use of Currently Available Markers

are indications thatthe use of measure

More appropriate use could be made of individual markers already available. the clinical utility of the markers by en Screening in high-risk groups for tumors abling earlier stages of .the cancer to be using tumor-derived markers like CEA has detected.103 None of the markers that ‘¿have'been shown to be ‘¿unproductive. Most beenclaimedininitial studies tobe general markers do have a place in following thera indicators forcancerhave yetfoundappli peutic response, assessing prognosis, and cability, because of either a lack of sensi detecting relapse. Most of theseusesrely tivity for detection of early tumors or non on serial measurements of the marker with specificity due to pathologic alterations in analytic methods that provide consistent non-neoplastic diseases. results. Rather than simply utilizing a tu Strategies to increase the sensitivity mor marker test during the initial eval and specificity of tumor marker tests are uation of cancer, following the levels of discussed below. tumor markers serially against the back

ments of both PAP and PSA could increase

120

- CA-ACANCERJOURNALFORCLINICIANS

ground

of clinical

and other diagnostic

findings will enhance the value of the tumor marker in providing information that could be used in therapeutic decisions and evalu

ation of prognosis. This has clearly been shown to be the case for HCG in choriocar cinoma, and shows promise for other mark ers for specific tumors.

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Erratum: Author'sCorrection Dr. Alex Ferenczy, author of the article, “¿Laser Treatment of Patients with Condylomata and Squamous Carcinoma Precursors of the Lower Female Genital Tract,― published in the November/December 1987 issue (Ca 37:334—347.1987), has informed us that there was an error in the labeling of Tables 6 and 7, which appear on page 345. In both tables, the Failure Rates were inadvertently labeled Cure Rates. Thus, in Table 6, “¿Laser Treatment Results for Vulvar Intraepithelial Neoplasia (Multifocal Le sions),―for the 17 patients with laser margins of less than 5 mm, the failure rate (not the cure rate) was 23.5 percent; and for the 9 patients with laser margins of 10—20mm, the failure rate was 11.0 percent. Similarly, in Table 7, “¿Laser Treatment Results for Condylomata Acuminata of the Vulva and/or Anal/Perianal Regions,― for the 105 patients with laser margins of less than 5 mm, the failure rate was 20 percent; and for the 55 patients with laser margins of 10—20mm, the failure rate was 7 percent. However, in TableS, “¿Laser Treatment Results for Vaginal lntraepithelial Neoplasia,― which appears on the same page, the data are presented correctly, as cure rates. Thus, in Table 5, for the 5 patients with a single lesion, the cure rate is 100 percent; for the 15 patients with multifocal

lesions, the cure rate is 75 percent; and for the total of 20 patients, the cure rate is 80 percent.

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