REVIEW

Tumour markers in gastrointestinal malignancy:

What use to the clinician?

RR Lll 'ER YACYSI IYN, MD, FRC PC , ( ,RANT D M 1\ t 'LEAN, MR. Ci JR, FRACP

BR YACYSHYN, GD MACLEAN. Tumour markers in gastrointestinal malig­nancy: What use to the clinician? Can J GastroenteroJ 1992:6(6) :329-333. A numbe r of tumour markers h ave been identified in patients wi ch gast ro intestina l malignanc ies. A ltho ugh these markers have limited clinical application , a knowledge of their use and shortcomings wi 11 he lp prepare for newe r applications 111 gastro intestina l on cology. Tumour markers recently have been used as a serological means of monitoring gastro intest ina l ma lignancy for recurre nce and have been stud ied experimentally by radionuclcotidc imaging using radiolabc llcd markers. More recently, the use of tumour antigens as specific can cer vaccines has aurac tcd the auencio n of gastro intestina l oncologists as therapeut ic agents.

Key Words: Active s/)ecific immu11otl1era/)y , Gastroi11tesd11al malignancy, T umour markers

De l'utilite des marqueurs de tumeurs pour le clinicien clans le cancer des voies digestives

Un certain nombre J c marquems J e tume urs ont ete identifies chez des gatients atreints de cancer des voies d igestives. Bien quc ces marque urs aicn t unc applica­tion clinique limitcc, une conna issance de lcur utilisation ct de lcurs inconvcniencs contri bue ra a u dcvcloppcmcnt de nouvcllcs aprlicat ions en on­cologie gast ro inccstina lc . Les ma rqucurs des tumeurs o ne rcccmmcnt cte utilises a titre de mcthodc scrologique pour survciller lcs recidives dans lcs cas de cance r Jes voies digestives ct one etc erudies cxpctimenta lcmcnt par l'imagerie a l'aiJ c Jc radio-nuclcoti<lcs utilisant des marqucurs radio -act ifs. Plus rcccmment , !'utilisation d'an tigenes anti -tumoraux a titre de vacc ins contre certa ins cance rs specifiqucs a attire !'attention des oncologues specia listcs Jes voics d igest ives, sur lcur emploi comme agents thcrapeutiques.

Deparrmmrs of Medicini> , U11i1•L1·siry u[ A lhena and Crn.,~ Cana,· /mriwr<', Edmonron, Alhena Co11"eS/)()nde1m.' and reprint.I: Dr 13 Y(1cysh\ln , l)e/1t.m mem of Medicine, Di1•isirn1 uf

Gasrruenrerolugy, 2 E3. I I \'(I airer Mackenzie H t!cdch Sciences Cen ere, Uniwrsit)' uf A/here a, Edmonrun. Alb<?na T6G 2/U . Telef>lwne (403) 492-5957, Fax (403) 492-3340

Rewwd for /mhlic11C111n M11y ., , / l)9 2. Acce/1Ccd ./ 1111<' 9, 199 2

CAN J GASTROENTERl11 Vni 6 Nl) 6 Nl WEMI\FR/DECE~IHH\ 1992

DURI Nl , Tl IE P;\~T !)El:Al)E, AJ)­

vance~ in chemistry and hyhrid­l1ma tcc hnolngy ha\'e cnah led the iJcrui ficat ion o( GlllCL'hl~M>Ciatcd ant igcm. W hat do these tumour markers mean ? Du they h,1\/l' c lin ical relevance ! C an they he u~ed for ~c romon itoring cance r pat ients! W hat

ha~ been the i mpnct nn the manage­ment u( gast roin test ina l ma lignam:ie, ? In add ition t () ,issays fo r Lnrc ino­emhryonic antigen (CEA) and alphn fctoprm cin, t hl'rc arc now ,1s,ays fo r such markers as CA 19-9 ,rnd CA l 2 5. Hllwcver, claims for the ir un li t)' have met with a mixture of e nrh u, 1a, m and cynic ism.

Mo ·t \l rhe rece ntl y Jcscn hcd tum\>ur marke r, arc glycnprnt c ins ur glycolipids. T hese are nnt c.mccr-spec­itk. However. t he re .1rc quanti tati ve tir qrn1li tativc Lhangc, in the exprcss1,m ol certa in 1 . .dycucnnjug,ne,; rn.in y d t hc,c ch ange, mi,e L'arly du ring malign.in t trnnsfnrmari nn . Hakrnnnri ( I ), in re­viewing rh c ;1hc rrnn t glycosylarinn found in cancer cells, has described these t um,1ur marke rs ,h likel y a rising from a bnormal nc tivatin n of glycnsy l transforase, or incomplete glyco~ylat i(\11 with precursor accumul.1tion . As J-h1ko­mnr i suggests, rh is aberrant glycn,y la-

l29

Y1\l 'Y:;I IYN ANn MACLEAN

tion is probably the end resul t of altered genes nr oncogenes. Some nf the ma rkers seen on cancer cells me nnr­m11 lly crypt ic within the membrane of no rmal cel ls and may also appc;:ir as a result of membrane conforma ti1)na l cha nges. However, some of the ma rke rs arc simply expressed in inc reased quan­tities compa red with norma l counte r­part ce ll s, while others a rc expressed by cclb where Lhe norma l counterpart ce lls J o not express such antigens but where the same antigens can be found on oth er cells e lsewhere in the hody ( for example, the express ion of hl1lod gmup antigens in colorcctal cancer ce lls).

O ld 's centra l h ypm hcsis shi fted the focus in immunn-oncnlogy from argu­me nts around 'immune surve illa nce' LO

acceptance of the basic 1enet - the ex is­tence of tumour-associated a ntigens (2) . While earlier researc h had focu~ed on transplantat ion antigens a nd mole­c ules re lated to the major hisw com­pmibility (MI-IC ) antigens, inte rest in the past 20 years has focused on the ahnnrmal express ion of g lycocnn ­juga tcs and pept ides which likely result from gene rearrangements or on­cogenes ( 3).

S tudy of the expression of cancer-as­sociated ant igens has also c reated new opportuni tics for detection of meta­stases using monoclo na l ant ihodics an~l immunoscint igraphy, anJ h as enahlcJ developme nt of rcsc.1rc h in to the potentia l of ,,ctivc specific immuno­therapy using 'cancer vaccines'. How might this impact tbe ma nagement of gastmin1 cstinal cancers?

BACKGROUND Various antigens have bee n propos­

ed and tested f(>r c linical diagnns i, and monitoring of disease states, including cancer. T hese include: norma l di ffe ren­tiation am igcns, MI-IC antigens, viral nntigcn~. oncogcnc-rclaccd antigens, oncofcrnl antigens a nd other glyco lipid m glycoprntc in antigens. Normal di f­fc rentint ion antigens include T, B and cellul ar activa tio n ma rkers, c linically used co diagnose and follow lymphoma. MHC a nt igens, clinica lly importan t in rejection of t ransplanted t issue, h ave hccn described as being cxprc~scd in cnlnrccta l carc inoma (4) as we ll as in

no

the intestina l mucosa in infla mmarury howel disease and celiac sprue (5).

Viral a ntigens, in par1 ic ular h epa­titi s B, arc s trongly assoc ia ted with hepatoccl lular carc inomn, which a lso is associated with the oncofetal a ntigen A lpha- 1-fc toprore in.

O ncogenes, o r ac tivated pmcn-on­cogcncs, may be ma rkers of a prcma lig­nan t state (6-8) . The knowledge that cellular oncogenes play a role in car­c inogen esis ha~ led m the ir study as diagnostic toob , fo r example, in colo­recrnl carc inoma where the RAS fa mily of oncogenes ha, hccn studied. T o date, they nrc more important fro m a patho lngirn I pe rspective in ncoplasia and have not evolved a diagnostic role (9).

A ltered carhohyJrn te molecules have hecn found on tumo ur cells ( I , I 0, I I ) . Some of these markers arc rclmed to human blood gro up antigens including Lewis (Le ) and the normally c rypt ic Tho1me n-FreiJenre ic h (TF) antigen , a precursor of the MN blood group amigens (42).

Recent reviews h ave descrihcd the appearance of TF and its related cpi­wpcs Tn and STn early during ma lig­n:mt trnnsfonnation in colonic mucosa, suggcsring the ir ut ility in the early his­LOlngical dcLecLion of gastrointestinal t ract cancer~ (1 ,10) . Of c linical rele­vance, TF cxpres~ion on c,m ccr ce lls has been associated with tumour ag­gress iveness and metastasis ( 12, J 3), poss ibly in the same way ,1dhesion molecules fac ilitate lymphocyte intcr­,ictiom ( 14).

SERUM MARKERS IN CLINICAL USE

Some of t he cell -surface cancer-as­sociated glycnconjugatcs appear to be useful t:-i rgc ts for the detec tio n of metastatic disease using mo noclona l antibodies a nd immunoscin t igraphy (1 5- 17). When shed in to scrum, some of these markers may have func tiona l significance, inc luding immunosup­prcss ivc effects ( 18). I lowcvcr, these scrum tumour marke rs may also be use­ful for Jl1l)J)itoring disease progressio n or rcspunse to therapy ( l 9) . Numerous serolugical rests wit h potentia l for mnnitnring o r de1ccting malignancy

have hccn described. Several of these arc now in routi ne clinical use - cg, CA 125 in mon itori ng ovarian cancer,, prownc specific acid phosphatase in mon itori ng prostate cancer, and f3 human chorion ic gonadotrophi n and a lpha fcwprote in in mo ni to ring germ eel l ca ncers.

W ith spec ific relevance rn the mcl nagc mcn t of gasLroin tcsti na l 1rac1 cancers, there arc three a reas where results to date have hecn encourag· ing: the immunohiswchcmic,11 iden ­t ifica t ion of cance rs using mon1l­clonal a nti hodies in vitro (20); radio­immunndeLectinn nf mernsrnses usi ng rndiolahcllcd monoc lonal a ntihodie~ (2 1 ); and th e pote ntial for sc mmon1-to ri ng wi th mo noclonal a ntibodies whic h d etect e lcva tcd serum levels of newl y idc n1 ifi ed cancer-as~oc iaced a ntigens in pat ients with meta~rntic disease (22) .

New marke rs, iden ti fied hy mono­clon,11 antihod1cs, currently he ing studied for uti lity in mam1ging gastro­intest ina l Lract cancers inc lude CA 15-3, CA 19-9 a nd CA 125, and may ndd to the marker~ currently used, CEA a nd a lpha fctoprotcin .

The key quest ion has hccn whether t hc~c marke rs have , uffic icn t spec­ific ity and ~emitivity co he clinica ll y useful. Because of the he terogenei ty of individua l cancer~ and the ir expression of t hese markers, recent reviews h ave descr ibed evaluating comhinat ions of tumour ma rkers in the hope of impnw­ing sensitivity, specific ity and clinical ut ility. In breast cancer, it appears that combinations of marker~ may have greater specific ity nnd pred ictive va lue (23,24). For colorecta l ca ncer, eleva­t ions of C EA (4YX)) and CA 19-9 (34 % ) arc not cl~ predictive as when comhincd with CA 125 a nd SLEX

(s ia lylaccd Lewis cpitopc) . However, the predict ive v,1lue was srill only 57% in one st udy (22).

Ratios of various marker, have been studied f{)r t he ir d iagnostic or prognos­t ic value. for example, in t he diagrn1sis of carc inoma of un known primary using logarith mic ratios, it has been pmposcJ that the ratio of C A 15-3 en C EA can be used to separate hrca~t carci noma from colnrecw l canCl' r ( 2 5 ).

C.I\N J GASTRUl'NT l: ROI V()! 6 Nu 6 Nl 1\1.MHI R/ DH HIHI R ! 992

SERUM TUMOUR MARKERS FOR GASTROINTESTINAL

CANCERS Carcinoembryonic antigen: T his well ­known fami ly of related glycoprote ins was first recognized by an antibody pro­duced in rabb its vaccinated with human colonic adenocarcinoma (26). Since the development of sensitive ra<lioassays, it has become apparent that elevations of C EA occur in a numhcr of benign conditions inc luding ~cvere liver disease, inflammatory le!>ion~ (especia lly of the ga~trointcsti n al tract), trauma, scp~is, infarction, renal impairmen t, collagen-vascular dise,1ses and moking (27). Its ex press ion is heccrogcnemts by cancers and fl uctuat ­ing trends have proven d ifficult to in ­terpret in clinical monitori ng, but it is the best studied marker in gastroinres­tmal oncolocgy. Due ro its relatively low specificity and sensi tivity, however, CEA is not useful as a sole d iagnostic test for prcviou~ly undetected cancer (28). Monitoring nf CEA ha~ hcen claimed co be uf henefi t in patients with elevated preoperative CEA levels (29). While ir is a common prac t ice to ev;.i l­uatc CEA leve ls rcguh1 rl y, for example every three months, there have been no studies which have confirmed that chi~ is beneficial to patients. However, the lack of benefit may reflect the lack of currently usefu l systemic therapy for colorectal cancers, as well as the hetero­genous expression nf CEA (with conse­quent misleading trends). CA 19-9: The antigen CA 19-9 i, the ,ialylatcc.l fo rm of the Lewb A antigen. It has been found in increased quan­tities in scrum of patients wi th colorec­tal, gastric and pancreatic cancer 00-32 ). However, while pat ients with hulky cancers often h;.ivc elevated CA L 9-9 leveb, most pmienb with earl y btagc cancers have norrnal levels. Thus, there i, limited value in trying to monitor pa­tients for the early detec tion of rcl;ipsc.

Among normal individuals, the highest values were found in women agc<l LO to 40 years. Elevated va lue, were also seen with pregnancy (33), ,uggcsting a relationship with hor­monal change,. Smoker,' va lues arc reportedly only minimally different from nonsmokers' 04 ).

Several ben ign J isca~c~ have CA 19-9 level~ elevated above those found in norma l individuals. Examples in­clude c irrhosis (35,36), cho lcsrasis (33,35,36), acu te renal fail ure (35), peritonitis (36), Jiabcre~ (35) and various autoimmune (33) and endo­c rine d iseases (36). ln tcrestingly, 5% of the North American population i, Lewi, ;1- b- and may be unable to

produce CA 19-9 (3 7). CA 19-9 is e levated in 2 7 to 60'Xi of

pmients with gasLric cancer wiLh a higher sens itivity (3 7%) and ~pecificiry (80 to LOO%) than CEA (38-40). ln patients with carci noina of the pancreas, CA 19-9 has a po~itivc predictive v;1 luc nf 59% and a negative predictive value of 92% (4 1 ). As a single ma rker, it has not been proven to have clinical uti li ty for seromonitoring. Perhap, it will he of use in a combined panel of diagnnst ic markers or as a rnr­get an tigen o r rad ioimmunodctecti on (42 ).

C A 125: This antigen, first dcscrihed using th e monoclonal antihody OC 125, appears to be a high molecular weight g lycoprote in (43) which has heen identified in colonic epithelium as well a~ pd\'iC organs and chc peritoneal cavity. Elevated levels of CA l2 5 have been reported in 80% of pmicnts wi th ep ithel ia l lWarian ca ncer (43) and em­ph;.isis has been on its use a~ a scrum marker for monitoring pati ents with nonrnucinous ovarian cancer ( 19,44 ). CA 125 is present in cerv ical mucous a nd has been found e levated during mcnstruacion and pregnancy ( 44-46). ln addi tion, scrum antigen clcvatiom occu r in patients with ben ign and malignant asc ircs (48,49), and have heen found elevated following hcan fai lure a nd even infectious mononucle­osis (unpublished data).

Eleva Led levels have a lsn been fuund tn serum of patients wirh carc inoma of the pancrca~. lung, hrc,ist a nd ga~tro­intc~t ina I trnct. However, CA 125 ha~ hcen disappointing as a diagnostic mar­ker for gastrointc~tina l malignancy. In stud ies to date, its greatest potentia l ;.ippear~ to be in combination with other markers such as CEA, CA 19-9 ,md SLEX in the management ,)! colo­rectal carcinoma (22).

CAN J GASTRL)ENTERl)t VOi 6 Nl) 6 NLWl:MBFR/DEl 'EMBI-R 1992

Gastrointestinal tumour markers

C A 15-3: CA 15-3 i~ nnlllhcr high molcculnr weight glycoprotein. At­tempts h;.ivc been made tn u"c CA I 5- 3 to fo ll ow paticms or to dete rmine prognosis in patients with mcrnsrntic breast ca n ce r. Elevated levcb in patients with benign liver di~ell.'le have heen shown (23,24). Tll d ate t h h marker'~ spec ificity ha~ precluded 1r from being used routinely in nonselecrcd c linical popubuons, and it has not been shown LO have clinical utility as a single marker fo r scro monitoring patient~ with gastni­intcstinal cancers. CA 50: CA 50, a more recentlydesrnh­ed marker for gast rointestinal trnct c,,n­cers, appe;.irs rn he related closely w CA l 9-9 and ha, hccn descri bed as the afucosyl form Df the sh1 lylatcd Lcwb amigen. Its cl inical u,c i~ st ill experi­mental.

SCREENING Recause of l.ick of necessary

speci fi ci ty and sen:,iti\'ity. no rumour marker has yet hcen shmvn to he cost­effec t ivc in pupulacion :,crccning. Fur­t hermore, n,mc has been shown to he reliable in reachi ng a definitive diag­nosis in a pat icnt with metasuiuc adenocarcinoma of unknown primary. T herefore, cautiun should be taken in making assumptiom when managing a pnticnt with cancer mctast,H ic LO tlw gastrointestinal tract who is found, Fur example, LO have nn elevated CA l 25 level. Similm ly, a metastasis ,1ssrn.: iatcd with elevated CEA 1s nlll necessarily gastmimcstinal in origin. Perhap.~ the greatest impediment to using scrum tumour markers in patients with gastrointest inal tract cancers effect i\'c­ly b the lack of chemorhcrnpy effecti ve against metasuuic disease. Arc there any therapeutic a lternatives? Active specific immunotherapy: T he expression of nit ercd carbohydrate mol­ecule" exprc~sed lll1 tumour Leib has led tl1 :,pcculat inn that these migh t he use­ful immunogem and targets for acnvc "pccific immunntherupy ( AS I ). Recent wmk has shmvn that shed rumour mark­ers may he immuno~uppressivc, inh ibit­ing an effect ive immune response agaim t the cancer. An Edmonton based group is stud yin g, in horh an imal

Yi\l 'Y'-.l !YN ANn M".l ' L l'".N

mndcl, and ea rl y cl inica l t ri,1ls , the potential o( synthet ic g lycoconjugares fo r AS ! in ,1denncarc inunws ( 14, 18). Cyc lophospha mide is used prior to AS! in an ,ll tempt to inhih it the suppresso r T ce ll ,1ctiv1ty induced hy the shed scru m mucin -a ss,1c iatcd g lycocon ­jugates.

In t he stud ies tn dat e of 2 3 pnricnts wi t h metastat ic O\'an an m hreast can ­cer, to xic ity has hecn mini mal. Most pmie nts have developed lrnpte n­specifi c immune rcspun, e, fo ll,l\ving AS!, wi th in vitro studie:,, showing c ytotox ic it y for relcv:mt tumour ce lls. Some patie nts wit h earl y mc rnstal ic breast cancer (o r m inima l d isease bur­den) appe,1r to ha VL' had c lin ic al o r rad io ll1gical responses LO this AS ! using syn t he tic 'vacc ine;. T he signi fi cance ,11 the,e rcsp,1nscs cannot he analyzed in these ph ,1 sc I st udies, hut phase 11 stud ie, arc plan ned for Jl,llien ts with luw d isease hurdc n from metastatic hreast or colo rectal cancers. T h is ap­proac h adds a new dimension to the

ACKNOWLEDGEMENTS: Many 1hanb 1,1 Wendy McEachern lor expert Sl'Cre1.uial a,;.,i,1ann: 111 prep;1r.1J 1lln of this manu:-crip1.

REFERENCES I. 1 lakt,mnn S. Aherr:1 111 glycu.,1,la1i,111 in

c incer cell mem hrn nes as f, icused nn glyc()l1p1,k Overview and perspl'l't ives. Caneer Re, I 98 >;4 5:2405.

2. Oki LJ. R,,yse EA. lmmunlllngy ,1f expel'l llll'llt :d lllll\\lrs. Ann Rev Mc,I 1964:15: 167.

3. W,,n .:el Rl), Phill ips C. Sehrciher 11. Multirle tumor sreedk :mtigem l'Xpressed on a smglc tumuur ce ll. Na1ure 1983:104:165.

4. Daar AS, Fugg lc SV, T ing A, Fahre JW. Anrnnalm1s expression of I IDL-DR on human colnrecwl cancer cell,. J lmmunnl 1982; 129:447.

5. Scntt H, Snlhe1m BG, Brnndtzneg r. Thnrsh\ E. HLA- DR like antigens 111 the epithelium of the human s1m1 II int estine. Sennd J lmmunnl 1980; 12: 77.

6. DuRois GC. Law LW. Appclla E. Punficat1on and bH1chem1cal pnipenies of u1mor-ass,,ci,1tcJ a111 1gen, from n1cliiylchulan1hrenc induced mu n Ill' s,m:11111:1,. Proc N.11 I Sci 1982:79:7669.

7. Cooper l ~M. Cellular 1rnmti,r111ing gene,. Science 1982;2 I 7:80 I .

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3,2

study of tumnur markers in colnrcc tal cancers. A rc there markers relevant in suppressing most immunity to t he c.rn­cer! Arc these markers c lues rn effec­t ive A SJ formu lations? Scromonitoring will hecomc rclcvnnt i ( A S! pro\'es to have a clin ical ro le in t hl' rhc rnpy of gastrointestinal cancers.

CONCLUSION In the past two decades, an ,1w:1 rc­

ness of aherrnn t glycosylat ion in can­cers and t he p11tcntial of h yhridt1ma tech nology has led rn a renewed or ­t imism in t he search for rumo ur mci rkers ,bsod a tcd with gast ro intes­t inal cnnccrs. T h e 'go ld srnmlard' has been C EA . Whi le rh is an tigen hm, no t proven as useful cl inicall y as 11riginall y hoped , it has scrv1:d as ,l re minder .incl n challe nge that gastro intestina l can­cers ma y have quan t itat ivcl y or qua Ii ta­ti vc l y inc reased expression of g lycopro­tc ins and glyco lipids which may have fut ure c linical util ity. Recen tly describ­ed ll1lH10cl,1nal ant ihodic, ag,1inst

Cl' llu lar ,,nu>genes .md mulrb1ep c;1rcinngenes1s. Science 198 3;222:77 1.

9. T ramc.:r DL, Kline T, McCabe FL,

10.

11.

12.

I 3.

14.

15.

ct al. Binlng1ca I charnct eri:nt ion .ind oncngene expressilln in human cnlol'l'ctal c.1rcinoma cell Imes. lm J Caneer 1988:41 :287. lt:kow11 : SI I. 8100111 EJ , Lob l WA, et al. A novel mucin :mtien a,soc iated with pmgnn, i, in cul,ll'ecrnl ClllCl'r p,H ient,. Cancer 1990;9: 160. H:1k()m11n S. G lycnsphmgolipids in cellulnr in1er,Kll1>11 , diffrrentiminn and ,mcogenes1,. Ann Rev Riochcm 198 1 ;50:731. Summers J L, Cllnn JS, WnrLI RM . Fal,ir WI I, Miller AW Il l, Weinstein RS. Prognllsb in rn rc inom,1 of the.: urinary hladder hased upon t i,sue bklllLI group A RH ,md Thums.:n­Freidcnrc1ch antigen srn ru, and bryotype ol the initial tum,,r. C:mcer Res 198 3;48:9 l4-9. Dow JA. di Sant 'Agnese, r. Cockett ATK. Expressi,111 ,if blond gn)up precursor T -nnugcn m, a prognu, 1 ic marker lor human hladder cancer treated hy hac ill w, calmettc-gucrin ,md intcrlcukin-2. J Un,! 1989; 142:978-82. Springer TA. Adhes ion rccc.:p1ors llf the immune system. Narurl' 1990; 146:425- 34. Macl enn GL), Lnngcnecker BM. C lin ica l significanc.: of I he Thnm,c.:n· Frc1dcnre1ch antigen. Scmin Cancer

1rnukcrs such a, C A 19-9, CA 12 5 and CA 50 have enabled , tudy ol thl· potentia l o f th ese markers 111 ,cl'llll1()n1-1,1ring, for iden ti ficminn o( response tn l hcrapy and for early de tec tion uf re lapse or recurrence of d isease after t reatmcnt. These same markers ma') also prove uscl'ul as targets lnr immunu­dctcc tion ,if metaswric disease u, ing rndio lahclled nwn,lcl11nal anrihndil·, a nd immunnsc intngr,iphy.

A n exc iting area of tumour marker appl ic::ir ion is the new fi eld of ASI. Result.'> from phase I stud ies in pa tient , with ovarian carc inoma and brea,1 c,111 -cer suggest t he val uc nf phase 11 st ud1e, to determine the response rntc to thi , tKWcl therapy. The study of tumnur m,1rkers has previously f\lcuscd on the pote nti al nf such marke rs for ;,eromoni­ro ri ng. Perhap~ L he detect io n of thc,e new m,1rkcr, b pniv iding rhe oppor­tunit y to undersrnnd hc u c r malignancy a nd to try much needed a l1c rnat1w manageme nt strategies fo r gastrom tcs­ti na l cnncers.

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20. Yuan M, lt:kol\'it: SI I, Ferrell LI), l'l nl. Exprc,sinn ,11 Lewi, X and s1:1lyln1 cd Lewi , X ,111t ig1:ns in human e,,lorectal polyp,. J Nm l C:rncl·r Inst 1987;78:479.

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