Bauer, J.

Hayes, D. F.

Lemarchand, T.

Leyvraz, S.

Mach, J. P.

Perey, L.

Reymond, M.

Tondini, C.

van Melle, G.

English

PubMed

L Perey

DF Hayes

C Tondini

G van Melle

J Bauer

T Lemarchand

M Reymond

JP Mach

S Leyvraz

Crossref

British Journal of Cancer

Elevated CA125 levels in patients with metastatic breast carcinoma

Hayes, D.F.

Mach, J.P.

Serveur académique lausannois

Br. J. Cancer (1990), 62, 668-670SHORT COMMUNICATIONElevated CA125 levels in patients with metastatic breast carcinomaL. Perey', D.F. Hayes2, C. Tondini2, G. van Melle3, J. Bauer', T. Lemarchand4, M. Reymond4,J.P. Mach' & S. Leyvraz''Service d'Oncologie, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland; 2Laboratory of ClinicalPharmacology and Breast Evaluation Centre, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA;3Institut de Medecine sociale et pre'ventive, Universite de Lausanne; 4Laboratoire de biochimie clinique, CHUV, Lausanne; and51nstitut de biochimie, Universite de Lausanne, Switzerland.Several markers are available for evaluation and monitoringof patients with breast cancer. Approximately 40-70% ofpatients with metastatic disease have elevated CEA levels(Haagensen et al., 1978; Hayes et al., 1986; Myers et al.,1978; Tormey & Waalkes, 1978; Tormey et al., 1977), whileapproximately 70-95% of such patients have elevated CA15-3 levels. Moreover, serial CA15-3 levels are superior to CEAfor monitoring disease course (Fujino et al., 1986; Hayes etal., 1986; Maigre et al., 1988; Pons-Anicet et al., 1987; Ton-dini et al., 1988). Circulating levels of CA125 are elevated inmore than 80% of patients with epithelial ovarian carcinoma(Alvarez et al., 1987; Bast et al., 1983; Canney et al., 1984;Sekine et al., 1985) and antigen changes correlate withdisease course in these patients (Alvarez et al., 1987; Bast etal., 1983; Canney et al., 1984; Niloff et al., 1985). CA125levels have been reported to be greater than 35 U ml' inonly 12-18% of patients with breast cancer (Bast et al.,1983; Kawahara et al., 1986). Using a higher cut-off of65 U ml-', Omar and colleagues have reported elevatedCA125 levels in six of 33 patients (18%) with metastaticbreast carcinoma (Omar et al., 1989). However, little isknown about the correlation rate of this circulating antigenwith disease course in metastatic breast carcinoma.Between October 1987 and December 1988, at least threeserial serum samples were collected from 40 consecutivepatients with breast carcinoma. In 11 patients the first samplewas drawn when metastases were diagnosed, before initiationof any therapy for relapse. Twenty-nine patients hadpreviously received one or more modalities of treatment formetastatic disease prior to collection of the first sample andwere monitored during a subsequent treatment regimen.All patients were routinely staged before initiation oftherapy as follows: physical examination, alanine amino-transferase (ALAT), aspartate aminotransferase (ASAT),alkaline phosphatase (AP) and serum gamma glutamyl-transferase (SGGT), complete blood count (CBC), chest andbone radiographs, bone scan, and thoraco-abdominal CT-scan. If thoracic CT-scan only was performed, then patientshad an abdominal evaluation with US. During follow-up,physical examination was performed at least once a month.ASAT, ALAT, AP and SGGT were performed each month.Circulating antigens were assayed every 4 to 6 weeks atphysician discretion. Bone metastases were monitored bystandard radiographs and bone scans were performed only toevaluate new bone or an increase of previously present bonepain. Hepatic involvement was evaluated by abdominal ultra-sound and/or CT-scan if ASAT, ALAT, AP or SGGT wereelevated. Clinical course was scored as progressive disease(PD), stable disease (SD) or responsive disease (RD) accord-ing to the WHO criteria for clinical evaluation (Miller et al.,1981). Responsive disease included both complete and partialresponses.Serum was stored at - 20'C until assayed for CA125,CA15-3 and CEA. CA125 and CA15-3 were quantified byimmunoradiometric assays (Abbott CA125 kit, AbbottLaboratories USA and CIS ELISA CA15-3 kit, Saclay, Gif-sur-Yvette, France). CEA was determined by enzymeimmunoassay according to a procedure previously described(Buchegger et al., 1982). For each marker, a cut-off valuewas selected below which levels from 98.5% of healthy nor-mal women are found (BAST et al., 1983; Hayes et al., 1986).These cut-off levels may be compared since they providedsimilar specificities in normal women and were as follows:CA125, 35 U ml-'; CA15-3, 30 U ml-'; and CEA, 5.0 ng ml-'.The variation between the antigen level measured at maxi-mal clinical evaluation (AGm) and the initial antigen level(AGj) was expressed as a percentage of the initial level. Avariation of the antigen levels of > 25% from the initialantigen level was considered a significant change (Hayes etal., 1986; Lokich et al., 1980; Tondini et al., 1988). If theantigen levels never exceeded the cut-off value, then changes,even if > 25%, were not considered to correlate with diseasecourse. The correlation between antigen level variation anddisease course was determined separately for PD, RD andSD as previously described (Tondini et al., 1988). Among the40 patients, 18 were scored as PD, 15 as RD and seven asSD.Before initiation of treatment in previously untreatedpatients or before a change of treatment in previously treatedpatients, CA125 levels were above 35 U ml-' in 16 of 40patients (40%). CAl 5-3 was above 30 U ml' in 30 of 40patients (75%) and CEA was above 5.0 ng ml' in 21 of 39(54%) patients (one sample missing) (Table I). Although theobserved sensitivity of CA15-3 was higher, the differencesbetween the three assays were not statistically significant.Median values of the circulating antigens drawn at firstevaluation were: 25.5 U ml' for CA125 (range 3.0-3,045);94.5 U ml-' for CA15-3 (range 8.0-2,490) and 6.1 ng ml-'for CEA (range 0.3-348). In three of the 24 patients withTable I Sensitivity of circulating antigens in metastatic breastcancerAntigen(cut-off)CA125(35 U ml-')CA15-3(30 U ml-')CEA(5 ng ml-')Number of patients (%) with antigen levelsgreater than or equal to cut-off level16/40 (40%)-30/40 (75%)21/39b (54%)aNo statistically significant differences between the assays. bOnesample missing.Correspondence: L. Perey, Laboratory of Clinical Pharmacology,Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115,USA.Received 15 January 1990; and in revised form 9 May 1990.'." Macmillan Press Ltd., 1990Br. J. Cancer (1990), 62, 668-670CA125 LEVELS IN METASTATIC BREAST CANCER 669CA125 level below the cut-off at the first determination,CA125 increased >)25%, to a level above the cut-off, duringdisease course. In the eight patients with RD and with adecrease of CA125 levels of > 25%, the range of variationwas 45-98% (median 77%). The range of variation ofCA15-3 and CEA was similar in patients with RD (median70% and 80% respectively). In the seven patients with PDand with CA125 increase of > 25%, the range of variationwas 60-2,173% (median 668%). This is higher than themedian variation of CA15-3 and CEA in patients with PD(94% and 142% respectively).CA125 changes correlated with disease course in 17patients (42.5%), while CA15-3 changes correlated in 24patients (60%) and CEA changes in 16 patients (40%) (TableII). Although CA15-3 had a higher correlation, thedifferences between the correlation rates of the markers werenot statistically significant. The higher correlation withdisease course of CA15-3 levels compared to that of CEA isconsistant with previously published results (Hayes et al.,1986; Pons-Anicet et al., 1987; Tondini et al., 1988). Interest-ingly, the correlation with clinical course for CA125 wassimilar to that for CEA. Correlations of each marker weresimilar for PD and RD (Table II). All three circulatingantigens were poor indicators of SD. However, CA125 hadthe highest correlation rate for SD (CA125, 28%, CA15-3,14%; and CEA, 14%).The correlation of each marker when used separately wascompared to combinations of any two, and to all markerstogether. Combining CA125 and CA15-3 increased the cor-relation rate to 72.5% compared to 42.5% for CA125 and60% for CA15-3 alone. Combining CA15-3 and CEAresulted in a modest increase in correlation rate to 67.5%from 60% for CA15-3 and 40% for CEA alone. Combiningall markers together produced a correlation of 75%. Further-more, although combining CA125 and CEA resulted in acorrelation rate greater than either of the two alone (55%),this correlation was less than that of CA15-3 alone (60%).The difference between the correlation of the combined cir-culating antigens, either as doublets or all together, was not,however, significantly different from the correlation rate ofCA15-3 alone. These results confirm the previous report thatcombining CA15-3 with CEA did not enhance the clinicalutility of these markers in patients with metastic breastcancer (Tondini et al., 1988). However, in three patientsCA125 was elevated and correlated with disease course whileCA15-3 was never elevated and of no utility. Thus, althoughCA125 was not as commonly elevated in metastatic breastcarcinoma as CA15-3, when it was elevated the correlationwith disease course was as satisfactory as both CA15-3 andTable II Correlation of antigen level variations with diseasecoursePatients (%) with antigen levelvariations that correlated withDisease No. disease coursecourse patients CA125 CA15-3 CEAPD 18 7 (39%) 11 (61%) 8 (44%)RD 15 8 (53%) 12 (80%) 7 (47%)SD 7 2 (28%) 1 (14%) 1 (14%)Overall 40 17 (43%) 24 (60%) 16 (40%)CEA. In this regard, CA125 may be useful in specific caseswhen the other assays are not elevated.Our results suggest that CA125 levels are more commonlyelevated in patients with metastatic breast carcinoma thanpreviously reported. In this study, CA125 was elevated in40% of patients with metastatic breast cancer, almost threetimes as high as in prior studies (Bast et al., 1983; Kawaharaet al., 1986). Furthermore, CA125 levels correlated withdisease course in 42.5% of patients. Our population may bemore representative of patients with metastatic disease sinceCA15-3 and CEA levels parallel those of previous studies(Hayes et al., 1986; Tondini et al., 1988). Although desig-nated as a marker for ovarian cancer, CA125 is elevated inother adenocarcinomas arising from the pancreas (45-59%)(Bast et al., 1983; Haglund, 1986) and the gastrointestinalsystem (49%) (Bast et al., 1983). Our results confirm thatCA125 cannot be used to distinguish sites of origin of meta-static adenocarcinoma. Nor can the range of CA125 eleva-tion be used to distinguish the origin of metastatic adenocar-cinoma, since levels as high as 3,000 U ml- were seen inpatients with disseminated breast cancer. Serum CA125 levelsare also elevated in various benign diseases, including hepaticcirrhosis, hepatic granulomatosis and peritonitis (Ruibal etal., 1984), and in non-malignant pleural effusions (Pinto etal., 1987). Our patients with elevated CA125 had no knownbenign hepatic disease and two patients with chronicallyabnormal hepatic function tests, attributed to benignhaemangiomas documented by CT-scan, had normal CA125throughout their disease courses.In summary, CA125 is more commonly elevated in meta-static breast carcinoma patients than previously recognisedand can serve as a marker to monitor disease course ifCA15-3 is not elevated. However, the performance character-istics of CA125 in breast cancer are not as satisfactory as forCA15-3, which should be considered the marker of choice inpatients with disseminated breast carcinoma.ReferencesALVAREZ, R.D., TO, A., BOOTS, L.R. & 5 others (1987). CA125 as aserum marker for poor prognosis in ovarian malignancies.Gynecol. Oncol., 26, 284.BAST, R.C., KLUG, T.L., ST. JOHN, E. & 9 others (1983). A radioim-munoassay using a monoclonal antibody to monitor the courseof epithelial ovarian cancer. N. Engl. J. Med., 309, 883.BUCHEGGER, F., METTRAUX, C., ACCOLA, S., CARREL, S. &MACH, J.P. (1982). Sandwich enzyme immunoassay using threemonoclonal antibodies against different epitopes of carcino-embryonic antigen (CEA). Immunol. Lett., 5, 85.CANNEY, P.A., MOORE, M., WILKINSON, P.M. & JAMES, R.D. (1984).Ovarian cancer antigen CA125: a prospective clinical assessmentof its role as a tumor marker. Br. J. Cancer, 50, 765.FUJINO, N., HAGA, Y., SAKAMOTO, K. & 4 others (1986). 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Cancer, 59, 218.PONS-ANICET, D.M.F., KREBS, B.P., MIRA, R. & NAMER, M. (1987).Value of CA15-3 in the follow-up of breast cancer patients. Br. J.Cancer, 55, 567.RUIBAL, A., ENCABO, G., MARTINEZ-MIRALLES, E. & 4 others(1984). CA125 seric levels in non malignant pathologies. Bull.Cancer (Paris), 71, 145.SEKINE, H., HAYES, D.F., OHNO, T. & 5 others (1985). CirculatingDF3 and CA125 antigen levels in serum from patients withepithelial ovarian carcinoma. J. Clin. Oncol., 3, 1355.TONDINI, C., HAYES, D.F., GELMAN, R., HENDERSON, I.C. & KUFE,D.W. (1988). Comparison of CA15-3 and carcinoembryonicantigen in monitoring the clinical course of patients with meta-static breast cancer. Cancer Res., 48, 4107.TORMEY, D.C. & WAALKES, T.P. (1978). Clinical correlation betweenCEA and breast cancer. Cancer, 42, 1507.TORMEY, D.C., WAALKES, T.P., SNYDER, J.J. & SIMON, R.M. (1977).Biological markers in breast carcinoma. III. Clinical correlationswith carcinoembryonic antigen. Cancer, 39, 2397.

Elevated CA125 levels in patients with metastatic breast carcinoma.

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Elevated CA125 levels in patients with metastatic breast carcinoma.

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Serveur académique lausannois