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Transcription

1 Plsm Prolctin Levels in Ptients with Brest Cncer DAVID P. ROSE, MD, PHD,' AND BRIAN T. PRUITT, MDt The plsm prolctin levels of 98 helthy women 22 to 65 yets old showed strong inverse correltion with ge. This reltionship persisted for older premenopusl nd postmenopusl women (ged 3 to 65 yers) whose results were compred with those of 34 premstectomy erly brest cncer ptients, nother 38 studied four to six weeks fter mstectomy, nd 38 with dvnced disese (ge rnge, 3 to 77 yers). There ws no correltion between ge nd plsm prolctin in ny of the brest cncer groups. When ptients nd controls were clssified ccording to their menopusl sttus, the premstectomy nd postmstectomy erly brest cncer groups both showed significntly higher prolctin concentrtions thn the corresponding controls (P <.1 in ll cses). These bnormlities were prticulrly prominent in the ptients studied fter surgery, lthough the difference ws significnt only for the postmenopusl groups (P <.5). Plsm cortisol nd urinry free cortisol levels were norml in postmstectomy ptients, suggesting tht stress ws not the cuse of elevted prolctin levels. In dvnced brest cncer, elevted plsm prolctin concentrtions were found only in the postmenopusl ptients. Cncer , ESPITE THE CONVINCING EVIDENCE tht prolctin D hs n importnt role in the development nd growth of some experimentl mmmry crcinom^,'^.^^ the sitution for humn brest cncer is less cler. Elevted plsm prolctin concentrtions were reported in ptients with metsttic di~ese'~.~' but could hve resulted from the response to the stress of severe illness. In erly brest cncer, some investigtors found no bn~rmlity,'*'~.'~,'~,~'*~~ while others observed incresed bsl plsm prolctin levels in proportion of their ptients.'~'~ A review of the literture22 indicted tht these conflicting results my hve risen, t lest in prt, from filure to tke into ccount the effects of ge nd menopusl sttus on circulting prolctin levels, the use of inpproprite controls, nd deficiencies in sttisticl nlysis. In the present study, we ttempted to void these confounding fctors when ssying bsl plsm prolctin in erly brest cncer ptients before or fter mstectomy nd in group with recurrent disese. Pr From The Division of Clinicl Oncology, Wisconsin Clinicl Cncer Center, University of Wisconsin Medicl School, Mdison, Wisconsin. Supported by reserch grnt nos. CA17579, CA1452 nd R25 CA from the Ntionl Cncer Institute. * Professor of Humn Oncology. t Reserch Associte, Deprtment of Humn Oncology. Address for reprints: D. P. Rose, MD, PhD, Division of Clinicl Oncology, Wisconsin Clinicl Cncer Center, 6 Highlnd Avenue, Mdison, WI Accepted for publiction November 13, 198. ticulr ttention ws pid to the influence of ge on the plsm prolctin level in both helthy women nd brest cncer ptients. Mterils nd Methods Assys were performed on 98 helthy women ged 22 to 64 yers, 59 of whom were premenopusl nd 39 beyond the menopuse. None were tking orl contrceptives, estrogens, phenothizines, or other drugs known to lter the plsm prolctin concentrtion. Plsm ws lso obtined from 34 erly brest cncer ptients on the dy before mstectomy nd from nother 38 ptients four to six weeks fter mstectomy. Plsm cortisol nd urinry free cortisol (UFC) excretion were lso determined in 18 premstectomy nd 2 postmstectomy ptients nd 23 with dvnced disese. A totl of 38 ptients with metsttic brest cncer ten weeks to six yers fter mstectomy ws lso studied, six of whom hd been treted previously by oophorectomy. The remining 32 in this group hd untreted dvnced disese, nd none hd received cytotoxic drug djuvnt therpy fter mstectomy. None of the cncer ptients were tking drugs known to cuse hyperprolctinemi. Plsm smples were obtined t 7 to 9 AM; the subjects were in resting stte. The smples were stored t 7 C. Prolctin levels were determined by rdioimmunossy;'2 regents supplied by the Ntionl Pituitry Agency, Ntionl Institutes of Helth, were used; nd the results were expressed in terms of humn pro 8543X/81/1215/2687 $.75 Americn Cncer Society 2687

2 2688 CANCER December Vol. 48 = 2.5 E \ r;l z 1.5 I 6 1. lx.5 cn J I I I I I I Q ool FIG. I. The reltionship between plsm prolctin (log,,,) nd ge for 73 helthy controls 3 to 65 yers old. r =.59. lctin N.I.A.M.D.D. VLS3. Plsm cortisol nd UFC ssys were performed s described previo~sly;~~ the 24 hr. urine collections commenced immeditely fter blood smpling. The plsm prolctin concentrtions were not distributed normlly in either the brest cncer or control groups but becme so fter logrithmic conversion. The log,, ws used for purposes of sttisticl nlysis by Student's t test. In ddition, the Mnn Whitney U test ws used to nlyze the dt; similr levels of significnce were obtined by the two methods. Vlues of P <.5 were regrded s significnt. For purposes of comprison, the upper limits of norml for plsm prolctin were defined s the corresponding control group men plus 2 SD. Results The 98 helthy women showed strong negtive correltion between the plsm prolctin concentrtion nd ge (r =.73). This influence of ge ws evident within the group of premenopusl norml women. The men ( f SD) plsm prolctin concentrtions for the 25 ged 21 to 29 yers ws 15.1? 5.3 ng/ml, wheres for the 34 ged 3 to 47 yers it ws 9.1 & 3.6 ng/ml (P <.1). The men plsm prolctin level for the 39 postmenopusl helthy women ws 4.9 k 2.2 ng/ml. The 73 helthy women ged 3 to 65 yers were designted the control group for comprison with the cncer ptients, whose ges rnged from 3 to 77 yers. The control plsm prolctin results, converted to the log,,, re plotted with ge in Figure 1 nd show the expected negtive correltion (r =.59). There ws no correltion between plsm prolctin nd ge in the erly brest cncer ptients (r =.11, Fig. 2) nor in those with recurrent disese (r = +.12, Fig. 3). For ll subsequent nlyses, the controls nd ptients were clssified ccording to their menopusl sttus. Regrdless of whether the smples were obtined before or fter mstectomy, both the premenopusl nd postmenopusl erly brest cncer groups hd elevted 2.5 t \ C 2. 6 Z 1.5 l I 1. K.'5L 2 nj. O O oo "8 O. O 8.* FIG. 2. Plsm prolctin (loglo) results for 34 premstectomy () nd 38 postmstectomy () ptients plotted with ge. c Y 2. CJ, F [r I I I I I I I. I FIG. 3. Plsm prolctin (loglo) levels in 38 dvnced brest cncer ptients plotted with ge.

3 No. 12 PROLACTIN LEVELS AND BREAST C A. Rose nd Pruitt 2689 TABLE I. Plsm Prolctin Levels (ng/ml)* in Premenopusl Helthy Women, Premstectomy nd Postmstectomy Erly Brest Cncer Ptients, nd Ptients with Advnced Brest Cncer Premenopusl Postmenopusl Plsm prolctin % elevtedt Plsm prolctin % elevted Helthy controls Erly brest cncer, premstectomy Erly brest cncer postmstectomy Advnced brest cncer 9.1 f 3.6 N = f 32.4$ N = * 25.3$ N = f 2.8 N=9 6% 29% 67% I I% 4.9 f 2.2 N = f 15.9$ N = f N = f N = 29 3% 5% 82% 59% * The vlues were converted to log,, before sttisticl nlysis by Student s t test. t Defined s the control group men + 2 SD. $ Significntly different from corresponding control group = P <. I. plsm prolctin concentrtions (Tble 1; P <.1 in ll cses). In ddition, higher levels occurred in the postmstectomy thn in the premstectomy ptients, lthough the difference ws sttisticlly significnt only in the older ptients (P <.5). The incidence of bnormlities ws greter in the postmenopusl ptients, both in smples obtined before mstectomy (5% versus 29%) nd fter surgery (82% versus 67%). Two premenopusl ptients with prolctin levels of 46. nd 58. ng/ml fter mstectomy were observed to hve glctorrhe from the remining brest t the time the plsm smples were tken for ssy. Tble 2 summrizes the plsm prolctin nd cortisol nd the UFC excretions for the cncer ptients nd controls. Despite the elevted plsm prolctin concentrtions, the corticosteroid levels were norml in the brest cncer groups. In dvnced brest cncer, only the postmenopusl group showed elevted plsm prolctin levels (Tble 1 ). Thirteen of the 23 (57%) nturlly postmenopusl ptients nd four of the six who hd been treted previously by oophorectomy hd incresed levels when compred with the postmenopusl control vlues. Discussion The present study demonstrted negtive correltion between ge nd plsm prolctin level in helthy women but not in the brest cncer ptients. There is direct reltionship between chnges in the plsm estrdiol nd prolctin concentrtions during the menstrul cycle,8 nd reduction occurs in the circulting estrdiol level s womn pproches the menopuse.26 This decline in the ovrin function of older premenopusl women ccounts for the decrese in plsm prolctin levels with ge tht we observed in the premenopusl control group. While some previous investigtors hve lso reported n influence of ge or menstrul function on the plsm prol~tin,~~.~~ others filed to observe such n ss~cition.~ ~ Investigtions of bsl plsm prolctin levels in brest cncer hve yielded conflicting results. Kw et ~ 1. detected ~ no bnormlities in ptients, some of whom hd recurrent disese, studied t n unspecified time fter mstectomy. Their results were not nlyzed in reltion to menopusl sttus, but the medin ges of the ptients (51 yers) nd controls (54 yers) were TABLE 2. Plsm Prolctin (PrL) nd Cortisol (C), nd Urinry Free Cortisol (UFC) Excretion (Men f SD) in Helthy Controls nd Brest Cncer Ptients Plsm PrL Plsm C U FC Age ng/ml pg/ I ml ~ / 2 hr 4 Controls (I 8) 47 * f f f 18.4 Premstectomy (18) brest cncer 57 f k 31.4: 12.9 f f 25.1 Postmstectomy (2) brest cncer 47 f II 3.2 f 27.8* 11.6 f f 27.4 Advnced (23) brest cncer 51 f f 15.2* 13.4 * f 25.8 The number of subjects in ech group is given in prentheses. * Significntly different from the control group, P <.1 (Mnn Whitney test).

4 269 CANCER December VOl. 48 similr. Sheth et l.* determined plsm prolctin in 98 brest cncer ptients of unspecified disese stge nd in premenopusl nd postmenopusl women. No bnormlities were found in the cncer ptients, but number of the controls, prticulrly those studied fter the menopuse, hd plsm prolctin levels considerbly higher thn the vlues obtined by most other investigtors using the sme N.I.A.M.D.D. stndrd. Ptients with benign brest disese were used s controls in some brest cncer studies in which no bnormlities were However, this my hve been n inpproprite choice; other hormonl bnormlities re known to be common to the two di~eses,~.~~ nd some ptients with benign lesions hve elevted plsm prolctin levels.6 In the present study, incresed plsm prolctin concentrtions were found in both premenopusl nd postmenopusl brest cncer ptients with operble disese. The bnormlities were prticulrly prominent in smples obtined four to six weeks fter mstectomy. Although the norml plsm cortisol levels nd UFC excretions render it unlikely tht these results rose from stressmedited prolctin relese, the very high vlues should still be interpreted with cution. Surgicl trum3 nd other injuries to the chest wll hve been ssocited with n increse in plsm prolctin nd glctorrhe, nd presumbly mstectomy my hve the sme effect. The extent of the stimulus involved is illustrted by the occurrence of glctorrhe in two of our ptients. Elevted plsm prolctin levels were found in 59% of nturlly postmenopusl nd surgiclly cstrted ptients with metsttic brest cncer, but in only one of nine premenopusl ptients. There were no pprent differences in the extent of metstsis or tumor burden between the two groups, nd there ws no evidence to suggest tht the postmenopusl ptients were subjected to greter degree of diseserelted stress. Although most previous investigtors filed to detect ny bnormlity of plsm prolctin in brest cncer ptients, Aldinger et l. hve lso reported elevted levels of the hormone. They ssyed smples from 16 premenopusl nd 29 postmenopusl norml women nd 148 brest cncer ptients. When the results were nlyzed, however, the controls were considered s single group. The plsm prolctin ws incresed in 24% of ptients with operble primry brest cncer, who were studied t n unspecified time fter mstectomy, nd in 19% of ptients with metsttic disese. The role of prolctin in the growth of rt mmmry crcinoms is well e~tblishedl~.*~ by suppressing plsm prolctin concentrtions, both ergot derivtives nd nlogues of luteinizing hormonerelesing hormone23 re effective ginst some of these tumors. In contrst, the significnce of elevted plsm prolctin levels in humn brest cncer remins to be determined. Although some humn brest cncers contin prolctin receptors,l1s2 nd prolctin increses the estrogen receptor content2 nd generl protein synthesis in the MCF7 cell line, ntiprolctin drugs hve proven to be of little vlue in treting the disese. A possible explntion for this filure is tht humn growth hormone, circulting levels of which re unffected or even incresed by prolctinsuppressing drugs, is lctogenic nd binds effectively to the prolctin receptor.28 Perhps, the elimintion of both peptide hormones is necessry to chieve therpeutic response in humn brest cncer. REFERENCES 1. Aldinger KA, Schultz PN, Blumenschein GR, Smn NA. Thyroidstimulting hormone nd prolctin levels in brest cncer. Arch Intern Med 1978; 138: Brrett A, Morgn L, Rggtt PR, Hobbs JR. Bromocriptine in the tretment of dvnced brest cncer. Clin Oncol 1976; 2: Berger RL, Joison J, Brvermn LE. Lcttion fter incision of the thorcic cge. N Engl J Med 1966; 274: Brennn MJ, Bulbrook RD, Deshpnde N, Wng DY, Hywrd JL. Urinry nd plsm ndrogens in benign brest disese. Possible reltion to brest cncer. Lncer 1973; 1: Burke RE, Gffney EV. Prolctin cn stimulte generl protein synthesis in humn brest cncer cells (MCF7) in longterm culture. Life Sci 1978; 23: Cole EN, Sellwood RA, Englnd PC, Griffiths K. Serum prolctin concentrtions in benign brest disese throughout the menstrul cycle. Eur J Cncer 1977; 13: Europen Brest Cncer Group. Clinicl Tril of 2Brergocriptine (CB 154) in dvnced brest cncer. Eur J Cncer 1972; 8: Frnchimont P, Dourcy C, Legros JJ, er /. Prolctin levels during the menstrul cycle. Clin Endocrinol 1976; 5: Frnks S, Rlphs DNL, Segrott V, Jcobs HS. Prolctin concentrtions in ptients with brest cncer. Br Med J 1974; 4: Heuson JC, WelbroeckVn Gver C, Legros N. Growth inhibition of rt mmmry crcinom nd endocrine chnges produced by 2Brergocryptine, suppressor of lcttion nd nidtion. Eur J Cncer 197; 6: I. Holdwy IM, Friesen HG. Hormone binding by humn mmmry crcinom. Cncer Res 1977; 37: Hwng P, Guyd H, Friesen H. A rdioimmunossy for humn prolctin. Proc Nil Acd Sci USA 197 I; 68: Jones MK, Rmsy ID, Collins WP, Dyer GI. The reltionship of plsm prolctin to 174 oestrdiol in women with tumours of the brest. EurJ Cncer 1977; 13: Kw HG, De JongBkker M, Engelsmn E, Cleton FJ. Plsmprolctin in humn brest cncer. Lncer 1974; 1: Mnni A, Trujillo JE, Person OH. Predominnt role of prolctin in stimulting the growth of 7,12dimethylbenz()nthrceneinduced rt mmmry tumor. Cncer Res1977; 37: Mittr I, Hywrd JL, McNeilly AS. Hypothlmicpituitryprolctin xis in brest cncer. Lncet 1974; 1: Morley JE, Dwson M, Hodgkinson H, Klk WJ. Glctorrhe nd hyperprolctinemi ssocited with chest wll injury. J Clin Endocrinol Merbol 1977; 54:

5 No. 12 PROLACTIN LEVELS AND BREAST CA. Rose nd Pruitt Murry RML, Mozffrin G, Person OH. Prolctin levels with LDOPA tretment in metststic brest crcinom. In: Boyns AR, Griffiths K, eds. Prolctin nd Crcinogenesis, Crdiff Alph Omeg Alph, 1972: Ohgo S, Kto Y, Chihr K, lmur H. Plsm prolctin responses to thyrotropinrelesing hormone in ptients with brest cncer. Cncer 1976; 37: Prtridge RK, Hhnel R. Prolctin receptors in humn brest crcinom. Cncer 1979; 43: Person OH, Lleren, Lleren L, Molin A, Butler T. Prolctindependent rt mmmry cncer: model for mn? Trns Assoc Am Physicins 1969; 82: Rose DP. Endogenous hormones in the etiology nd clinicl course of brest cncer. In: Rose DP, ed. Endocrinology of Cncer, vol. 1. Boc Rton: C.R.C. Press, 1979: Rose DP, Pruitt B. Modifiction of the effect of gondoliberin nlog on 7,12dimethylbenz()nthrceneinduced rt mmmry tumors by hormone replcement. Cncer Res 1979; 39: Rose DP, Stuber P, Thiel A, Crowley JJ, Milbrth JR. Plsm dehydroepindrosterone sulfte, ndrostenedione nd cortisol, nd urinry free cortisol excretion in brest cncer. Eur J Cncer 1977; 13: Shfie S, Brooks SC. Effect of prolctin on growth nd the estrogen receptor level of humn brest cncer cells (MCF7). Cncer Res 1977; 37: Shermn BM, West JH, Korenmn SG. The menopusl trnsition: nlysis of LH, FSH, estrdiol, nd progesterone concentrtions during menstrul cycles of older women. J CIin Endocrinol Metbol 1976; 42: Sheth NA, Rndive KJ, Suriy JN, Sheth AR. Circulting levels of prolctin in humn brest cncer. Br J Cncer 1975; 32: Shiu RPC, Friesen HG. Properties of prolctin receptor from the rbbit mmmry glnd. Biochem J 1974; 14: Thoms BS, Kirby P, Symes EK, Wng DY. Plsm dehydroepindrosterone concentrtion in norml women nd in ptients with benign nd mlignnt brest disese. Eur J Cncer 1976; 12: Vekemns M, Robyn C. Influence of ge on serum prolctin levels in women nd men. Br Med J 1975; 4: Willis KJ, London DR, Wrd HWC, Butt WR, Lynch SS, Rudd BT. Recurrent brest cncer treted with the ntioestrogen tmoxifen: correltion between hormonl chnges nd clinicl course. Br Med J 1977; 1: Wilson RG, Buchn R, Roberts MM, ef l. Plsm prolctin nd brest cncer. Cncer :