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(CANCER RESEARCH 52, 4719-4723. September I, 1992]

Influence of Tamoxifen on Plasma Levels of Insulin-like Growth Factor I andInsulin-like Growth Factor Binding Protein I in Breast Cancer Patients1

Per Eystein L0nning,2 Kerstin Hall, Asbj0rn Aakvaag, and Ernst A. Lien

Departments of Oncology Â¡P.E. L.J, Internal Medicine [E. A. L.J, and Biochemical Endocrinology [A. A.], Haukeland University Hospital, N-502I Bergen, Norway,and Department of Endocrinology, Karolinska Sjukhuset, S-I04 01 Stockholm, Sweden [K. H.J

ABSTRACT

Plasma levels of insulin-like growth factor I (IGF-I) and insulin-likegrowth factor binding protein I (IGFBP-I) were measured in fasting

blood samples obtained from 16 postmenopausal breast cancer patientsbefore and during tamoxifen treatment for 1 to 6 months. Tamoxifensuppressed total plasma IGF-I by a mean of 28.5% (/' < 0.001) butelevated plasma IGFBP-I by a mean value of 78% (/' < 0.001). Changes

in plasma levels of growth hormone, insulin, or insulin C-peptide were

not observed. These findings suggest that tamoxifen exerts its influenceon plasma IGF-I and IGFBP-I by mechanisms other than those known

to regulate the plasma levels of these peptides, primarily growth hormone and insulin, respectively. A dual effect suppressing plasma IGF-Iand elevating plasma IGFBP-I suggests that tamoxifen may have a

significant influence on endocrine and possibly paracrine delivery ofIGF-I to breast cancer cells in vivo.

INTRODUCTION

Tamoxifen is the endocrine treatment modality most frequently used for the treatment of breast cancer. About two-thirds of the tumors of postmenopausal breast cancer patientsthat express positive estrogen receptor values may respond totamoxifen when this drug is given as the first-line endocrinetreatment for metastatic disease (1, 2). While tamoxifen isthought to act by blocking estrogen stimulation of the tumorcell, certain observations are not explained by this "classical"

model. First, we do not know why one-third of the patients withestrogen receptor-positive tumors do not respond to the drug.Second, it is not known why patients develop resistance totamoxifen therapy. In most cases resistance is not due to theovergrowth of endocrine-resistant cells, since tumors resistantto tamoxifen after an initial response may successively respondto other forms of endocrine drugs like aromatase inhibitors (3).Alternative mechanisms for tamoxifen action have been suggested (4-6), but there is no general agreement concerning thecontribution of any of these mechanisms to the effect of tamoxifen in vivo.

Insulin-like growth factor I is a potent mitogen for breastcancer cells in vitro (7, 8). The majority of human breast cancerscontain receptors for IGF-I3 (9-12), and antibodies blockingthe IGF-I receptor have been shown to inhibit the growth ofseveral breast cancer cell lines in vitro (13). These findingssuggest that IGF-I may play a key role in controlling breastcancer growth through autocrine, paracrine, or endocrine stimulation.

Tamoxifen has been shown to suppress plasma levels of totalIGF-I (14-16). The majority of IGF-I in plasma circulates

Received 2/28/92; accepted 6/19/92.The costs of publication of this article were defrayed in part by the payment of

page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1Supported by grants from the Norwegian Cancer Society and the SwedishMedical Research Council.

2 To whom requests for reprints should be addressed.3 The abbreviations used are: IGF-I, insulin-like growth factor I; IGFBP-I, in

sulin-like growth factor binding protein I; CV, coefficient of variation; GH. growthhormone.

bound to proteins (IGFBP). It has been postulated that thebiological effect of plasma IGF-I may be modulated through

changes in the concentration of its binding proteins. The binding protein IGFBP-I has been suggested to have a biologicalrole as a buffer regulating the level of free IGF-I as this bindingprotein, contrary to total IGF-I, undergoes rapid diurnal variation ( 17). In this study we measured plasma levels of IGF-I andIGFBP-I in 16 fasting postmenopausal breast cancer patientsbefore and during a 6-month period on tamoxifen therapy. Wealso measured the plasma levels of growth hormone, insulin,and the insulin-C- peptide, since growth hormone and insulinare known to be the major physiological factors controllingplasma IGF-I and IGFBP-I levels, respectively (18, 19).

PATIENTS AND METHODS

Patients. Sixteen postmenopausal breast cancer patients who shouldstart tamoxifen therapy were enrolled in the study. Their median agewas 62.5 years (range, 46 to 76 years). A 46-year-old patient had had ahysterectomy 10 years before, and estradiol values before and duringtamoxifen therapy were in the postmenopausal range. One patient received tamoxifen 20 mg once daily as adjuvant therapy; the other patients received tamoxifen 30 mg once daily for primary stage III or IVdisease (8 patients) or due to relapse of breast cancer disease (7 patients). No patients had a diagnosis of diabetes or glycosuria.

Blood Sampling. Blood samples were taken from all patients beforecommencing tamoxifen therapy and after 1 to 6 months on tamoxifentreatment. A total of 2-5 blood samples were taken from each patient.

Fasting blood samples (20 ml in heparinized tubes) were obtained byvenipuncture together with blood samples obtained for routine analyses. Sampling was usually performed between 8 a.m. and 11 a.m., but ina few cases as late as 1 p.m. in some patients living a long distance fromthe hospital. Usually there was little intraindividual variation in sampling time, and there was no trend in favor of an earlier or later time forblood sampling in the control situation compared to time for bloodsampling on treatment.

Plasma was separated by sentrifugation within 30 min and stored atâ€”¿�20Â°Cuntil analysis.

Hormone Analysis. All samples from each patient were analyzed inthe same batch.

IGF-I was measured with a radioimmunoassay after acid ethanolextraction using des 1-3 IGF-I as ligand as previously described (20).When used as the standard this recombinant IGF-I (KabiGen Stockholm) does not differ significantly from the International Standard. TheCVs within and between assay were 5% and 11%, respectively. Thenormal ranges (x Â±2SD) of immunoreactive IGF-I in the age groups30-49 years, 50-69 years, and above 70 years were 15-42.6, 11.8-31.5,and 10.2-22 nivi,respectively.

In addition, IGF-I was measured using a commercial radioimmunoassay from Incstar Corporation (Stillwater, MM), using the procedure recommended by the manufacturer. This includes acid extractionof the plasma sample and chromatography on CIS Sep-Pak Plus cartridges from Waters Chromatography (Milford, MA). The methanoleluate was evaporated to dryness. The residue was reconstituted in zerostandard and assayed for immunological activity. The mean recoverythrough the extraction chromatography was 76.5%, and the CV withinand between assay was 10.0% and 15.3%, respectively, for a sample of13.4 nin. The normal range was 9-48 n\i for the whole age group.

4719

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IGF-I, IGFBP-I, AND TAMOXIFEN

IGFBP-I was measured by a radioimmunoassay as previously described (21). The intraassay and interassay CVs were 3% and 11%,respectively. The mean and range of IGFBP-I in healthy subjects aged30-70 years were 30 and 15-60 ng/ml.

Growth hormone and insulin in plasma were measured by commercial radioimmunoassay kits from Pharmacia (Uppsala, Sweden). Precision expressed as CV between assay was, for growth hormone, 9.2%for a sample of 10.2 Munits/ml and, for insulin, 8.8% for a sample of 111I>M.Insulin-C-peptide in plasma was quantitated using a radioimmunoassay kit from Diagnostic Products Corporation (Los Angeles, CA),with a between-assay precision of 11.3% for a sample of 1.1 HM.

Statistical Analysis of Data. Because the number of blood samplesobtained during treatment varied, the mean value of the samples duringtreatment was calculated for each patient and compared to the controlvalue obtained before treatment using the Wilcoxon matched-pairsigned-rank test. To test for a possible trend related to the duration oftreatment, control and treatment values from the nine patients who hadblood samples obtained after 1-2 months and after 3-4 months ontamoxifen therapy were compared by using the Friedman nonparamet-ric analysis of variance. If this test revealed a statistically significantdifference, values obtained in the different situations were compared bythe Wilcoxon matched-pair signed-rank test using a Bonferroni correction for the final P value. Trends were analyzed by using the Spearmanrank correlation coefficient (rs) unless otherwise specified. IGF-I valuesmeasured by the two different radioimmunoassays were compared using linear regression analysis. All P values were expressed as two-tailed.

RESULTS

Pretreatment Hormone Levels. Before tamoxifen treatmentthe mean value of plasma IGF-I measured in acid ethanol extracts was 22.2 n\i (range, 8.7 to 41.8 HM)when des 1-3 IGF-Iwas used as the tracer. Thirteen of 16 patients had plasmaIGF-I levels within the normal range for age. One patient aged70 years had a value (34.8 n\i) slightly above the normal rangefor age, but normal GH values. Two patients (64 and 77 years)had values below the normal range (10.4 and 8.6 ni\i), but measurable GH concentrations in these patients exclude GH deficiency. Using the commercial kit assay the mean plasma levelfor IGF-I was 16.1 n\i (range, 7.6 to 25.0 nivi). When IGF-Ivalues measured by the two different radioimmunoassays werecompared by linear regression analyses after logarithmic transformation, an R value of 0.91 (P < 0.001) was found.

The mean level of plasma IGFBP-I before tamoxifen treatment was 38 ng/ml (range, 18 to 76 ng/ml). All values werewithin the normal range. Mean values of growth hormone,insulin, and insulin C-peptide were 2.2 /iU/ml, 75 pivi,and 0.7nM, respectively. GH concentration ranged from undetectableto 6.8 iiU/ml. One patient had slightly elevated levels of insulinand C-peptide before treatment, two patients had plasma insulin and C-peptide at the upper normal level, and one patient hadslightly elevated plasma insulin.

There was a significant negative correlation between plasmalevels of IGF-I and IGFBP-I before treatment (Fig. 1; Spearman rs = -0.53, P < 0.05). Neither plasma IGF-I nor IGFBP-I

was correlated to the plasma levels of any of the other hormonesanalyzed (Table 1).

Alterations Caused by Tamoxifen Therapy. Alterations inplasma levels of IGF-I, determined in acid ethanol extract before and at different intervals after the start of tamoxifen treatment, are illustrated in Fig. 2. Tamoxifen suppressed plasmaIGF-I from a mean value of 22.2 nivito a mean value of 14.7 HMcalculated from the individual mean of each patient. The meansuppression was 28.4% (P < 0.001, n = 16). This level ofstatistical significance was independent of whether absolute orrelative values of suppression were used for statistical analysis.

o>C

Q.03

I

LLO

80 n

60-

40-

20-

1 O 2 O

IGF-I (nM)3 O 4 O

Fig. l. Plasma IGF-I and IGFBP-I values in individual patients before treatment (r, = -0.53, P = 0.004).

Table 1 Spearman rank correlation coefficients between plasma levels oflGF-I,IGFBP-I, growth hormone, insulin, and insulin C-peptide before treatment

and changes caused by tamoxifen treatment

IGF-I A IGF-I IGFBP-I A IGFBP-I

IGF-IA IGF-I

IGFBP-I

-0.92" -0.55*

0.460.28

-0.50e

-0.26

GHAGHInsulin

AInsulinInsulin

C-peptideA Insulin C-peptide-0.09

0.19 0.120.120.03

-0.18 -0.23-0.350.12

-0.26 -0.24-0.02-0.48

0.290.58rf

-0.320.38

-0.28"P = 0.0004.

* P < 0.04.CP = 0.054.d P = 0.025.

There was a significant negative correlation between the plasmalevel of IGF-I and the change caused by tamoxifen therapy(rs = -0.92, P = 0.004). Plasma IGF-I levels measured by the

commercial radioimmunoassay kit were somewhat lower (meanlevels of 16.1 HM and 11.6 nivi before and during treatment,respectively), but the relative suppression was in the samerange, with a mean suppression of 25.4% (P< 0.0025, n = 16).

Tamoxifen treatment elevated plasma IGFBP-I levels in 14of 16 patients (Figs. 2 and 3). The mean level was increasedfrom 37 ng/ml before treatment to 60 ng/ml during treatment.The mean increase was 77.7% (P< 0.001, n = 16). This level ofstatistical significance was independent of whether absolute orrelative values of suppression were used for the analyses. Theincrease in plasma IGFBP-I was weakly correlated to plasmaIGF-I suppression (rs = -0.50, P = 0.054), but it was notcorrelated to IGFBP-I pretreatment values.

Nine patients had blood samples obtained before treatment,after 1-2 months and after 3-4 months on tamoxifen therapy.When plasma IGF-I and IGFBP-I levels obtained in the different test situations were compared using the Friedman test formultiple comparison, there was a significant difference betweenthe values obtained in the three different situations for IGF-I(P < 0.01) as well as IGFBP-I (P < 0.05). Paired comparisonrevealed a significant difference between IGF-I values obtainedbefore treatment and following 1-2 months (P < 0.025) as wellas 3-4 months of therapy (P < 0.05). There was a significant

4720



IGF-I. IGFBP-I, AND TAMOXIFEN

100

tamoxifen influence on plasma IGF-I and IGFBP-I in patientsresponding and those not responding to tamoxifen treatment.

90-

n = 880-70-60-\T

1U,1n

= 11 JI*

<n=5A>^n

= 4 '^-^-^Jr

n

CLmLLo

250-

225-

200-

175-

150-

125-

100

n = 11

n = 5

0246

Time (months)Fig. 2. Relative changes in plasma IGF-I (A) and IGFBP-I (B) during tamox

ifen treatment in 16 women with breast cancer. Points, mean; ears, SEM.

difference between the values of IGFBP-I obtained before andfollowing 3-4 months of therapy and a nonsignificant trend(P < 0.10) in favor of higher IGFBP-I values following 1-2months of therapy compared to the control situation. There wasno significant difference in plasma levels of either IGF-I orIGFBP-I after 1-2 months compared with 3-4 months ontamoxifen therapy.

Tamoxifen treatment had no influence on the mean plasmalevels of growth hormone, insulin, or insulin C-peptide. Theincrease in plasma IGFBP-I was found to be positively correlated to pretreatment plasma insulin levels (P = 0.025). Therewas no other correlation between plasma insulin, insulin-C-peptide, and growth hormone or between changes in these hormones during tamoxifen treatment and changes in plasmaIGF-I or IGFBP-I (Table 1) .

One patient had tamoxifen as adjuvant treatment for a stageII carcinoma. Of the remaining 15 patients, 7 received tamoxifen and local radiotherapy for stage III carcinomas, while 3patients had tamoxifen following surgical removal of a localrelapse. Thus, the response to tamoxifen therapy could be assessed in 5 patients only, of whom 2 had a partial response, 2had stabilization of their disease, and one patient progressedafter 3 months on therapy. There was no difference between

DISCUSSION

Pretreatment Hormone Levels. Most patients included inthis study had values of IGF-I, IGFBP-I, growth hormone, andinsulin within the normal ranges defined for the methods. Twopatients had a plasma IGF-I value slightly below the lowernormal limit for their age, and one patient a slightly elevatedplasma IGF-I, but none of these patients had any abnormalvalues for the other hormones. The lower concentration ofIGF-I obtained with the commercial kit method in comparisonto the values obtained in acid ethanol extracts using des 1-3IGF-I as the ligand may be due to losses during the extractionprocedures (76.5% mean recovery).

The correlation coefficient between plasma IGF-I values obtained with the two different assays is comparable to correlationcoefficients obtained by comparing other methods (20). Ourfinding of a negative correlation between plasma levelsof IGF-Iand IGFBP-I has been reported for normal individuals (22), butothers did not find such a relationship (23).

Validity of Data. Because IGFBP-I undergoes a diurnal variation all blood samples were obtained after an overnight fast(24, 25). The rapid fall in its plasma levels in the early daytimeseems to be related to food intake, since plasma levels aresustained during the daytime in fasting individuals (26). Thus,while the exact time for blood sampling could vary by l hbetween the corresponding test situations for individual patients, this should have little impact on our results. While IGF-Ihas been found to be slightly lowered during sleep, its plasmaconcentration has been found to be stable during the day (27).

Influence of Tamoxifen Treatment. The results from thisstudy confirm previous findings (14-16) that tamoxifen treatment suppresses plasma IGF-I levels in breast cancer patients.Colletti et al. (14) compared plasma IGF-I in breast cancerpatients on tamoxifen to breast cancer patients not receivingtamoxifen and found the mean value of IGF-I to be twice ashigh among patients not receiving tamoxifen treatment. Pollaket al. (15) measured plasma IGF-I among patients randomlyassigned to tamoxifen versusplacebo and found that the meanvalue of plasma IGF-I was 36% lower among patients receiving

100-1

80-

O)C

CLmu.o

60-

40-

20-

Before DuringFig. 3. Individual plasma IGFBP-I values obtained before and during tamox

ifen treatment in 16 patients. When plasma IGFBP-I was measured on more thanone occasion in a patient, the mean value of these measurements was used as theon-treatment value.

4721



IGF-I, IGFBP-l, AND TAMOXIFEN

tamoxifen. In a previous study (16) we measured IGF-I beforeand during tamoxifen treatment in breast cancer patients andfound a reduction in plasma IGF-I of 28.5%. However, none ofthese studies obtained blood samples according to a strict protocol including overnight fasting. Thus, while this study includes a limited number of patients, it shows a modest butsignificant influence of tamoxifen on plasma IGF-I measured insamples obtained from the same patients before and duringtamoxifen treatment under standardized conditions. While theIGF-I values obtained with the commercial kit method were

somewhat lower compared to the values obtained with the acidethanol des 1-3 IGF-I assay, the two methods gave a similarmean value of suppression (25.4% and 28.4%, respectively).

Growth hormone is the major factor controlling total plasmaIGF-I (18). In accordance with earlier reports (28, 29), we didnot find any alterations in plasma growth hormone levels during tamoxifen treatment in our patients. Nor did we observe anycorrelation between pretreatment plasma growth hormone levels or any change in this hormone during tamoxifen treatmentcompared to plasma IGF-I. Thus, tamoxifen seems to suppresstotal plasma IGF-I levels by mechanisms not involving the secretion of growth hormone.

The influence of tamoxifen on IGFBP-I has not beenadressed previously. The large majority of IGF-I in humanplasma is protein bound (30). IGFBP-I is one of the bindingproteins in the "low-molecular-weight (Mr 40,000-50,000)complexes" with IGF-I (31) and has received much interest

because of its role in human physiology and pathophysiologicalconditions (32, 33). The biological role of this binding proteinis not fully understood, although several functions have beensuggested. In contrast to total plasma IGF-I levels and otherIGF-binding proteins, IGFBP-I undergoes rapid changes during the day. IGFBP-I has been suggested to act as an importantmodulator of the small free fraction of IGF-I in plasma (17).While only a few percent of total IGF-I is bound to IGFBP-I inplasma (34), a doubling of the IGFBP-I concentration mayreduce the free fraction considerably. The relative amount of"small" binding proteins, including IGFBP-I, is much higher in

the lymph than in the plasma (35). This suggests that the smallbinding proteins but not the high-molecular-weight IGFBP-3complexes pass through the endothelial wall (36). While thetissue concentration of IGFBP-I is not known, the possibilityexists that this protein plays an important biological role indifferent tissues, including breast cancers, in vivo. In vitro investigations suggest that IGFBP-I can reduce the biologicalactivity of IGF-I (37, 38), but it is also suggested that it mayadhere to the surface of the cell and enhance the effect of IGF-I(39). Thus, the influence of IGFBP-I on IGF-I biological activity i/i vivo is currently not clarified. An increase in the plasmalevel of this protein by 78% may cause a similar increase in thetissue concentration of this protein. If the major effect ofIGFBP-I is to reduce the fraction of free, biologically activeIGF-I, an increase in the concentration of this protein mayreduce IGF-I stimulation to the tumor cell. Alternatively, if thefunction of IGFBP-I is to enhance IGF-I delivery to the cells, anincrease in the concentration of this protein could be a mechanism causing tamoxifen resistance in certain patients.

Insulin suppresses plasma IGFBP-I levels (19, 40-42)through the suppression of its production but also by increasingits transcapillary transport (43). IGFBP-I has been consideredto be the "growth hormone-independent IGFBP," but one

group found growth hormone to suppress plasma IGFBP-I(44). Our present data suggest that tamoxifen acts on plasma

IGFBP-I by mechanisms not involving growth hormone or insulin. The suppression of tamoxifen on plasma IGF-I mimicsthe action of oral estrogen given in high doses to patients withacromegaly (45) or tall girls (46), as well as its action duringoral estrogen replacement therapy given to menopausa! women(47). A similar effect does not seem to occur after cutaneousestrogen administration (48). This difference could be explained by the high concentration reaching the liver through theportal vein following oral administration. In contrast to thesuppressive effect on IGF-I, estrogen in high doses elevatesIGFBP-I levels in both men and women.4 Tamoxifen acts as anestrogen agonist on plasma proteins like sex hormone-bindingglobulin, corticosteroid-binding hormone, and testosterone-binding hormone (49, 50), and it is of interest to observe that itsinfluence on IGF-I and IGFBP-I seems also to be estrogenagonistic.

IGF-I may be delivered to the tumor cells following autocrine, paracrine, or endocrine excretion. Recent evidence suggests that IGF-I is not secreted in significant amounts by breastcancer cells (8, 51) but by fibroblasts surrounding the cancercells (52). Most of the circulating IGF-I as well as IGFBP-I arebelieved to be of hepatic origin (53). As far as we are aware,there are currently no data evaluating the influence of tamoxifen on IGF-I and IGFBP-I secretion by fibroblasts. The possibility exists that tamoxifen acts similarly on fibroblasts andhepatocytes. If so, tamoxifen treatment could also enhance theproduction of IGFBP-I in the vicinity of the tumor. Thus, whilethe quantitative importance of endocrine compared to paracrine delivery of IGF-I to breast cancer cells is not known, thepossibility exists that alterations in the plasma levels of IGF-Iand IGFBP-I reflect corresponding alterations in the levels ofthese peptides in the tissue surrounding the tumor. If so, tamoxifen could also modify paracrine IGF-I stimulation in breastcancer cells.

The results of this study suggest that tamoxifen treatmentmay have a dual influence on the biological activity of IGF-I inbreast cancer patients by modifying its total plasma level andthe level of its binding proteins. In vitro as well as in vivo studiesshould be undertaken to clarify these mechanisms and theirbiological significance.

ACKNOWLEDGMENTS

The technical assistance of Agot KirkebÃ¶and Agneta Hilding as wellas the secretarial work of Hildegard 11jorlung are greatly appreciated.

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