prediction of clinical outcome with estrogen and progestin...

(CANCER RESEARCH 46, 5380-5384, October 1986]

Prediction of Clinical Outcome with Estrogen and Progestin Receptor

Concentrations and Their Relationships to Clinical andHistopathological Variables in Endometrial Cancer1

Antti J. I. Kauppila, Hannu E. Isolalo, Seppo T. Kivinen, and Reijo K. VihkoDepartments of Obstetrics and Gynecology [A. J. 1. K., S. T. KJ and Clinical Chemistry [H. E. I., R. K. V.J, University ofOulu, Oulu, Finland

ABSTRACT

Concentrations of cytosol estrogen (ERG) and cytosol progestin (PRQreceptors were assayed in malignant tissue specimens of 230 patientswith endometrial cancer, and those of nuclear estrogen and nuclearprogestin receptors, and 17/8-hydroxysteroid dehydrogenase activities inabout 100 specimens. Endometrial cancer was at an early stage in 205and advanced in 25 patients. As a supplement to surgical and radiationtherapy, all patients received p.o. medroxyprogesterone acetate (100 mga day) for 2 years. The follow-up time varied from 12 to 96 months(median, 42 months).

Concentrations of ERC, PRC, nuclear estrogen, and nuclear progestinreceptors in endometrial cancer tissue were significantly lower in clinicalstages IH-IV than in clinical stage I. In clinical stage I, ERC and PRCappeared in significantly lower concentrations in anaplastia than in moderately and well differentiated malignancies. The concentrations of thesereceptors were increased in obese patients, and the activity of 17/8-hydroxysteroid dehydrogenase was increased in patients younger than 50years, suggesting that endogenous female steroid hormones modify thepattern of female steroid receptors in malignant endometrium. In clinicalstage I, 13 of 153 patients with adequate therapy contracted a recurrentdisease. Poor prognosis was predicted by anaplastic structure of themalignancy (/' < 0.001 ). low tissue concentrations (0-30 fmol/mg protein)of ERC alone (/' = 0.006), PRC alone (/' = 0.010), and ERC and PRCsimultaneously (/' = 0.004). All 101 patients who simultaneously had

ERC and PRC in concentrations higher than 30 fmol/mg protein remaineddisease free for 2 years, whereas all recurrences in patients with receptor-poor tumors appeared during the 2 years of medroxyprogesterone acetatetreatment. In clinical stage II, with 30 patients, no prognosis indicatorspredicted the clinical outcome, whereas in clinical stages III + IV, with25 patients, low ERC concentrations were associated with a worsenedprognosis (/' = 0.045).

Conclusively, cytosol and nuclear estrogen and nuclear progestin receptor concentrations and 170-hydroxysteroid dehydrogenase activitygive valuable information about the endocrine associations in endometrialcancer. Cytosol estrogen and cytosol progestin receptors appeared to beuseful predictors of recurrent disease. They also have the potential todistinguish between patients expected to benefit from adjuvant progestintherapy and those expected to be unresponsive to the same treatment.

INTRODUCTIONIn endometrial cancer clinical and histopathological indica

tors of prognosis (1-4) are used in the planning of individualtreatment strategies. Because endometrial cancer belongs to thecategory of hormone-dependent neoplasias, endocrine indicators such as female sex steroid receptors have been expected toserve as a new basis for categorization of patients with endometrial cancer as far as prognosis and treatment modalities areconcerned (5-10). In this and other centers, it has been shownthat ERC2 and PRC receptors are present in endometrial ade-

Received 1/31/86; revised 6/26/86; accepted 6/27/86.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 inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1This work was supported by grants from the Research Council for Medicineof the Academy of Finland and by the Finnish Cancer Foundation.

J The abbreviations used are: ERC, cytosol estrogen receptor; PRC, cytosolprogestin receptor, ERN, nuclear estrogen receptor, PRN, nuclear progestinreceptor, 17-HSD, 170-hydroxysteroid dehydrogenase; TAH, total abdominalhysterectomy; BSO, bilateral salpingo-oophorectomy; MPA, medroxyprogesterone acetate.

nocarcinoma specimens in lower concentration than in normalendometrium (11-13), whereas the concentrations of nuclearfemale sex steroid receptors (ERN, PRN) tend to be higher inmalignant than in normal tissue (13). The activity of the endometrial progestin-specific protein, 17-HSD, does not appear todiffer between these two types of tissue (13). In addition, thereceptor concentrations decrease in relation to the loss ofdifferentiation (12,14-20) and advancement of the disease (20-23). The clinical outcome has been shown to be more favorablein patients with receptor-positive (15, 19, 21, 24-26) or receptor-rich (10, 22, 27-29) tumors in comparison with receptor-negative or receptor-poor tumors, respectively.

The present study on 230 patients is a continuation of ourprevious investigations on the clinical use of cytosol and nuclearfemale sex steroid receptor and 17-HSD measurements inendometrial cancer. It relates these measurements to multipleclinical and histopathological variables and prognosis in thispatient population, which has been partly described earlier (10,22) but which is now approximately double in number and hasan extended follow-up time.

MATERIALS AND METHODS

Patients

The study population consisted of 230 patients (Table 1). Endometrial cancer was of clinical stage I (A' = 175) or II (N = 30) in 205 cases(89%) while 25 patients (11%) had an advanced disease of clinical stageIII (N = 15) or IV (N = 10) (30). In clinical stage I, 12.6%, in stage II,34.6% and in stages HI-IV. 56.0% of the patients had an anaplasticmalignancy (30).

In clinical stage I preoperative intracavitary irradiation was followed1 week later by TAH plus BSO, and postoperative vaginal or pelvicirradiation (anaplastic malignancy, deep myometrial infiltration, oroccult cervical spread were indications for pelvic irradiation) (31). Inclinical stage II, all 26 operated patients received pelvic irradiation.Eleven patients in stage I and 4 in stage II received radiotherapy alone,with combined internal and external irradiation.

In clinical stage III, 10 patients were treated with combined internaland external radiotherapy alone, and together with TAH and BSO in5 additional cases. In clinical stage IV, the treatment consisted ofradiotherapy alone in 7 cases, together with TAH and BSO in 2 cases,while no therapy was given in 1 case. All patients received p.o. medroxyprogesterone acetate, 100 mg a day for 2 years. The follow-up timevaried from 12 to 96 months (median, 42 months). For 86 patients(37%) it was 5 years or more, while in 48 cases (21%) it was 1 to 2years. None of the patients was lost to follow-up.

In each case, endometrial curettage was performed before any therapy. The specimen was divided into two identical parts; one was forhistological analysis and the other one for receptor determinations andwas kept at -70' ( until assayed. Only cases with histological confir

mation of malignant tissue were accepted for receptor analysis.

Methods

Assays. Tritiated 17|8-estradiol and 16<*-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione were used as the labeled ligands in cytosol andnuclear ER and PR measurements, respectively, as described elsewhere

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STEROID HORMONE RECEPTORS AND ENDOMETRIAL CANCER

Table 1 Mean and SEs of the ages and weights of the patients, concentrations ofcytosol progestin and estrogen receptors (final per mg protein), nuclear progestin,

and estrogen receptors (sites per cell), and the activity of 17^-hydroxysteroiddehydrogenase (estradiol to estrone/30 min) in clinical stages I, Â¡I,and III+iy.

ClinicalstageINo.MeanSEnNo.MeanSEIII-IVNo.MeanSEAge(yr)17560.50.73060.50.72565.51.7Wt(kg)17473.71.12971.22.82567.52.7ERC17514613309216255025PRC174309313025175256528ERN826959613534107515941PRN933009552152717952599625517-HSD870.490.09150.660.3330.760.41

Analysis of variance (/')

I vs. III+IVI vs. IIII vs. III+IV

<0.01 <0.05 <0.001 <0.01<0.05

<0.05

(13, 32). The activities of 17-HSD were measured essentially as de

scribed by Tseng and Gurpide (33).Definitions. In this paper, cytosol receptors refer to those found in

the cytosol fraction following homogenization and ultracentrifugationof the tissue in buffer. Correspondingly, nuclear receptors refer to thosefound in the nuclear fraction. The lowest detectable level was 3 fmol/mg protein for ERC, 6 fmol/mg protein for PRC, 100 sites/cell forERN, and 210 sites/cell for PRN. Specimens containing 30 fmol/mgprotein or less of ERC or PRC, 350 sites/cell or less of ERN, and 1500sites/cell or less of PRN were classified as receptor poor and for therespective receptor concentrations higher than those limits were classified as receptor rich.

The clinical condition of the patient was assumed to be unaffectedby clinical stages I and II disease; hence, the combined patient population of these stages was used in the comparison of receptor data withclinical parameters. On the other hand, because the clinical outcome issignificantly related to stage per se of an early disease, comparisons ofthe receptor concentrations with survival figures and other prognosisindicators were done separately for clinical stages I and II.

Statistics. Analysis of variance was used in the statistical comparisonsof cytosol and nuclear estrogen and progestin receptor concentrationsand 17-HSD activities with multiple clinical and histopathologicalvariables, and when appropriate, the degree of significant differencewas estimated by the nonparametric tests of Kruskal-Wallis and Mann-Whitney. The difference was taken to be statistically significant when/' was smaller than 0.05. Survival figures were estimated using theKaplan-Meier product-limit method on the basis of the most recentinformation of the clinical condition. Generalized Wilcoxon and generalized Savage test statistics were used in the comparison of cumulativeproportions of disease-free patients (stages I and II) or survivors (stagesIII + IV) in the different groups. Calculation of Spearman rank correlation coefficients was used in the analysis of the relationships betweenthe histopathological grade of differentiation of the tumor, myomet rialinfiltration of the malignancy, and the data of ERC and PRC. Allstatistical tests were performed using BiomÃ©dicalcomputer programs'

statistical software, revised 1983 (University of California), on a Univac1100 computer.

RESULTS

Clinical Stage and Receptors. Concentrations of ERC, PRC,ERN, and PRN were significantly higher in clinical stage I thanin clinical stages III + IV (Table 1). In addition, ERC concentration was higher in clinical stage I than in stage II, and PRNconcentration in clinical stage II than in stages III-IV.

Histopathological Grade and Receptors. Concentrations ofERC and PRC in grade 1 + 2 tumors were significantly higher

than in grade 3 malignancies in clinical stage I (Table 2). Inclinical stage II the receptor variables did not differ significantlybetween these histopathological categories (data not shown). Inclinical stages III + IV the concentration of PRC in grades 1 +2 tumors [N = 11; 140 Â±57 (SE) fmol/mg protein] wassignificantly higher (P < 0.05) than in grade 3 tumors (N = 14;7 Â±2 fmol/mg protein).

Spearman rank correlation coefficients (Table 3) showed thatthe histopathological grade of the malignancy and the concentrations of ERC and PRC were significantly (P < 0.001) negatively correlated with each other. In addition, there was a strongpositive correlation between the concentrations of ERC andPRC.

Myometrial Invasion. The concentrations of ERC, PRC,ERN, and PRN and the activity of 17-HSD did not differsignificantly between the deeply invasive and superficial tumorsin clinical stage I or II. The degree of myometrial invasion hadno correlation with histopathological grade of the tumor or theconcentrations or ERC and PRC (data not shown).

Age. In clinical stages I + II, 24 patients were younger than50 years and 181 were 50 years or older. The activity of 17-HSD was higher in the younger than in the older women (1.33Â±0.53 versus 0.41 Â±0.06 estradiol to estrone/30 min; P <0.006).

Weight. In clinical stages I + II, 22 patients weighed morethan 90 kg and 180 were less than this. The tumors of overweight women had significantly higher concentrations of ERC(233 Â±41 versus 127 Â±11 fmol/mg protein; P < 0.02) andPRC (517 Â±112 versus 278 Â±29 fmol/mg protein; P < 0.03)than those of the other women.

Other Clinical Parameters. Diabetes, hypertension, or parityhad no relationship to any of the other parameters measured(data not shown).

Disease-free Survival in Stages I and II. In clinical stage I, 11patients died of concurrent disease and 11 patients receivedradiotherapy alone. They were excluded from the analysis ofcorrected disease-free survival data. The results from the wholematerial (175 patients) did not show any basic differences fromthe data to be presented below for the corrected material (153patients). Recurrent disease appeared in 13 patients in clinicalstage I at 5 to 28 months (mean, 15.7 months) after treatment.At the time of analysis, two patients were alive with recurrentdisease while the other patients died of the disease 9 to 36months after treatment. In two cases recurrent disease appearedsimultaneously at pelvic and distant sites whereas in all othercases only distant mÃ©tastaseswere found. In clinical stage II, 5patients contracted distant recurrent disease 2 to 26 monthsafter therapy. Two patients were alive with the disease at theend of follow-up while three patients died of the malignancy 12to 14 months after therapy. In clinical stages III and IV, 22 ofthe 25 patients died of the malignant disease 1 to 23 monthsafter therapy. Two patients were disease free, and one patientwas alive with the disease at the end of the 60-month follow-

up.The disease-free survival of 153 patients in clinical stage I

correlated significantly with the ERC (Fig. I/O, and PRC (Fig.IB) concentrations when tumors were categorized into receptor-rich and receptor-poor groups and also with the grade of the

tumor (Fig. IE). The combined data of ERC and PRC, categorized as shown in Fig. 1, C and D, also predicted prognosis.

In the categories of patients having receptor-rich tumors,almost all recurrences appeared in close association with thetermination of the adjuvant MPA treatment.

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Table 4 Predictive values of positive and negative tests, respectively, sensitivity, and specificity of the conventional (histopathological grade, myometrial invasion) andendocrine (ERC, PKC) risk indicators in the detection of recurrent disease in the group of 178 patients with adequately treated stage I or II endometrial cancer. In

parentheses, after each variable, the assumed criterion of poor prognosis is indicated (positive when present, negative when absent).

Riskindicator

Recurrent disease

Present Absent Total Predictive value

ERC (0-30 fmol/mg protein)PositiveNegative

Sensitivity, 10:18 = 56%; specificity, 121:160 = 76%

PRC (0-30 fmol/mg protein)PositiveNegative


Histopathological grade (grade 3)PositiveNegative


Myometrial invasion (more than one-half ofmyometrial depth)

PositiveNegative


Histopathological grade (grade 3) plus ERC(0-30 fmol/mg protein)

PositiveNegative

108

18

99

18

126

18

41216

99

18


Other combinations were weaker than "grade + ERC," and are not shown

39121160

43117160

17141158

25114139

7151158

49129

52126

29147

29126

16160

Positive test, 10:49 = 20%Negative test, 121:129 = 94%


Positive test, 12:29 = 4Negative test, 141:149- 95%



60

20 ERc 0-30

N.20

PRc 0-30

NÂ«19

GRADE1 and 2

,N. 11

GRADE 3NÂ»14

60

6 12 18 24 6 12 18 24

MONTHS

6 12 18 24

Fig. 2. Lifetime analysis of patients with stages III-1V endometrial adenocar-i inuma in relation to ERC (I Ko (A) and PRC (PRc) (B) data and histopathological grade (Q.

ing at 24 months, of the initial 25 patients with stage III or IVdisease, had a receptor-rich and well- or moderately differentiated tumor (Fig. 2). The ERC concentration alone was ableto identify patients with a less aggressive clinical course. Inearly disease, in agreement with previous studies (23, 28, 29),ERC and PRC were potent predictors of recurrent disease. Theuse of these indicators in combination did not significantlyimprove the predictive value of either of these variables. Inaddition, low receptor concentrations and an anaplastic structure of the tumors were partly parallel and partly differentprognosis indicators. In calculations of sensitivity, specificity.and predictive values of the different potential risk indicators,histopathological grade of the tumor seemed to be more precisethan ERC or PRC in predicting clinical behavior of endometrial

cancer. This finding is in contrast to the observation of Creas-man et al. (29) who found grade, ERC, and PRC to be independent indicators and receptor concentrations to be moresensitive than grade. In our study, only 32 of all the 205 tumors(16%) in stages I + II were anaplastic, whereas this was thecase in 22% in Creasman's study in the corresponding group of

patients (29), indicating differences in the criteria of histopathological grading. This suggests that due to the differences inthe criteria of histopathological classification of endometrialcancer in different centers, it is difficult to make generalizedconclusions based on this criterion. It is possible that receptormeasurements could be better standardized and receptor datawould be internationally better comparable.

In spite of the fact that an anaplastic malignancy was anindication for more aggressive therapy in the present study,patients with such malignancies have significantly poorer survival figures than patients with well- or moderately differentiated tumors. The potentiation of therapy with pelvic irradiation and adjuvant MPA therapy thus could not eliminate thehazards generally known to be associated with anaplastic endometrial cancers (1-4). Because most of the recurrent lesionsappeared outside the pelvic cavity, adjuvant treatment withcytotoxic drugs alone or together with pelvic irradiation mightbe recommendable in these cases.

It is also clinically important that there was no single case ofrecurrent disease during the 2-year period of MPA administration if ERC and PRC concentrations were simultaneouslyhigher than 30 fmol/mg protein. All recurrences detected so farin this category appeared soon after termination of adjuvantMPA treatment. Whether this is due to an arresting effect of

5383




progestin or whether the late manifestation of recurrent diseaseis an inherent property of such cases is not known at present.In addition, all recurrences in patients having receptor-poortumors appeared during MPA administration. Put togetherwith previous data of the beneficial effect of MPA in advancedendometrial cancer (34, 38, 41), our findings call for studies asto whether adjuvant use of MPA in the form of long-termtreatment should be restricted to patients with receptor-richtumors.

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1986;46:5380-5384. Cancer Res Antti J. I. Kauppila, Hannu E. Isotalo, Seppo T. Kivinen, et al. and Histopathological Variables in Endometrial CancerReceptor Concentrations and Their Relationships to Clinical Prediction of Clinical Outcome with Estrogen and Progestin

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