Relationship Between the Progesterone, Androgen, and Glucocorticoid Receptor and Response Rate to Endocrine Therapy in Metastatic Breast Cancer

[CANCER RESEARCH 39, 1973-1979, June 1979]

Relationship between the Progesterone, Androgen, and Glucocorticoid Receptor and Response Rate to Endocrine Therapy in Metastatic Breast Cancer

Joseph C. Allegra, Marc E. Lippman,' E. Brad Thompson, Richard Simon, Audrey Barlock, Linda Green, Karen K. Huff, Hoan My T. Do, Susan C. Aitken, and Robert Warren

Medicine Branch (J. C. A., M. E. L., A. B., K. K. H., H. M. T. 0., S. C. A., R. Wi, Laboratory of Biochemistry(E. B. TI, and Biostatistics Section, Clinical Oncology Program (R. S.), National Cancer Institute, Bethesda, Maryland 20205, and Department of Oncology, Howard University, Washington, 0. C. 20059 (L. G.j

ABSTRACT coid receptor is found in many normal human tissues (4, 23) and in over 50% of human breast cancer specimens (3, 22). The influence of steroid hormone receptors on response rate The present study describes response rate to endocrine then to endocrine therapy in 85 patients with metastatic breast apy as a function of progesterone, androgen, and glucocorti cancer was determined in a retrospective study. We have coid receptor status in a series of patients with metastatic previously reported that estrogen receptor status has an over breast cancer. whelming influence on predicting response to therapy when compared to other prognostic variables. In the present study, we expand our analysis to include the results of progesterone, MATERIALS AND METHODS androgen, and glucocorticoid receptors. Of 18 patients whose Receptor Assays. Biopsies of metastatic or inoperable 10- tumors contained progesterone receptor, 11 responded to calized breast cancer were trimmed of excess fat and nontu endocrine therapy, compared to 8 of 26 patients with low or morous tissue and divided, with a portion submitted for confirm absent progesterone receptor. Progesterone receptor in ing pathology in all cases. Samples for steroid hormone recep creased the predictive index of the estrogen receptor in a ton assays were kept on ice and then frozen in liquid nitrogen group of patients who had received no prior therapy, but it did within 20 mm. Steroid hormone receptor assays were pen not help in patients who had received prior endocrine therapy. formed as described previously (15, 16). When sufficient sam None of four patients whose tumors were estrogen receptor pIe permitted, Scatchard analyses were performed to quantify negative but progesterone receptor positive responded to en the number of binding sites; otherwise, assays were performed docnine therapy. At the present time, there are trends suggest in duplicate at one or 2 concentrations of steroid hormone ing a possible association between androgen and glucocorti chosen to exceed several times the expected equilibrium dis coid receptor and response to endocrine therapy. These trends sociation constant. Data were analyzed using computer-as are apparent only with a cutoff value of 10 fmol/mg cytoplasmic sisted methods (1). A positive androgen or glucocorticoid re protein, and the distributions of androgen and glucocorticoid ceptor assay was taken to be equal or greaten than 10 fmol of receptor values for responders and nonrespondens are not [3H]dihydrotestosterone or [3H]dexamethasone binding per mg significantly different. Knowledge of androgen receptor status of cytoplasmic protein. A positive progesterone receptor was does not increase the predictive index in estrogen receptor taken to be equal or greaten than 20 fmol of R 5020 binding positive tumors or estrogen receptor-negative tumors. Gluco per mg of cytoplasmic protein. The value of 10 fmol for the corticoid receptor positivity may increase the predictive index androgen and glucocorticoid receptor was chosen as a cutoff in estrogen receptor-positive tumors, but not in estrogen re because it corresponds to the lowest sensitivity of the assays. ceptor-negative tumors. These values are similar to those chosen by other authors (20, 22). The value of 20 fmol/mg of cytoplasmic protein for the INTRODUCTION progesterone receptor was derived from a previous analysis which correlated progesterone receptor values and response Estrogen receptor analysis plays a major role in predicting rate to cytotoxic chemotherapy (2). In that study, the distnibu response to endocrine therapy in metastatic breast cancer. tion of progesterone receptor values in chemotherapy respond Patients whose tumors possess the estrogen receptor will ers and nonresponders was significantly different by Wilcoxon respond to endocrine therapy 50 to 70% of the time, while lack rank sum analysis. A value of 20 fmol/mg of cytoplasmic of the estrogen receptor is associated with a response rate of protein gave the best separation of responders and nonre less than 10% (18). It has also been suggested that the pres sponders. This value for progesterone receptor positivity is ence of both the estrogen receptor and the progesterone similar to that value used in other laboratories. receptor in a tumor will further increase the response rate to Patients. Eighty-five patients with metastatic or surgically endocrine manipulation (17). Many human breast cancers also unresectable primary breast cancer had one on more steroid possess an androgen receptor (3, 8, 14, 20, 24), and both hormone receptor assays performed immediately prior to the androgens and antiandrogens are effective endocrine thera institution of endocrine therapy. In all cases, assessment of pies in some breast cancer patients (7). A specific glucocorti response was performed using standardized response criteria (6). In brief, complete response required the disappearance of 1 To whom requests for reprints should be addressed, at Building 1 0, Room 6B02, Medicine Branch, National Cancer Institute, NIH, Bethesda, Md. 20205. all measurable disease, including healing of all bone lesions Received June 16, 1978; accepted February 21, 1979. and a return of the patient to a premorbid performance status.

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Partial response required a shrinkage of at least 50% in all 75% were postmenopausal; and they had a mean Karnofsky measurable disease. Although a given lesion might not regress performance index of approximately 87. Approximately 50% to this extent, regression averaged over all lesions had to be of the group had received prior chemotherapy and/or prior equal to or greater than 50%. No new lesions could appear, endocrine therapy. and no growth could be observed in a preexistent lesion. For Of these 85 patients, 44 had a progesterone receptor assay purposes of this study, no patient was classified as having a performed; 54 had an androgen receptor assay performed, partial response unless improvement was maintained for 2 and 44 had a glucocorticoid receptor assay performed. Fewer months on more. Objective response equals the sum of com patients had receptors assessed for hormones other than es. plete plus partial response. Any patient not achieving this trogen because of sample size limitations and the higher priority degree of improvement was termed a nonnesponder. All pa given to the estrogen receptor. tients' records were examined and assessed by individuals (A. Progesterone Receptor. Of the 44 patients who had a B., J. A., R. W., L. G.) unaware of steroid hormone receptor progesterone receptor assay performed on their tumor, 18 results. were progesterone receptor positive and 26 were progesterone All of the patients were treated with standard endocrine receptor negative. The characteristics of these 2 groups are therapies. Possible therapies used in these patients consisted listed in Table 1. The progesterone receptor-positive and of estrogens (diethylstilbestrol, 5 mg p.o. 3 times a day), -negative groups are similar with respect to age, menopausal antiestrogens (tamoxifen, 2 to 100 mg/sq m p.o. twice a day), status, Karnofsky performance index, disease-free interval, androgens (Halotestin, 7 mg/sq m p.o. twice a day), medical number of sites involved with metastatic disease, and propor adrenalectomy (aminoglutethimide, 500 mg p.o. 4 times a day, tion of patients with visceral involvement with tumor. plus hydrocortisone, 10 mg p.o. 4 times a day), oophorectomy, The distribution of progesterone receptor and its association and surgical adrenalectomy. No patient was treated with pitui with response rate to endocrine therapy are shown in Chart 1. tany ablative therapy. These various endocrine therapies were Of 18 patients, 11 (61%) whose tumors contained progesten distributed equally between the 2 groups. In addition, a given one receptor in excess of 20 fmol/mg of cytoplasmic protein therapy was administered using a common set of guidelines responded objectively to endocrine therapy, whereas 8 of 26 independent of receptor status. patients (35%) responded whose tumors contained less than Statistical Analyses. Comparisons of proportions were per 20 fmol (p = 0.09). It is important to note, however, that formed by the contingency x2 test with continuity correction. although the 20-fmol value appears useful in predicting re Comparison of continuous on ordered polychotomous distni sponse to therapy in this study, the distribution of progesterone butions was performed by the Wilcoxon rank sum test adjusted receptor values among responders and nonresponders is not for ties (13). This latter test requires no distributional assump significantly different when analyzed by Wilcoxon rank sum tions of the data, as would a t test. analysis. Table 2 lists objective response rates to endocrine Association among quantitative variables was evaluated us therapy as a function of both estrogen and progesterone ne ing the rank correlation coefficient of Kendall (11). This method ceptor status. Of 14 patients, 11 (79%) whose tumors con was used in order that the significance of an association could tamed both estrogen and progesterone receptor responded, be tested without assuming a linear relationship on bivaniate compared to 8 of 14 (57%) whose tumors contained estrogen normal sampling distributions. The rank correlation coefficient receptor but lacked progesterone receptor. This difference is does not, however, have the same interpretation as the usual not statistically significant (p > 0. 1). None of the 4 patients Pearson correlation r, in the sense that the r2 is the proportion whose tumors lacked estrogen receptor but contained proges of total variance explained by the linear association. All signif tenone receptor responded to endocrine therapy. icance levels correspond to 2-sided statistical tests. The ability of the progesterone receptor to increase the predictive index of the estrogen receptor is better demon RESULTS strated if we analyze only patients who have not received prior therapy. These data are illustrated in Table 3. In this subset of Eighty-five patients had at least one steroid hormone recep patients, 6 of 7 (86%) responded if their tumors contained both ton assay performed, followed immediately by an endocrine receptors, compared to a response rate of 3 of 9 (33%) in therapy. Briefly, the 85 patients had a mean age of 50 years; those patients whose tumors contained estrogen receptor but

Table 1 Characteristicsof the patientsstatusMean treated with endocrine therapy as a function of progesteronereceptor pro gesteronereceptorvalueMedian(fmol/mgMenopausal

involvedcytoplas sta disease No. of sites tumorNo. tus (%)free in with metastatic KarnofskytervalVisceralpatientstein)Preofmic pro @3Progesterone PostindexCmos.)disease1 2 receptorPositive187433 6/18Negative26427 6789 Â±12a145/184/18 8/18 11/26pb>0.1>0.1>0.1>0.1>0.1 3392Â±12189/266/26 9/26

a Mean Â± S.D. b Progesterone receptor positive versus progesterone receptor negative.

1974 CANCER RESEARCH VOL. 39

bOOr tory oven the past 3 years. Note that the Kendall rank cornela tion coefficient is a positive 0.22 with a p value less than 0.0001 . This analysis demonstrates that, as estrogen receptor values increase, there is a corresponding increase in pnogeS terone receptor values. C 0) A In this small series of patients analyzed in this endocrine 0 0. therapy trial, in which 50% have received prior therapy (a U E subset of Chart 2), no significant quantitative relationship be @ 100- I tween estrogen receptor and progesterone receptor can be C-, demonstrated. When those patients who received prior therapy 0) E are compared with those patients who did not receive prior therapy, we find a stronger correlation between estrogen and A progesterone receptor values among the group of patients not 0a. receiving prior therapy. The Kendall rank correlation coefficient w of log (ER + 1) versus log (PR + I ) for the 25 patients UuJ receiving endocrine therapy who had prior treatment is 0.09, zLu 10@-@ 0 where ER is estrogen receptor, and PR is progesterone recep Lu A Responders tor. It is not significantly different from zero (p = 0.54). For the 5- @AA C,, â€˜@Non-Responders Lu L 19 nonpreviously treated patients currently receiving endocrine 0a. therapy, the Kendall rank correlation coefficient is 0. 17 but is also not significantly different from zero (p = 0.33). There is a trend toward a stronger quantitative relationship between estrogen receptor values and progesterone receptor values in the subset of patients who received no prior therapy. These A AA A At/A A.\ A AAAA data suggest thatthe lack of a quantitative relationship between Chart 1. Objective response rate to endocrine therapy as a function of pro estrogen receptor and progesterone receptor in patients having gesterone receptor status. Responders Include those with complete as well as received prior therapy may indicate that progesterone receptor partial responses. levels are no longer an estrogen-dependent function and may Table2 explain the failure of the progesterone receptor to increase the Objective response rate to endocrine therapy as a function of predictive index in this group of patients as compared to estrogen and progesterone receptor status patients who have not received prior therapy. rateEstrogen Response Further evidence that prior therapy may affect the ability of positiveProgesteronereceptor the progesterone receptor to predict response to endocrine receptorPositive1 therapy is found when we analyze the distribution of receptor 14Negative8/14Estrogen 1/ values of responders and nonnespondensas a function of prior negativeProgesteronereceptor therapy. As stated previously, this distribution is not signifi receptorPositive0/4Negative0/12 cantly different for the entire group of 44 patients. When the distribution are analyzed as a function of prior therapy, the distributions of the progesterone receptor-positive and -nega Table3 tive groups receiving prior therapy are not different at p = Objectiveresponserateto endocrinetherapyas a functionof 0.90, compared to the distributions of the groups not receiving progesterone receptor status in patients who are estrogen receptor positive and who have received no prior therapy 3.6 KendallRankCocrelavon=O.fl Response rate (p< 0.0001) 3.2 Estrogen receptor positive, progesterone receptor 6/7 (86)a @ positive 0 11 2.8 Estrogen receptor positive, progesterone receptor 3/9 (33) p negative 2.4 a aNumbersinparentheses,percentage. I 2.0 lacked progesterone receptor. Thus, in patients who have I 1.6 I received no prior therapy, the progesterone receptor does 1.2 appear to increase the predictive index of the estrogen recep 8 0.8 ton. We wondered why progesterone receptor might correlate 0.4

@ less well with endocrine response in patients with prior therapy. 0.0â€”,(35) We therefore examined the dependence of progesteronere 0.0 0.2 0.4 0.6 0.8 1.0 12 1.4 1.6 1.8 2.0 2.2 2.42.6 2.8 3.0 3.2 34 ceptor on estrogen receptor. Chart 2 illustrates the quantitative LOGI 14ProgesteroneReceptor relationship between estrogen receptor values and progester Chart 2. QuantItative analysis of estrogen receptor and progesterone recep one receptor values. The I 75 patients included in this chart tor. The log of 1+ estrogen receptor Is plotted versus the log of 1+ progesterone receptor. The 175 patIents Included In this chart are comprised of all patients on are comprised of all patients on whose tumors estrogen and whose tumors estrogen and progesterone receptor assays were performed in progesterone receptor assays were performed in our labora our laboratory over the past 3 years. (35). number of data points.

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prior therapy (p = 0. 13. This trend also suggests that prior Androgen Receptor. Of the 54 patients who had an andro therapy is altering the ability of the progesterone receptor to gen receptor assay performed on their tumor, 19 were andro predict response to endocrine therapy. gen receptor positive and 35 were androgen receptor negative. Finally, we examined the possibility that some defect in assay The 2 groups were similar with regard to age, menopausal methodology might be responsible for our failure to observe a status, Kannofsky performance index, disease-free interval, good correlation between progesterone receptor values and and proportion of patients with visceral involvement. response to endocrine therapy for the entire group of 44 The distribution of the androgen receptor and its association patients. This seemed unlikely, based on the good quantitative with response to endocrine therapy are shown in Chart 4. Of correlations between estrogen and progesterone receptor. If 19 patients whose tumors contained androgen receptor, 11 progesterone receptor assays were not true measures of pro responded to endocrine therapy, compared to 11 of 35 patients gesterone receptor concentration, one would not anticipate a whose tumors were androgen receptor negative (p = 0.1 1). statistically significant association between progesterone re Thus, there is a trend for androgen receptor to predict endo ceptor and estrogen receptor. This results from the known cnine response. However, Wilcoxon rank sum analysis fails to dependence of progesterone receptor concentration on estro reveal a significant difference in the distribution of androgen gen responsiveness and the correlation between estrogen re receptor values among patients responding on failing to re sponsiveness and quantity of estrogen receptor. spond to endocrine therapy. One criterion sometimes used to ensure that radiolabeled In Table 4, we analyze the relationship between response to binding would be to progesterone receptor is that the binding endocrine therapy and both estrogen and androgen receptor affinity for the putative receptor is higher than some arbitrary status. As seen in this table, although androgen receptor is cutoff. Chart 3 shows progesterone receptor values as a func able to predict response to therapy, the estrogen receptor has tion of the dissociation constant of the progesterone receptor. an overwhelming influence on response rate. No differences The 41 patients included in this chart are comprised of patients were observed between androgen-positive and -negative tu whose progesterone receptor data were analyzed by Scat mors with regard to response rate in those patients in the chard analysis. Thus far, only 8 of these patients have been estrogen receptor-positive group. Furthermore, androgen re treated with endocrine therapy. The majority of the dissociation ceptor positivity did not alter the low response rate in the constant values are less than 6 nM. The majority of these estrogen receptor-negative tumors. assays were performed using [3H]pnogesteronewith or without Chart 5 shows androgen receptor values as a function of the unlabeled progesterone. Cortisol (1o@ M) was also added to dissociation constant of the androgen receptor. The 34 patients both competed and uncompeted tubes to block binding of included in this chart are composed of patients whose andro labeled ligand to corticosteroid-binding globulin and glucocon gen receptor data were analyzed by Scatchard analysis. Thus ticoid receptor. Thus, it is likely that we are measuring binding to the progesterone receptor. 1000 â€” A positive association was found between the amount of progesterone receptor and the receptor dissociation constant. The Kendall rank correlation is a positive 0.30 (p < 0.007). At the present time, we have preliminary data only with regard to the relationship between binding affinity of the receptor and C response rate. In the 8 patients studied, thus far, there is no obvious relationship between the receptor dissociation con stant and response rate to endocrine therapy. 100

A - A 36 -KendallRankCorrelation=0.30 . 0 (p< .007) A 32@

. 0 I2.8- 2.4 00 A A @ 2.0 AA ADO 10 â€”â€”â€” I 1.6 : c@:r A Responders

@ . D@ Non-Responders + 1.2

@ 0.8

0.4 cb

@ 0.0@ i i i i I I I I I IIIIIII DO 0.0 0.8 1.6 2.4 3.2 4.0 4.8 5.6 6.4 7.2 80 8.8 9.6 10.411.212.012.8 DISSOCIATiONCONSTANT(x10) 1Afl)@1A@@r1n An Chart 3. Progesterone receptor as a function of the receptor dissociation constant. The log of 1+ progesterone receptor is plotted versus the progesterone Chart 4. Objective response rate to endocrine therapy as a function of andro receptor dissociation constant. The 41 patients included in this chart are com gen receptor status. Responders include those with complete as well as partial prised of all patients whose progesterone receptor data were analyzed by responses. The dotted line at 10 fmoi/mg cytoplasmic protein is the cutoff used Scatchard analysis. in this study for separating androgen receptor-positive from -negative patients.

1976 CANCERRESEARCHVOL. 39

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1979 American Association for Cancer Research. Hormone Receptors and Response to Endocrine Therapy Table4 when responders and nonresponders are compared by Wil Objective response rate to endocrine therapy as a function of coxon rank sum analysis. estrogenreceptorandandrogenreceptorstatus Table 5 examines the ability of the glucocorticoid receptor rateEstrogen Response to increase the predictive index of the estrogen receptor. Of receptor positive 23 patients whose tumor contained both receptors, I 9 (82%) Androgen receptor Positive 11I 15 (73)a responded to endocrine therapy. The comparison group of Negative 10/16(63) patients with estrogen receptor-positive and glucocorticoid Estrogen receptor negative receptor-negative tumors is too small at the present time to Androgen receptor Positive 0/4 (0) perform a meaningful comparison. Unfortunately, glucocorti (5)a Negative 1/19 coid receptor positivity did not alter the low response rate in NumbersInparentheses,percentage. estrogen receptor-negative tumors.

@ 2.7 RankOcirelation-0.Q DISCUSSION (pâ€˜.009) 14 Since Jensen et al. (10) first reported that human breast cancer specimens contain estrogen receptor and that estrogen receptor status is useful in predicting response to endocrine 1@ â€œ @::@ , ,â€˜ ,@â€˜ therapy, there have been a large number of reports correlating estrogen receptor status with response rate to endocrine then 1000- @ 0 . A

-I 0.6

03-

@ 0.0@ i i i I I 1I1IIIIIIII C @ 0.0 0.8 16 24 3.2 40 4.8 5.6 6.4 7.2 ao 8.8 9.6 10.411.212.012.8 a) 0 DISS0@lAT1ON 00NSTANT (xlO') .@ Chart 5. Androgen receptor as a function of receptor dissociation constant. The log of 1+ androgen receptor is plotted versus the androgen receptor 100 dissociation constant. The 34 patients included in this chart are comprised of all 0 patients whose androgen receptor data were analyzed by Scatchard analysis. U 0) E

far, only 6 patients have been treated with endocrine therapy. 0 E As with the progesterone receptor, the majority of the dissocia tion constant values are less than 6 n@. These assays were 0 a-5- performed using a protamine sulfate methodology which gives Lu 0 a lower apparent affinity than found using a dextran-coated Lu charcoal technique. It is used because binding of [3H]dihydro 0 0 10 testosterone to sex steroid-binding globulin is not seen with 0 0 5- A Responders this method. As with progesterone receptor, a positive associ 0 0 0 Non-Responders ation was found between the amount of androgen receptor and 0 0

the receptor dissociation constant. The Kendall rank correla ..J tion coefficient is a positive 0.32 (p < 0.009). In 6 patients studied at the present time, we find no association between the receptor dissociation constant and response rate to endo

crine therapy. A @ Glucocorticold Receptor. Of the 44 patients who had a rir@@ Ar@r1 glucocorticoid receptor assay performed on their tumors, 34 Chart 6. Objective response rate to endocrine therapy as a function of glu were glucocorticoidreceptor positiveand 10 were glucocorti cocorticold receptor status. Responders Include those with complete as well as partial responses. coid receptor negative. These 2 groups were similar with regard to age, menopausal status, Karnofsky performance index, dis Table5 ease-free interval, and proportion of patients with visceral Objective response rate to endocrine therapy as a function of disease. The distribution of the glucocorticoid receptor and its estrogen receptor and glucocorticoid receptor status association with response to endocrine therapy are shown in rateEstrogen Response Chart 6. Of 34 patients whose tumors contained greater than receptor positive Glucocorticoid receptor 10 fmol of glucocorticoid receptor per mg of cytoplasmic Positive 9/23 (82)8 protein, 20 had an objective response to endocrine therapy, Negative 2/5 (40) compared to 2 of 10 patients in the glucocorticoid receptor Estrogen receptor negative Glucocorticoid receptor ne9ative group. Although this is of borderline statistical signif Positive 1I 11 (9) icance (p = 0.07), it is important to note that there is no (0)A Negative1 0/5 difference in the distribution of glucocorticoid receptor values Numbers in parentheses, percentage.

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1979 American Association for Cancer Research. J. C. Allegra et al. apy (19). We have recently reported that the presence of ditions, receptor translocated to the nucleus would be unde estrogen receptor predicts response to endocrine therapy ap tected. Thus, some estrogen receptor-positive, progesterone proximately 65% of the time and that there is a quantitative receptor-negative hormone responders may in reality be pro relationship between the amount of estrogen receptor and the gesterone receptor positive. A second factor, not usually men response rate to endocrine therapy (3). Furthermore, estrogen tioned in the literature, may result from the interpretation of receptor positivity is overwhelmingly the most important factor assay results. That is, there may be 2 groups of values termed in predicting response to therapy when compared to other , â€˜negative' â€˜in a given set of receptor assays. In one group, the prognostic factors, such as extent of disease or visceral tumor assay appears satisfactory, but by Scatchard analysis only a involvement. few receptor sites are identified; these assay results are usually In this report, we show that progesterone receptor status below some cutoff value, but above zero. A second group also correlates with response to endocrine therapy. Analyzing represents the no receptor-detected group. In our hands, this progesterone receptor status alone, 61% of patients whose represents a collection of different kinds of results, including tumors possessed progesterone receptor responded to endo assays in which there are no differences between competed crine therapy, compared to 35% whose tumors lacked proges and uncompeted tubes, and assays in which there may be terone receptor. Horowitz and McGuire (9) have previously competable counts, but no Scatchard plot is generated. Addi shown that the response rate in progesterone receptor-nega tionally, since most assay artifacts tend to give false-negative tive tumors is only 6 of 24 (25%), compared to 14 of 20(70%) results, one would anticipate that the zero receptor assay might in the receptor-positive group. In their series, progesterone be less accurate as a group than the low but negative receptor receptor positivity improved the predictive index of the estro values. Inspection of Charts 1 and 4 reveals that exclusion of gen receptor. Patients whose tumors contained both estrogen the zero receptor groups apparently increases the discniminant and progesterone receptor had a response rate of 70%, com value of the receptor. Obviously, this point will require further pared to a rate of 37% in patients whose tumors contained investigation. estrogen receptor but lacked progesterone receptor. These Quantitative estrogen receptor determinations may be of data are consistent with the theory that, in human breast more value than progesterone receptor in predicting response cancer, progesterone receptor is under control of estrogen to endocrine therapy, for several reasons: (a) prior therapy acting through its receptor. Bloom et a!. (5) have also reported does not affect the predictive index of estrogen receptor; (b), data in agreement with Horowitz and McGuire, but in a small all 4 of our patients who were progesterone receptor positive series of patients. Leclercq et al. (12) found no benefit of but estrogen receptor negative failed to respond to endocrine progesterone receptor positivity with regard to predicting re therapy; (C)Pollow et a! (21) have recently shown that proges sponse to endocrine therapy. tenone receptor concentration in normal mammary cytosol of Overall, we are not able to show an increase in the predictive premenopausal women depended on the day of the menstrual index of the estrogen receptor in tumors also containing pro cycle and that the binding of progesterone was highest around gestenone receptor. In our series, prior therapy appears to be the time of ovulation. an important determinant of the ability of the progesterone The role of the androgen and glucocorticoid receptors in receptor to predict response. This is probably not a methodo predicting response to endocrine therapy has not been studied logical difficulty for several reasons: (a) we are able to dem as extensively as have the estrogen and progesterone necep onstrate high-affinity binding to the progesterone receptor; (b) tons. Persijn et al. (20) reported a response rate of 4 of 11 there is a strong quantitative relationship between estrogen (36%) in patients whose tumors contained androgen receptor, receptor values and progesterone receptor values; and (c) we compared to 1 of 20 (6%) in tumors lacking androgen receptor. have demonstrated a negative correlation between progesten The number of patients was too few to determine if the pres one receptor values and response to cytotoxic chemotherapy ence or absence of androgen receptor influenced the predictive (2). It is interestingthat, in our small series of patients, if we index of estrogen receptor. Our data also exhibit a similar trend separate the patients according to pniontherapy, there is indeed with 57% of patients responding whose tumor contained an a strong trend suggesting that progesterone receptor is predic drogen receptor, compared to 31% in the androgen receptor tive. The distribution of progesterone receptor values of re negative group. At the present time, we have too few patients sponders and nonnesponders and the quantitative relationship who have received androgen therapy alone, to comment on the between estrogen and progesterone receptor both approach ability of androgen receptor to predict response to androgen statistical significance in patients not receiving prior therapy. therapy. Androgen receptor was not able to increase the pre These data suggest that prior therapy is, in some manner, dictive index of estrogen receptor. altering the relationship between estrogen and progesterone There are no data which currently analyze the ability of the receptor. glucocorticoid receptor to predict response to endocrine then At least 2 other factors may contribute to the failure of apy in metastatic breast cancer or to alter the predictive index progesterone receptor determinations to separate perfectly of the estrogen receptor. Our data suggest that tumors which hormone-dependent from -independent tumors. First, Saez et possess both estrogen and glucocorticoid receptors have a 2 have recently shown that cytoplasmic progesterone necep high response rate. At the present time, the comparison be ton levels are inversely correlated with plasma progesterone tween patients whose tumors contain estrogen receptor, with levels. Since our assay uses cytosol under nonexchange con on without glucocorticoid receptor, is too small to perform a meaningful comparison. The presence or absence of gluco 2S@Saez,P. M. Martin, and C. Chouvet. Breast adenocarcinoma ER and PGR content in pre and post menopausal patients, in relation to plasma estradiol and corticoid receptor did not alter the low response rate of estro progesterone, personal communication. gen receptor-negative tumors.

1978 CANCERRESEARCHVOL. 39

ACKNOWLEDGMENTS cancer cell line with estrogen, androgen, progesterone and glucocorticold receptors. Steroids, 26: 785â€”795,1975. We wish to thank the many collaborating physicians who submitted clinical 9. Horwitz, K. B., and McGuire, W. L. Estrogen and progesterone: their rela material for analysis and allowed examination of their patients' records, including: tionship in hormone dependent breast cancer. In: W. L. McGulre, J. P. Drs. Alford, Blom, Borssuck, Camaller, Casey, Egan, Funderburk, Gold, Hiltabi Raynaud, and E. L. Baulied (eds.). Progesterone Receptors In Normal and dIe, lsaacson, Jonas, Jones, Kiernan, Kim, Kirson, Kison, Kleinberg, MacDonald, Neoplastic Tissues, pp. 103â€”124.New York: Raven Press, 1977. Mitchell, Moore, Palmer, Pertin, Schein, Scully, Thistlethwaite, Tsangaris, Wat 10. Jensen, E. V., De Sombre, E. R., and Jungblut, P. W. Estrogen receptors in kins, and Wherry. hormone responsive tissues and tumors. In: R. W. Wlssler, 1. L. Dao, and S. We would also like to thank C. Baughman and V. Tinley for their assistance in Wood. Jr. (eds.), Endogenous Factors Influencing Host-Tumor Balance, p. reviewing patient records at the George Washington University Medical Center, 15. Chicago: University of Chicago Press, 1967. M. Allegra for her assistance In reviewing the records at Georgetown University, 11. Kendall, M. G. Rank Correlation Methods. New York: Hafner Press, 1962. and P. De Steffano for assistance In data management and computerization. 12. Leclercq, G., Heusen. J. C., Deboel, M. C., Legros, N., Longeval, E., and We would also like to thank Dr. D. C. Tormey (formerly of the Medicine Branch) Matthelem, W. H. Estrogen and progesterone receptors in human breast and Dr. R. C. Young and the members of the Medicine Branch, National Cancer cancer. In: W. L. McGuire, J. P. Raynaud, and E. L. Baulled (eds.), Proges Institute, for their assistance with this study. terone Receptors in Normal Neoplastic Tissues, pp. 14 1- 153. 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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1979 American Association for Cancer Research. Relationship between the Progesterone, Androgen, and Glucocorticoid Receptor and Response Rate to Endocrine Therapy in Metastatic Breast Cancer

Joseph C. Allegra, Marc E. Lippman, E. Brad Thompson, et al.

Cancer Res 1979;39:1973-1979.

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