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1 Jpn. J. Clin. Oncol. 1980, 10 (1) 61 ~ 68 Re-Evaluation of Clinical Parameters in Relation to Estrogen Receptor Assay in Predicting Response to Major Endocrine Ablation Therapy in Patients with Advanced Breast Cancer YASUO NOMURA, M.D., JUN YAMAGATA, M.D., KAZUO KATAYAMA, Ph.D.*, NAOHIRO YOSH1TAN1, Ph.D.* AND MICHIO TANAKA, Ph.D.* Department of Breast Surgery, National Kyushu Cancer Center Hospital, Fukuoka * Shionogi Research Laboratory, Osaka Abstract The response to major endocrine ablation therapy (adrenalectomy with oophorectomy and its modifications) was evaluated from combining the variable of the presence or absence of the estrogen receptor (ER) in tumors, and 11 other clinical variables in 64 patients with advanced breast cancer. The variables used in computation were the age and menopausal status of the patients, the disease-free interval, the performance status, the site(s) of metastases (local chest wall, lymph node, bone, lung, and liver), urinary excretion of 17- ketosteroids (17-K.S), and the 17-KS/17-OHCS ratio in urine. The probability of regression in the therapy was computed with Cox's linear logistic regression model. The single most important factor that contributed to the probability of regression was shown to be the presence or absence, not the concentration, of ER. In analyzing 38 patients with ER-positive tumors, the presence and amount of the liver metastases, and of the bone metastases, and the 17-KS/ 17-OHCS ratio in urine were all shown to be significant in giving the probability. Even when the results of ER assay of the tumors were not included in the computation, a formula of the probability of regression could be constructed from these three factors. It is suggested that in addition to the ER assay of breast cancer tissues, some biological characteristics of the patients may have significant relationships to the response to endocrine therapy. Introduction cgr for endocrine therapy by clinical and laboratory criteria with the hope of im- Many attempts have been made to select proving the remission rate of 30 to 40% suitable patients with advanced breast can- achieved by random selection. Recently estrogen receptor assays of the tumors have Received December 18, jyen us mqre rationa, and jnf This work was supported in part by matl0n relatlve to the Grants-in-Aids for Cancer Research from the response of the pa- Ministry of Health and Welfare (54-3), and tients to endocrine therapy (McGuire el al., from the Ministry of Education, Science and 1975). It is, however, rather disappointing Culture (301044). that nearly 40% of the ER-positive breast Reprint requests: Yasuo Nomura, M.D., c,.,.,.. ~ t. c r, L o XT cancers fail to respond K to endocrine therapy. FJ Department of Breast Surgery, National Kyushu Cancer Center Hospital, 595 Notame, There ma y be numerous reasons for this lack Minami-ku, Fukuoka 815, Japan. of exact correlation, such as heterogeneity

2 62 NOMURA et al. Jpn. J. Clin. Oncol. June 1980 of the cancer cell population in the tumors, the role of other hormones in regulating the growth of cancer cells, the defects of the postreceptor pathways in estrogen action in cells, the clinical problems of evaluating the responses, and possibly other factors (Nomura et al., 1978). In the present paper, we will show whether or not the information from computing the patients' clinical parameters with the results of ER assay of the tumors can improve the predictability of response in the patients. Materials and Methods Major Endocrine Ablation Therapy One hundred eighty patients with advanced or metastatic breast cancer have been subjected to major endocrine ablation therapy since The treatment consisted of three methods; i) bilateral adrenalectomy, ii) Inokuchi's method (left suprarenal-inferior mesenteric venous shunt with right adrenalectomy) (Inokuchi et al., 1976), and iii) Dargent's method (transplantation of the adrenal gland into the portal circulation after bilateral adrenalectomy) (Dargent et al., 1964). Oophorectomy was performed concomitantly in patients who had not already had their ovaries removed. Of these patients, 64 were chosen for the present study, because both the response of the patients to therapy and the results of ER assay in the tumors before therapy were clearly known. These 64 patients were composed of 36 adrenalectomized, 14 who were subjected to Tnokuchi's method, and 14 who submitted to Dargenfs method. Similar response rates were obtained among the three methods, being 36.1% (13/36), 28.6% (4/14), and 42.9% (6/14), respectively. The degree of response of the patients to therapy was based on the UfCC assessment, which was performed six months after the operation. The categories of response were divided into complete (CR) and partial response (PR) (objective regression), no change, and mixed or failure (progressive disease). Clinical Parameters of the Patients A vailable for the Assessment of Response to Therapy The following variables of the patients were taken into consideration for estimating the probability of response, in addition to the results of ER assay of the tumors: the age and menopausal status of the patients, the disease-free interval, the performance status of the patients according to the UICC assessment, site(s) of metastases, urinary excretion of 17-ketosteroids (17-KS), and the 17-KS/17-OHCS ratio in urine. The site(s) of metastases were divided into local chest wall, lymph node, bone, lung, and liver, and the values 0, 1, or 2 were assigned according to the absence of metastasis, the presence of a single metastasis, or the presence of disseminated metastases, in each metastasic site. In cases of liver metastases, however, the values 0, 1, 2 or 3 were assigned after laparotomy in the major endocrine ablation therapy for the patients with no liver metastasis (value 0), with a small metastatic focus in one lobe (value 1), with liver metastases in both lobes in smaller numbers (value 2), or with massive liver metastases in both lobes (value 3), according to the General Rules for the Gastric Cancer Study in Surgery and Pathology (Japanese Research Society for Gastric Cancer, 1974). Other clinical variables were also analyzed, such as the histological type of the cancer, the stage of the cancer at the time of primary treatment, prior treatment(s) and the response, the method of menopause and the years since menopause, whether the cancer was primary advanced or metastatic, and the interval between the recurrence and the beginning of therapy. The response to therapy and the duration of regression were evaluated after all patients had been undergoing the therapy for at least six months.

Vol. 10, No. 1 ESTROGEN RECEPTORS AND ENDOCRINE THERAPY 63 Analysis of Probability of Response Results Cox's linear logistic regression model according to Heuson et al. (1977) was used.

3 Vol. 10, No. 1 ESTROGEN RECEPTORS AND ENDOCRINE THERAPY 63 Analysis of Probability of Response Results Cox's linear logistic regression model according to Heuson et al. (1977) was used. The procedures employed here, relative to maximum likelihood and the selection of significant variables, were almost the same as those in their report. After selection of some significant variables from the clinical and laboratory variables as mentioned before, the probability of response was calculated for each patient by the following equation: ln(pi/\-pi) = b n + b,x u + + bnxni where b, = estimated coefficients; X = selected variable; subscript / = /-th number of patients; and Pi = the predictive ratio of /-th patient in responding to therapy. Estrogen Receptor Assay The methods used for estrogen receptor assay have been described in detail elsewhere (Nomura, 1976; Nomura et al., 1978). Briefly, the supernatant of the homogenate of cancer tissues obtained before the endocrine therapy, centrifuged at 105,000 g, were incubated with increasing quantities of 17/3-estradiol-(6, 7-8 H). The separation of bound isotopes from free isotopes was performed by the dextran-coated charcoal method. The dissociation constant and number of binding sites were calculated by Baulieu's proportion method (Baulieu and Raynaud, 1970) or Scatchard's method (Scatchard, 1949). Protein was measured by the Lowry method (Lowry et al., 1951). All samples were verified histologically for the presence of cancer. The ER values were transformed to the logarithmic scale, and negative ER was estimated as 15, if necessary, for the sake of logarithmic transformation. Of 64 patients with advanced breast cancer, 38 or 59% had ER-positive tumors before the therapy. Of these 38 patients, 23 or 60.5% showed objective regression (CR; 9, PR; 14). In contrast, there were no patients showing objective regression among the 26 who had ER-negative tumors. In the 64 patients, the linear logistic regression model was applied with the aid of a computer using ER values and 1 1 clinical variables in relation to the response categories in the UICC assessment. The presence of ER in the tumors was shown to be the single most valuable factor. In the 38 ER-positive cases the probability of regression was estimated by the formula: ln(p/l-p) = L rat B (see Fig. 1). The same analysis was applied to the whole series of 64 ER-positive and -negative cases. The following formula was obtained: ln(p/l-p) = R L rat. (Fig. 2), where R shows the ER concentration on a logarithmic scale. When the ER values of the tumors were excluded from the computation, the following formula was put together from the other parameters: ln(p/l-p) = B L rat. (Fig. 3). The adequacy of the linear logistic regression models was tested by the Chi-square test, and in each formula shown in Figs. 1-3, P values greater than 0.7 were obtained (0.7<P<0.8 in Fig. 1, 0.995<P<0.1 in Fig. 2, 0.7 <P<0.8 in Fig. 3), indicating that the fit was satisfactory. There w"as no correlation between the combinations of these parameters including ER values and the duration of regression or the survival time of the patients. Discussion In advanced breast cancer patients who had ER-positive tumors, approximately 60% of the patients responded well to major

4 64 NOMURA et al. Jpn. 1. Clin. Oncol. June 1980 endocrine ablation therapy, while no regression was obtained in patients with ER-negative tumors. This relationship seems to be essentially the same as that reported in Western countries (McGuire et al., 1975). Thus by assaying ER in tumors, we can exclude from endocrine therapy those pa* tients who have ER-negative tumors. However, about 40% of the patients with ERpositive tumors did not respond to the - IOO % u XJ< HI u <M o u 50 % -10 therapy. There have bsen numerous preliminary approaches in predicting the response more precisely, such as quantitative measurement of ER (Heuson et al., 1977), and assay of progesterone receptor (McGuire and Horwitz, 1978), or androgen receptor (Trams and Maass, 1977). Heuson et al. (1977) showed the possibility of obtaining a higher probability of the response by using X = L rat B Fig. 1: Probability of regression to major endocrine ablation therapy in 38 patients with ER-positive advanced breast cancer. The probability of regression was estimated by the linear logistic regression model in 38 patients with ER-positive tumors, from the variables given in Materials and Methods. The model that best fit the variables was ln(p/l-p) = L rat B (shown on the abscissa), where P is the probability of regression (shown on the ordinate), L is the liver involvement (L = 0; no metastasis, L = 1; a small, solitary metastasis in one lobe, L = 2; metastases in both lobes, but small in number, L = 3; numerous, disseminated metastases in both lobes, p = ), rat. is 17-KS/17-OHCS ratio in urine (p = ), and B shows bone involvement (B = 0; no metastasis, B = I; solitary bone metastasis, and B = 2; disseminated metastases, p = ). # CR (complete response), O PR (partial response), ^ NC (no change), PD (mixed), PD (failure).

5 Vol. 10, No. 1 ESTROGEN RECEPTORS AND ENDOCRINE THERAPY 65 a multivariate analysis of clinical parameters including ER concentrations. They noted that the ER concentrations, as well as the age of the patients and the presence of bone metastasis, were the most meaningful variables. According to our analysis from the combination of ER values and 11 clinical variables, the single most important factor that contributed to the probability of regression was the presence or absence of ER, not the concentration of ER. In patients with ERpositive tumors, the presence and degree of the liver metastases, and of the bone metastases, and the 17-KS/17-OHCS ratio in urine were shown to be significant in increasing the probability (Fig. 1). Other clinical parameters such as menopausal status and age of the patients, disease-free interval, and histological patterns, which have been considered to be valuable loot t.93 B L rat. parameters in the prediction of response, proved to have little relation to the response. These results seem to be different from those reported by Heuson and his colleagues (1977). This difference may be caused by the difference in the backgrounds of the patients and also by the facts that the methods of endocrine treatments used by these authors varied greatly, whereas ours consisted of a single method of major endocrine ablation, and that the response rate of their ER-positive cases was lower than ours. On the other hand, in evaluating the total 64 cases with ER-positive and -negative tumors, the ER concentration was the most valuable parameter, followed by the presence or absence of liver metastases, and the urinary steroid ratio (Fig. 2). In this case, however, the probability of response estimated was shown to be much lower than Fig. 2: Probability of regression to major endocrine ablation therapy in 64 patients with ER-positive and -negative breast cancer. When the ER-negative cases were included in the calculation, the best fitting model was ln(p/l -P) = R L rat., where R is the number of binding sites of ER (log. femtomole/mg of protein), p = , L is the liver involvement (numerals the same as in Fig. 1, p = ) and rat. is the 17-KS/17-OHCS ratio in urine (p = ). In ER-negative cases, the ER value was estimated as -15 for the purpose of logarithmic transformation. ER ( ) cases.

6 66 NOMURA et al. Jpn. J. Clin. Oncol. June % u p. 50% X = B L rat. Fig. 3: Probability of regression in response to major endocrine ablation therapy in the 64 patients, irrespective of the presence of ER in the tumors. When the results of ER assay in tumors were excluded from the variables for the linear logistic regression model, the model that best fit the clinical and laboratory variables was ln(p/l-p) = = B L rat., where B is bone involvement (numerals the same as in Fig. 1, p = ), L, liver involvement (numerals the same as in Fig. 1, p = ), and rat., 17-KS/17-OHCS ratio in urine (p = ). that obtained in ER-positive cases alone (Fig. 1). Therefore, if the ER in the tumors were measured, the formula given in the legend for Fig. 1 is recommended for the prediction of response, because the ERnegative cases will be actually unresponsive to therapy. Even when the results of ER assay of the tumors were not included in the computation, a formula for the probability of regression could be constructed from the three factors shown in Fig. 3, although the probability obtained was much lower than that obtained with the inclusion of the ER values (Figs. 1 and 3). [n conclusion, the present study suggests that in addition to the ER assay of breast cancer tissues, which is actually, we think, one of the best methods for predicting the response, some biological characteristics of the patients such as found in this computation may have a significant relationship to the response to endocrine therapy. References Baulieu, E. E. and J. P. Raynaud, Eur J Biochem 13: 293, Dargent, M., M. Mayer and S. Poulain, Lyon Chir 60: 840, Heuson, J. C, E. Longeval, W. H. Mattheiem, M. C. Deboel, R. J. Sylvester and C. Leclercq, Cancer 39: 1971, Tnokuchi, K.., Y. Nomura, T. Ikejiri and N. Kaibara, Br J Surg 63: 639, Japanese Research Society for Gastric Cancer,

Vol. 10, No. 1 ESTROGEN RECEPTORS AND ENDOCRINE THERAPY 67 The general rules for the gastric cancer study in surgery and pathology. 9th ed. Kanehara Co. Ltd., Tokyo, 1974 (in Japanese). Lowry, O. H.

7 Vol. 10, No. 1 ESTROGEN RECEPTORS AND ENDOCRINE THERAPY 67 The general rules for the gastric cancer study in surgery and pathology. 9th ed. Kanehara Co. Ltd., Tokyo, 1974 (in Japanese). Lowry, O. H., N. J. Rosebrough, A. Farr and R. J. Randall, J Biol Chem 193: 265, McGuire, W. L., P. P. Carbone, M. E. Sears and G. C. Escher, Estrogen Receptors in Human Breast Cancer, (edited by W. L. McGuire, P. P. Carbone and E. P. Vollmer), Raven Press, New York, p. 1, McGuire, W. L. and K. B. Horwitz, Hormones, Receptors, and Breast Cancer, (edited by W. L. McGuire), Raven Press, New York, p. 31, Nomura, Y., Gann 67: 703, Nomura, Y., J. Yamagata, H. Kondo, K. Kanda and K. Takenaka, Hormones, Receptors, and Breast Cancer, (edited by W. L. McGuire), Raven Press, New York, p. 15, Scatchard, G., Ann NY Acad Set 51: 660, Trams, G. and H. Maass, Cancer Res 37: 258, 1977.

Relative Effect of Steroid Hormone Receptors on the Prognosis of Patients With Operable Breast Cancer

~~ Relative Effect of Steroid Hormone Receptors on the Prognosis of Patients With Operable Breast Cancer A Univariate and Multivariate Analysis of 389 Japanese Patients With Breast Cancer From the Study