Europ. J. Cancer Vo[. 13, pp. 749-752. Pergamon Press 1977. Printed in Great Britain
Correlation Between Urinary Steroids and Estrogen Receptor Content in Women with Early Breast Cancer* Y. J. ABUL HAJJ College of Pharmacy, University of Minnesota, Minneapolis, M N 55455, U.S.A. Abstract--The urinary levels of l l-deoxy-17-ketosteroids and estrogen receptor content in tumor tissues were determined in 76 patients with early breast cancer. Twenty-six postmenopausal and 16 premenopausal patients with estrogen receptor negative tumors wae found to excrete subnormal amounts of l l-deoxy-17-ketosteroids while 22 postmencpausal and 12 premenopausal patients with estrogen receptor containing tumors excrete near normal levels of urinary 11-deoxy-17-ketosteroids.
Estrogen receptors (ER) have been demonstrated in approximately 70% of human breast cancer [11, 12]. The absence of E R almost always indicates that the tumor will be resistant to endocrine therapy while their presence is associated with a remission of advanced breast cancer in about 55% of eases [13]. In view of the fact that both an abnormality in urinary excretion of steroid metabolites and E R content in m a m m a r y tumors have been shown to be predictors of hormone responsiveness, the present study was undertaken to determine whether there is any correlation between the E R content in human breast cancer and the urinary excretion of 11-deoxy17-ketosteroids.
INYRODUCTION ENDOCRINE responsive tumors in women with metastatic breast cancer constitute only 2040% of patient,~ treated by surgical ablation or by pharmacologic hormone therapy. A number of clinical, pathologic, and biochemical criteria have been used in an attempt to predict the clinical course of patients with breast cancer after therapy [1]. Various studies have indicated a possible association between abnormal levels of androgen and corticosteroid metabolites in urine and plasma and the occurrence of breast cancer. The most convincing endocrine abnormality in patients with breast cancer has been found to be a subnormal excretion of ll-deoxy-17ketosteroids ( l l - D O K S ) [2-5] which can predict with cont;iderable accuracy, either alone or in combination with urinary excretion of corticosteroids, the response to endocrine ablation therapy in patients with breast cancer. While these results have been supported by several investigators [4-7] others have disagreed with these findings [8-10]. The balance of evidence indicates that some steroid metabolites are present in abnormal concentrations in the urine and plasma of women, with breast cancer.
MATERIAL A N D M E T H O D S Control and cancer patients The subjects were patients admitted to the American University of Beirut Hospital and came from various countries of the Middle East. Eighty-eight per cent of the patients were Lebanese. The rest came from Syria and Jordan. A total of 76 patients with primary breast cancer were included in this study (28 premenopausal, mean age 44.6 + 4.4 years; and 46 postmenopausal, mean age 64.7 _+ 6-3 years). The controls were 27 healthy premenopausal (mean age 43.3 + 4.7 years) and 36 postmenopausal (mean age 62.4 __+4.6 years) women, none of whom were taking any form of steroid preparations. The urine from control subjects was collected at home from normal
Accepted 7 December 1976. "~This work was supported in part by a grant from the Graduate School, University of Minnesota. Part of this work was conducted at the American University of Beirut, Lebanon while on sabbatical leave from the University of Minnesota. 749
750
Y. J . Abul Hajj
healthy women, but in 9 instances, the urine was obtained from patients in a geriatric ward. Urine collection and analysis
Urine was collected from all patients 48 hr before operation. Urine analysis was done on 24-hr specimens stored at - 2 0 ° C without preservative. The techniques used for the determination of 11-deoxy-17-ketosteroids (etiocholanolone + androsterone + dehydroepiandrosterone) were based on that described by Thomas et al. [14].
The results show also that there is a significant difference between the mean levels of l l - D O K S in the pre- and postmenopausal control and cancer patients, there being a substantial reduction in l l-DOKS excretion after the menopause.
Urinary II-DOKS ( mg/24 hr)
Estrogen receptor determination
Estrogen receptor content of the tumor samples was carried out using the dextrancharcoal coated technique as determined previously [15]. Expression and evaluation o f results
The levels of urinary 11-deoxy-17-ketosteroids were calculated and expressed as means + S.D. in rag/24 hr urine. Results were evaluated statistically by use of the t-test. Differences between means were considered statistically significant at P < 0.05.
_~
::
"": .::
2
+.::5 .-:::
ER+
ER-
C
Fig. 1. Urinary ll-deoxy-17-ketosteroids (ll-DOKS) by postmenopausal women in control subjects (C) and breast cancer patients with estrogen receptor positive (ER+ ) and estrogen receptor negative ( E R - ) tumors. The horizontal bars show the means. Urinary II-DOKS (mg/24hr)
RESULTS The urinary excretion of 11-DOKS has been estimated in normal women and patients with primary breast cancer. The mean excretion of l l-DOKS (Fig. 1) in the normal postmenopausal group was found to be 1.66 + 0.88 rag/24 hr, 1.44 _+ 0.54 rag/24 hr in the postmenopausal ER positive group and 0.75 _+ 0.28 rag/24 hr in the postmenopausal ER negative group. There was no significant difference between the control group and the ER positive groups, P < 0.30, while the difference between the control group and the ER negative group was found to be very significant, P < 0.001. Figure 2 shows the distribution and the means of urinary 11-DOKS in normal premenopausal women and patients with ER positive and ER negative primary breast cancer. The mean excretion was found to be 4.18 ___ 0.47, 3.91 4_ 0.42, and 3.66 _+ 0.55 rag/24 hr, for the normal group, the ER positive group and the ER negative group, respectively. The results show that there was no significant difference between the control group and the E R positive group (P < 0.20), but that there was a significant difference between the control group and the ER negative group (P < 0.005).
::
C
ER+
ER-
Fig. 2. Urinary ll-deoxy-17-ketosteroids (II-DOKS) by ~OremenojOausal women in control subjects (C) and breast cancer patients with estrogen receptor positive (ER+ ) and estrogen receptor negative (ER - ) tumors. The horizontal bars show the means.
DISCUSSION Abnormalities in urinary excretion of steroid metabolites have been observed by Bulbrook and his colleagues in women with both primary [3] and advanced [4] cancer of the breast and have been related to the prognosis and outcome of endocrine surgery. These observations were supported by several groups of investigators [6, 7] while others have presented evidence [8-10] in variance with that presented by
Correlation Between Urinary Steroids and Estrogen Receptor Content Bulbrook and his coworkers. However, it is generally accepted that significantly low levels of androgen metabolites are associated with poor prognosis in patients with advanced breast cancer. The initial re,;ults of Jensen [16] on the use of E R content in breast tumor tissues for predicting response to endocrine therapy has been confirmed by other investigators [13]. The presence of E R in tumors of patients with advanced breast cancer increases the likelihood of response to endocrine therapy from about 25 to 55-60%. A favorable predicdon based on E R alone will, therefore, prove incorrect in approximately 40% of eases. But, in E R negative tumors the chances of regression in response to endocrine therapy are minimal, and so selection based on the E R assay alone will still save many patients from profitless major endocrine surgery. If in fact the low levels of urinary 11-DOKS excretion and the absence of E R are both predictors of hormone unresponsiveness, then they should correlate well in the same group of patients. O n the other hand, cases in which hormone dependence has not been lost, one might expect to have a near normal level of urinary 11-DOKS as well as the presence of E R in the same group of patients. The results obtained from this study show that there is good correlation between the absence of E R and low levels of l l - D O K S in both pre- and postmenopausal patients, though the significance levels are different. Also, there was a good correlation between the presence of E R and the near normal valLues for l l - D O K S in both the pre- and postmenopausal group. There was no significant diffe:rence between the means for 11-DOKS in patients with E R positive tumors and the control groups, yet one observes a slight decrease in the means for 11-DOKS in both the pre- and postmenopausal group with
mean differences of 0.27 and 0"22 rag/24 hr, respectively. This slight decrease in the mean level of urinary 11-DOKS in patients with E R positive tumors might be due to the contribution of the lower urinary 11-DOKS in those patients that do not respond to endocrine therapy, even though E R are present in the tumors of these patients. Whilst it is now well established that absence of E R in a breast tumor almost invariably indicates that the tumor will be resistant to endocrine therapy [13], the situation regarding the urinary levels of androgen metabolites remains equivocal. However, the fact that a good correlation was obtained between the absence of ER, and the low levels of 11-deoxy17-ketosteroids, suggests that patients unresponsive to endocrine therapy excrete subnormal amounts of 1 l-deoxy-17-ketosteroids. Furthermore, our results show that responsive patients, as determined by the presence of ER, excrete near normal values of 11-deoxy- 17-ketosteroids even though about 40% of patients with E R positive tumors are endocrine resistant. The findings obtained from this study may imply that only those tumors growing in a normal environment respond to the alterations in the environment brought about by the treatment and it remains to be seen whether patients with E R positive tumors that do not respond to endocrine therapy have in fact a significantly lower level of urinary 11-deoxy- 17-ketosteroids than patients with E R positive tumors that do respond to endocrine therapy.
Acknowledgements--The author wishes to thank Drs. V. Nassar, Pathologist, Dr. K. Bikhazi, Surgeon and Dr. I. Salti of the American University Hospital, Beirut, Lebanon, for their continued cooperation and support during this project. The skilled technical assistance of I. Sahli and N. Usama is also acknowledged and appreciated.
REFERENCES I. 2. 3. 4.
5.
H
75I.
A . P . M . FORREST and P. B. KUNKLER, Prognostic Factors in Breast Cancer. Livingston, Edinburgh (1968). tl.. D. BULBROOK,F. C. GREENWOODand J. L. HAYWARD,Selection of breast cancer patients for adrenalectomy by determination of urinary 17-hydroxycorticosteriods and aetiocholanolone. Lancet is 1154 (1960). R . D . BULBROOK,J. L. HAYWARD,C. C. SPICER and B. S. THOMAS,Abnormal excretion of urinary steroids by women with early breast cancer. Lancet il, 1238 (1962). R . D . BULBROOK,J. L. HAYWARD, C. C. SPICER and B. S. THOMAS, A comparison between the urinary steroid execretion of normal women and women with advanced breast cancer. Lancet ii D1235 (1962). R . D . BULBROOK,J. L. HAYWARDand B. S. THOMAS, The relation between the urinary 17-hydroxycorticosteroids and 11-keto-17-oxosteroids and the fate of patients after mastectomy. Lancet i, 945 (1964).
752
Y. J. Abul Hajj 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16.
S. KUMAOKI,N. SAKAUGHI,0. ABE, M. KUSAMAand O. TAKATONI,Urinary 17-ketosteroid execretion of women with advanced breast cancer, or. din. Endocr. 28, 667 (1968). H. MILLER and J. A. DURANT, The value of urine steroid hormone assays in breast cancer. Clin. Biochem. 1, 287 (1968). K . A . AHLQUIST,A. W. JACKSONand J. G. STEWARD,Urinary stcroid values as a guide to prognosis in breast cancer. Brit. med. J. i, 217 (1968). E . D . H . CAMERON,K. GRIFFITHS,E. N. GLEAVE,H. J. STEWART,A. P. M. FORP~ST and H. CAMPBELL,Benign and malignant breast disease in South Wales. A study of urinary steroids. Brit. med. or. iv~ 768 (1970). A.P. WADE,J. C. DAVIS,M. C. K. TWEEDIE,C. A. CLARKEand B. HAGGART, The discriminant function in early carcinoma of the breast. Lancet |~ 853 (1969). G. LECLERCQ,J. C. HEUSON, M. C. DEBOELand O. MATTHEIEM,Oestrogen rcccptors in breast cancer: a changing concept. Brit. med. J. l~ 185 (1975). L. LISKOWSKIand D. P. RosE, Experience with a simple method for estrogen receptor assay in breast cancer. Clin. chim. Acta. 67~ 175 (1969). W . L . McGumE, P. P. CARBONE,M. E. SEARSand G. C. ESCHER, Estrogen receptors in human breast cancer: an overview. In Estrogen Receptors in Human Breast Cancer. (Edited by W. L. McGuirc, P. P. Carbone and E. P. Vollmer) p. 1. Raven Press, New York (1975). B.S. THOMAS,R. D. BULBROOK,J. A. DURANT, H. MILLERand D. M. ROSEE, A rapid method for the estimation of I 1-deoxy-17-oxosteroids and its use in the management of patients with breast cancer. Clin. Biochem. 29 311 (1969). Y . J . ABUL HAjj, Metabolism of dehydroepiandrosterone by hormonedependent and hormone-independent human breast carcinoma. Steroids 26~ 488 (1975). E. V. JENSEH, G. E. BLOCK, S. SMITH, K. KYSER and E. R. DESOMBm~, Estrogen receptors and breast cancer response to adrenalectomy. Nat. Cancer Inst. Monogr. 34, 55 (1971).
Correlation Between Urinary Steroids and Estrogen Receptor Content in Women with Early Breast Cancer* Y. J. ABUL HAJJ College of Pharmacy, University of Minnesota, Minneapolis, M N 55455, U.S.A. Abstract--The urinary levels of l l-deoxy-17-ketosteroids and estrogen receptor content in tumor tissues were determined in 76 patients with early breast cancer. Twenty-six postmenopausal and 16 premenopausal patients with estrogen receptor negative tumors wae found to excrete subnormal amounts of l l-deoxy-17-ketosteroids while 22 postmencpausal and 12 premenopausal patients with estrogen receptor containing tumors excrete near normal levels of urinary 11-deoxy-17-ketosteroids.
Estrogen receptors (ER) have been demonstrated in approximately 70% of human breast cancer [11, 12]. The absence of E R almost always indicates that the tumor will be resistant to endocrine therapy while their presence is associated with a remission of advanced breast cancer in about 55% of eases [13]. In view of the fact that both an abnormality in urinary excretion of steroid metabolites and E R content in m a m m a r y tumors have been shown to be predictors of hormone responsiveness, the present study was undertaken to determine whether there is any correlation between the E R content in human breast cancer and the urinary excretion of 11-deoxy17-ketosteroids.
INYRODUCTION ENDOCRINE responsive tumors in women with metastatic breast cancer constitute only 2040% of patient,~ treated by surgical ablation or by pharmacologic hormone therapy. A number of clinical, pathologic, and biochemical criteria have been used in an attempt to predict the clinical course of patients with breast cancer after therapy [1]. Various studies have indicated a possible association between abnormal levels of androgen and corticosteroid metabolites in urine and plasma and the occurrence of breast cancer. The most convincing endocrine abnormality in patients with breast cancer has been found to be a subnormal excretion of ll-deoxy-17ketosteroids ( l l - D O K S ) [2-5] which can predict with cont;iderable accuracy, either alone or in combination with urinary excretion of corticosteroids, the response to endocrine ablation therapy in patients with breast cancer. While these results have been supported by several investigators [4-7] others have disagreed with these findings [8-10]. The balance of evidence indicates that some steroid metabolites are present in abnormal concentrations in the urine and plasma of women, with breast cancer.
MATERIAL A N D M E T H O D S Control and cancer patients The subjects were patients admitted to the American University of Beirut Hospital and came from various countries of the Middle East. Eighty-eight per cent of the patients were Lebanese. The rest came from Syria and Jordan. A total of 76 patients with primary breast cancer were included in this study (28 premenopausal, mean age 44.6 + 4.4 years; and 46 postmenopausal, mean age 64.7 _+ 6-3 years). The controls were 27 healthy premenopausal (mean age 43.3 + 4.7 years) and 36 postmenopausal (mean age 62.4 __+4.6 years) women, none of whom were taking any form of steroid preparations. The urine from control subjects was collected at home from normal
Accepted 7 December 1976. "~This work was supported in part by a grant from the Graduate School, University of Minnesota. Part of this work was conducted at the American University of Beirut, Lebanon while on sabbatical leave from the University of Minnesota. 749
750
Y. J . Abul Hajj
healthy women, but in 9 instances, the urine was obtained from patients in a geriatric ward. Urine collection and analysis
Urine was collected from all patients 48 hr before operation. Urine analysis was done on 24-hr specimens stored at - 2 0 ° C without preservative. The techniques used for the determination of 11-deoxy-17-ketosteroids (etiocholanolone + androsterone + dehydroepiandrosterone) were based on that described by Thomas et al. [14].
The results show also that there is a significant difference between the mean levels of l l - D O K S in the pre- and postmenopausal control and cancer patients, there being a substantial reduction in l l-DOKS excretion after the menopause.
Urinary II-DOKS ( mg/24 hr)
Estrogen receptor determination
Estrogen receptor content of the tumor samples was carried out using the dextrancharcoal coated technique as determined previously [15]. Expression and evaluation o f results
The levels of urinary 11-deoxy-17-ketosteroids were calculated and expressed as means + S.D. in rag/24 hr urine. Results were evaluated statistically by use of the t-test. Differences between means were considered statistically significant at P < 0.05.
_~
::
"": .::
2
+.::5 .-:::
ER+
ER-
C
Fig. 1. Urinary ll-deoxy-17-ketosteroids (ll-DOKS) by postmenopausal women in control subjects (C) and breast cancer patients with estrogen receptor positive (ER+ ) and estrogen receptor negative ( E R - ) tumors. The horizontal bars show the means. Urinary II-DOKS (mg/24hr)
RESULTS The urinary excretion of 11-DOKS has been estimated in normal women and patients with primary breast cancer. The mean excretion of l l-DOKS (Fig. 1) in the normal postmenopausal group was found to be 1.66 + 0.88 rag/24 hr, 1.44 _+ 0.54 rag/24 hr in the postmenopausal ER positive group and 0.75 _+ 0.28 rag/24 hr in the postmenopausal ER negative group. There was no significant difference between the control group and the ER positive groups, P < 0.30, while the difference between the control group and the ER negative group was found to be very significant, P < 0.001. Figure 2 shows the distribution and the means of urinary 11-DOKS in normal premenopausal women and patients with ER positive and ER negative primary breast cancer. The mean excretion was found to be 4.18 ___ 0.47, 3.91 4_ 0.42, and 3.66 _+ 0.55 rag/24 hr, for the normal group, the ER positive group and the ER negative group, respectively. The results show that there was no significant difference between the control group and the E R positive group (P < 0.20), but that there was a significant difference between the control group and the ER negative group (P < 0.005).
::
C
ER+
ER-
Fig. 2. Urinary ll-deoxy-17-ketosteroids (II-DOKS) by ~OremenojOausal women in control subjects (C) and breast cancer patients with estrogen receptor positive (ER+ ) and estrogen receptor negative (ER - ) tumors. The horizontal bars show the means.
DISCUSSION Abnormalities in urinary excretion of steroid metabolites have been observed by Bulbrook and his colleagues in women with both primary [3] and advanced [4] cancer of the breast and have been related to the prognosis and outcome of endocrine surgery. These observations were supported by several groups of investigators [6, 7] while others have presented evidence [8-10] in variance with that presented by
Correlation Between Urinary Steroids and Estrogen Receptor Content Bulbrook and his coworkers. However, it is generally accepted that significantly low levels of androgen metabolites are associated with poor prognosis in patients with advanced breast cancer. The initial re,;ults of Jensen [16] on the use of E R content in breast tumor tissues for predicting response to endocrine therapy has been confirmed by other investigators [13]. The presence of E R in tumors of patients with advanced breast cancer increases the likelihood of response to endocrine therapy from about 25 to 55-60%. A favorable predicdon based on E R alone will, therefore, prove incorrect in approximately 40% of eases. But, in E R negative tumors the chances of regression in response to endocrine therapy are minimal, and so selection based on the E R assay alone will still save many patients from profitless major endocrine surgery. If in fact the low levels of urinary 11-DOKS excretion and the absence of E R are both predictors of hormone unresponsiveness, then they should correlate well in the same group of patients. O n the other hand, cases in which hormone dependence has not been lost, one might expect to have a near normal level of urinary 11-DOKS as well as the presence of E R in the same group of patients. The results obtained from this study show that there is good correlation between the absence of E R and low levels of l l - D O K S in both pre- and postmenopausal patients, though the significance levels are different. Also, there was a good correlation between the presence of E R and the near normal valLues for l l - D O K S in both the pre- and postmenopausal group. There was no significant diffe:rence between the means for 11-DOKS in patients with E R positive tumors and the control groups, yet one observes a slight decrease in the means for 11-DOKS in both the pre- and postmenopausal group with
mean differences of 0.27 and 0"22 rag/24 hr, respectively. This slight decrease in the mean level of urinary 11-DOKS in patients with E R positive tumors might be due to the contribution of the lower urinary 11-DOKS in those patients that do not respond to endocrine therapy, even though E R are present in the tumors of these patients. Whilst it is now well established that absence of E R in a breast tumor almost invariably indicates that the tumor will be resistant to endocrine therapy [13], the situation regarding the urinary levels of androgen metabolites remains equivocal. However, the fact that a good correlation was obtained between the absence of ER, and the low levels of 11-deoxy17-ketosteroids, suggests that patients unresponsive to endocrine therapy excrete subnormal amounts of 1 l-deoxy-17-ketosteroids. Furthermore, our results show that responsive patients, as determined by the presence of ER, excrete near normal values of 11-deoxy- 17-ketosteroids even though about 40% of patients with E R positive tumors are endocrine resistant. The findings obtained from this study may imply that only those tumors growing in a normal environment respond to the alterations in the environment brought about by the treatment and it remains to be seen whether patients with E R positive tumors that do not respond to endocrine therapy have in fact a significantly lower level of urinary 11-deoxy- 17-ketosteroids than patients with E R positive tumors that do respond to endocrine therapy.
Acknowledgements--The author wishes to thank Drs. V. Nassar, Pathologist, Dr. K. Bikhazi, Surgeon and Dr. I. Salti of the American University Hospital, Beirut, Lebanon, for their continued cooperation and support during this project. The skilled technical assistance of I. Sahli and N. Usama is also acknowledged and appreciated.
REFERENCES I. 2. 3. 4.
5.
H
75I.
A . P . M . FORREST and P. B. KUNKLER, Prognostic Factors in Breast Cancer. Livingston, Edinburgh (1968). tl.. D. BULBROOK,F. C. GREENWOODand J. L. HAYWARD,Selection of breast cancer patients for adrenalectomy by determination of urinary 17-hydroxycorticosteriods and aetiocholanolone. Lancet is 1154 (1960). R . D . BULBROOK,J. L. HAYWARD,C. C. SPICER and B. S. THOMAS,Abnormal excretion of urinary steroids by women with early breast cancer. Lancet il, 1238 (1962). R . D . BULBROOK,J. L. HAYWARD, C. C. SPICER and B. S. THOMAS, A comparison between the urinary steroid execretion of normal women and women with advanced breast cancer. Lancet ii D1235 (1962). R . D . BULBROOK,J. L. HAYWARDand B. S. THOMAS, The relation between the urinary 17-hydroxycorticosteroids and 11-keto-17-oxosteroids and the fate of patients after mastectomy. Lancet i, 945 (1964).
752
Y. J. Abul Hajj 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16.
S. KUMAOKI,N. SAKAUGHI,0. ABE, M. KUSAMAand O. TAKATONI,Urinary 17-ketosteroid execretion of women with advanced breast cancer, or. din. Endocr. 28, 667 (1968). H. MILLER and J. A. DURANT, The value of urine steroid hormone assays in breast cancer. Clin. Biochem. 1, 287 (1968). K . A . AHLQUIST,A. W. JACKSONand J. G. STEWARD,Urinary stcroid values as a guide to prognosis in breast cancer. Brit. med. J. i, 217 (1968). E . D . H . CAMERON,K. GRIFFITHS,E. N. GLEAVE,H. J. STEWART,A. P. M. FORP~ST and H. CAMPBELL,Benign and malignant breast disease in South Wales. A study of urinary steroids. Brit. med. or. iv~ 768 (1970). A.P. WADE,J. C. DAVIS,M. C. K. TWEEDIE,C. A. CLARKEand B. HAGGART, The discriminant function in early carcinoma of the breast. Lancet |~ 853 (1969). G. LECLERCQ,J. C. HEUSON, M. C. DEBOELand O. MATTHEIEM,Oestrogen rcccptors in breast cancer: a changing concept. Brit. med. J. l~ 185 (1975). L. LISKOWSKIand D. P. RosE, Experience with a simple method for estrogen receptor assay in breast cancer. Clin. chim. Acta. 67~ 175 (1969). W . L . McGumE, P. P. CARBONE,M. E. SEARSand G. C. ESCHER, Estrogen receptors in human breast cancer: an overview. In Estrogen Receptors in Human Breast Cancer. (Edited by W. L. McGuirc, P. P. Carbone and E. P. Vollmer) p. 1. Raven Press, New York (1975). B.S. THOMAS,R. D. BULBROOK,J. A. DURANT, H. MILLERand D. M. ROSEE, A rapid method for the estimation of I 1-deoxy-17-oxosteroids and its use in the management of patients with breast cancer. Clin. Biochem. 29 311 (1969). Y . J . ABUL HAjj, Metabolism of dehydroepiandrosterone by hormonedependent and hormone-independent human breast carcinoma. Steroids 26~ 488 (1975). E. V. JENSEH, G. E. BLOCK, S. SMITH, K. KYSER and E. R. DESOMBm~, Estrogen receptors and breast cancer response to adrenalectomy. Nat. Cancer Inst. Monogr. 34, 55 (1971).
