The Prognostic Significance of Estrogen Receptors in Human Breast Cancer William S. Fletcher, MD, Portland, Oregon Benjamin S. Leung, PhD,* Portland, Oregon Charlene E. Davenport, BS, Portland, Oregon
The concept that some breast cancers might respond to endocrine manipulation was first introduced by Beatson [I] in 1896, when he found that two patients with advanced breast cancer responded to oophorectomy. This concept lay fallow until the early 1950s when Huggins and his associates [2-41 at the Ben May Laboratory, University of Chicago established that a number of cancers, including cancer of the breast, were hormonally responsive. It was for this and other related scientific discoveries that Doctor Huggins was awarded the Nobel Prize. Doctor Elwood Jenson, also of the Ben May Laboratories, built on these observations by bringing to the problem his expertise in the basic sciences. In 1971 he described the presence of an estrogen receptor (ER) in the cytoplasm of some breast cancer cells and indicated that patients with ERs in their tumor responded better to hormonal manipulation than patients without ERs [S-6]. Jenson’s observations were confirmed by our experiences with a series of breast cancer patients undergoing oophorectomy or oophorectomy and adrenalectomy [7-91. In 1975, the proceedings of an international symposium were published which summarized all of the information on ERs in human breast cancer to that time [IO]. Approximately 65 per cent of ER-positive patients were found to respond to hormonal manipulation, whereas only 7 per cent of ER-negative patients responded. At that symposium, Leung et al [11] reported on fifty-six stage IV breast cancer patients treated by endocrine ablation who had known ER values and measurable tumor, and had had no other therapy. Eight patients underwent oophorectomy only and were not considered evaluable. The remaining forty-eight patients underwent total endocrine
From the Division of Surgical Oncology. University of Oregon Health Sciences Center, Portland, Oregon. This work was supported in part by grant no. RlO AC 12279 from ths NatioMl Cancer Institute.department of Health, Education, and Welfare; Public Health Gant RR-334 from ths General Clinical Resources Branch, National Institutes of Health: and a gift from the Grand Chapter of Oregon, Order of the Eastern Star. Reprint requests should be addressed to William S. Fletcher, MD, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201. Present address: Cedars-Sinai Medical Center, Box 48750, Los Angeles, California 90048. l
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ablation by oophorectomy and adrenalectomy or hypophysectomy (1 patient); they were all reviewed independently by a team of investigators from the National Cancer Institute who confirmed the authors’ evaluation of the responses. The present study presents the long-term followup results of the forty-eight patients reported on in 1975 and shows clearly that ER-positive patients fare much better than ER-negative patients. Material and Methods Forty-eight female patients with biopsy-proven stage IV breast cancer and measurable tumors were treated by complete endocrine ablation only at or after the time of recurrence. One patient underwent hypophysectomy. The remainder had sequential bilateral oophorectomy followed by bilateral adrenalectomy. All patients were followed for at least two months without other anticancer therapy to evaluate the response to endocrine ablation. Most patients had large tumor burdens. Responses were categorized as follows: complete response, total disappearance of all measurable tumor for a period of two months or more; partial response, a 50 per cent reduction in diameter of the measurable tumor for two months or more; no change, neither a 50 per cent increase nor decrease in the diameter of the measurable tumor for two months or more; and progression, a 50 per cent increase in the diameter of the measurable tumor or documented progression of tumor elsewhere in the body within two months. Responses of the fifty-six patients reported on in 1975 [II] were as follows. Of those ER-positive patients undergoing total endocrine ablation, 65 per cent had a complete or partial response. The disease stabilized in several more of these patients, bringing to 76 per cent the proportion of ER-positive patients who benefited from endocrine ablation. Only three of the sixteen (19 per cent) ER-negative patients had a response, and two of these responses were short-lived. The ER determination in the one long-term ER-negative survivor was performed on bone marrow, which is now considered to be an unreliable tumor sample for this test. All but two of the forty-eight patients had chemotherapy or antiestrogen therapy for progressive disease after the two month period of observation [12,13]. The therapy was not the same for all patients but consisted of what was believed to be the most effective at the time. Most ER-
The American
Journal of Surgery
Estrogen Receptors and Breast Cancer positive patients who had responded to endocrine ablation subsequently responded to antiestrogen therapy [13]. No ER-negative patients responded to antiestrogens [12]. All patients were followed until death or to July 1977. Differences in survival between ER-positive and ERnegative patients were compared using the chi-square test for proportions in two independent samples. Results
As of July 1, 1977 seven of thirty-three (21 per cent) ER-positive patients were alive, whereas only one of fifteen (7 per cent) ER-negative patients was alive (p CO.025). The latter patient was the one whose ER value was established from a bone marrow specimen. Figure 1 depicts the mean survival of the two groups. Whether measured from the primary treatment, the time of recurrence, or the time of endocrine ablation, survival was 50 to 100 per cent longer (p
The concept that some breast cancers might respond to endocrine manipulation was first introduced by Beatson [I] in 1896, when he found that two patients with advanced breast cancer responded to oophorectomy. This concept lay fallow until the early 1950s when Huggins and his associates [2-41 at the Ben May Laboratory, University of Chicago established that a number of cancers, including cancer of the breast, were hormonally responsive. It was for this and other related scientific discoveries that Doctor Huggins was awarded the Nobel Prize. Doctor Elwood Jenson, also of the Ben May Laboratories, built on these observations by bringing to the problem his expertise in the basic sciences. In 1971 he described the presence of an estrogen receptor (ER) in the cytoplasm of some breast cancer cells and indicated that patients with ERs in their tumor responded better to hormonal manipulation than patients without ERs [S-6]. Jenson’s observations were confirmed by our experiences with a series of breast cancer patients undergoing oophorectomy or oophorectomy and adrenalectomy [7-91. In 1975, the proceedings of an international symposium were published which summarized all of the information on ERs in human breast cancer to that time [IO]. Approximately 65 per cent of ER-positive patients were found to respond to hormonal manipulation, whereas only 7 per cent of ER-negative patients responded. At that symposium, Leung et al [11] reported on fifty-six stage IV breast cancer patients treated by endocrine ablation who had known ER values and measurable tumor, and had had no other therapy. Eight patients underwent oophorectomy only and were not considered evaluable. The remaining forty-eight patients underwent total endocrine
From the Division of Surgical Oncology. University of Oregon Health Sciences Center, Portland, Oregon. This work was supported in part by grant no. RlO AC 12279 from ths NatioMl Cancer Institute.department of Health, Education, and Welfare; Public Health Gant RR-334 from ths General Clinical Resources Branch, National Institutes of Health: and a gift from the Grand Chapter of Oregon, Order of the Eastern Star. Reprint requests should be addressed to William S. Fletcher, MD, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201. Present address: Cedars-Sinai Medical Center, Box 48750, Los Angeles, California 90048. l
372
ablation by oophorectomy and adrenalectomy or hypophysectomy (1 patient); they were all reviewed independently by a team of investigators from the National Cancer Institute who confirmed the authors’ evaluation of the responses. The present study presents the long-term followup results of the forty-eight patients reported on in 1975 and shows clearly that ER-positive patients fare much better than ER-negative patients. Material and Methods Forty-eight female patients with biopsy-proven stage IV breast cancer and measurable tumors were treated by complete endocrine ablation only at or after the time of recurrence. One patient underwent hypophysectomy. The remainder had sequential bilateral oophorectomy followed by bilateral adrenalectomy. All patients were followed for at least two months without other anticancer therapy to evaluate the response to endocrine ablation. Most patients had large tumor burdens. Responses were categorized as follows: complete response, total disappearance of all measurable tumor for a period of two months or more; partial response, a 50 per cent reduction in diameter of the measurable tumor for two months or more; no change, neither a 50 per cent increase nor decrease in the diameter of the measurable tumor for two months or more; and progression, a 50 per cent increase in the diameter of the measurable tumor or documented progression of tumor elsewhere in the body within two months. Responses of the fifty-six patients reported on in 1975 [II] were as follows. Of those ER-positive patients undergoing total endocrine ablation, 65 per cent had a complete or partial response. The disease stabilized in several more of these patients, bringing to 76 per cent the proportion of ER-positive patients who benefited from endocrine ablation. Only three of the sixteen (19 per cent) ER-negative patients had a response, and two of these responses were short-lived. The ER determination in the one long-term ER-negative survivor was performed on bone marrow, which is now considered to be an unreliable tumor sample for this test. All but two of the forty-eight patients had chemotherapy or antiestrogen therapy for progressive disease after the two month period of observation [12,13]. The therapy was not the same for all patients but consisted of what was believed to be the most effective at the time. Most ER-
The American
Journal of Surgery
Estrogen Receptors and Breast Cancer positive patients who had responded to endocrine ablation subsequently responded to antiestrogen therapy [13]. No ER-negative patients responded to antiestrogens [12]. All patients were followed until death or to July 1977. Differences in survival between ER-positive and ERnegative patients were compared using the chi-square test for proportions in two independent samples. Results
As of July 1, 1977 seven of thirty-three (21 per cent) ER-positive patients were alive, whereas only one of fifteen (7 per cent) ER-negative patients was alive (p CO.025). The latter patient was the one whose ER value was established from a bone marrow specimen. Figure 1 depicts the mean survival of the two groups. Whether measured from the primary treatment, the time of recurrence, or the time of endocrine ablation, survival was 50 to 100 per cent longer (p
