Commentary (Lipton): Current Status of Endocrine Therapy for Metastatic Breast Cancer

This year approximately 200,000 new cases of breast cancer will be diagnosed in the United States. Primary surgical treatment plus adjuvant therapy will cure two-thirds of these patients. The remainder, unfortunately, will experience disease recurrence at varying intervals after surgery.

The first suggestion that there might be different biologic subtypes of human breast cancer came from an analysis of patients with untreated breast cancer. Physicians at Middlesex Hospital in England followed 250 women who received no therapy for breast cancer from 1905 to 1923. Two-thirds of these women survived for less than 4 years, whereas one-third lived for over 4 years, some of whom survived for up to 12 to 13 years [1]. The longer-surviving subgroup probably represented women with hormone-dependent breast cancer.

Human breast tumors are either hormone-dependent or hormone-independent based on their responsiveness or resistance to hormonal therapy. Hormone-dependent breast cancer grows more slowly; is more differentiated histologically; contains a lower fraction of cells in the DNA synthesis, or S phase, of the cell cycle; and has a lower proportion of aneuploid cells. These tumors depend on estradiol for growth.

First Direct Evidence of Hormone Dependence

A 1896 report by Dr. George Beatson was the first direct demonstration of hormone dependence of human breast cancer [2]. He observed near-complete tumor regression in some women with metastatic breast cancer whose ovaries were surgically removed. More recently, many investigators reported objective remission rates of 30% to 40% in patients treated with oophorectomy, adrenalectomy, or hypophysectomy [3]. These data clearly established the presence of the hormone-dependent subtype of breast cancer and documented its prevalence to be approximately one in three breast cancers.

The next major development occurred in the 1960s, when Dr. Elwood Jensen and colleagues reported the initial biochemical method to measure the estrogen receptor (ER) [4]. Later studies added the progesterone receptor (PR) as an additional marker for hormone-dependent breast cancer [5]. With ER and PR determinations, the hormone-independent (ie, receptor negative) subgroup can be identified with 95% accuracy and the hormone-dependent subgroupwith 70% to 75% accuracy.

A major goal of the 1970s and 1980s was the development of specific pharmacologic means for eliminating estrogen stimulation of breast cancer. These new agents could replace surgical endocrine ablation, such as oophorectomy, hypophysectomy, and adrenalectomy. Two approaches were used: (1) development of antiestrogens to block estrogen action, and (2) identification of agents to inhibit the biosynthesis of estrogen.

Unresolved Issues

The paper by Drs. Kimmick and Muss is an excellent review of the recent development of new agents available to the clinician for the treatment of hormone-dependent breast cancer. However, many problems remain. We do not cure patients with metastatic hormone-dependent breast cancer. Our new treatments are less toxic but barely more efficacious than those available to our teachers. Combinations of hormone treatments have not proven to be more effective than the sequential use of the same treatment modalities.

Kimmick and Muss address the question of why hormone-dependent breast cancer becomes hormone-independent at the time of disease progression. Another key question, why one-third to one-half of hormone-dependent breast cancers fail to respond to hormone therapy, will be a major focus of investigation into the 21st century.

New Biology of Breast Cancer

Recent work has given us a glimpse of the new biology of breast cancer. The growth of certain breast cancers may be regulated by growth factor-receptor interactions that are independent of estrogen control. The c-erbB2 (Her-2/neu) gene product is closely related to, and yet distinct from, the epidermal growth factor receptor (EGFR). The c-erbB2 protein has been shown to be a surface glycoprotein of 185 to 190 kd, as compared with the 170-kd protein encoded by the EGFR gene.

Recently, two groups of investigators reported that patients with ER-positive/c-erbB2-positive metastatic breast cancer are less likely to respond to hormonal treatment than patients with ER-positive/c-erbB-2-negative disease [6,7]. Regulation of the ER by c-erbB2 (Her-2/neu) signaling may provoke hormone-independent growth. Expression of c-erbB2 results in reduced levels of ER messenger RNA and downregulation of the receptor (unpublished data, Mahitosh M et al; and reference 8). Concurrent blocking of both the ER with tamoxifen and Her-2/neu with an appropriate antibody results in enhanced in vitro inhibition of human breast cancer cell lines [9].

Thus, a better understanding of hormone resistance and the mechanism of conversion from hormone-dependent to -independent breast cancer will lead to new treatments in the coming years.

References:

1. Bloom HJG, Richardson WW, Harries EJ: Natural history of untreated breast cancer (1805-1933): Comparison of treated and untreated cases according to histological grade of malignancy. Br Med J 2:213, 1962.

2. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestion for a new method of treatment with illustrative cases. Lancet 2:104, 1896.

3. Stanten RJ, Manni A, Harvey H, et al: Endocrine treatment of breast cancer in women. Endocrine Rev 11(2):221, 1990.

4. DeSombre ER, Greene GL, Jensen EV: Estrophilin and endocrine responsiveness of breast cancer, in McGuire WL (ed): Hormones, Receptors, and Breast Cancer, p 1. New York, Raven Press, 1978.

5. McGuire WL, Horwitz KB: Progesterone receptors in breast cancer, in McGuire WL (ed): Hormones, Receptors and Breast Cancer, p 31. New York, Raven Press, 1978.

6. Wright C, Nicholson S, Angus B, et al: Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer 65:118-121, 1992.

7 Leitzel K, Teramoto Y, Konrad K, et al: Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13:1129-1135, 1995.

8. Pietras RJ, Arboleda J, Wonguipat N, et al: HER-2/neu signaling regulates estrogen receptor in breast cancer (abstract #1516). Proc Am Assoc Cancer Res 36:254, 1995.

10. Witters L, Kumar R, Chinchilli V, et al: An enhanced inhibitory effect of the combination of tamoxifen plus HER-2/neu antibody on human breast carcinoma cells (abstract #2552). Proc Am Assoc Cancer Res 36:428, 1995.