Hormones and Breast Cancer
Breast tissue is sensitive to and affected by a variety of hormones, including estrogen, progesterone, somatostatin, mammostatin, mammary derived growth inhibitor (MDGI), mammary derived growth factor 1 (MDGF-1), inhibins, activins, androgens, glucocorticoids, thyroid hormone, ecosinoids, oxytocin and vitamin D. The two major hormones, estrogen and progesterone have specific receptors in breast tissue. The estrogen receptor is activated when estrogen is bound to it and the complex translocates to the nucleus of the breast cell where it induces cellular genes. The genes in turn encode for production of peptide growth factors and also result in the production of the progesterone receptor protein (Thus a patient cannot be PR+ but ER-, although they often appear to be clinically).
These same hormones affect breast cancer cell growth. The majority of breast cancers contain detectable levels of estrogen and progesterone receptors and older patients are more likely to be ER+. Estrogen is produced primarily in the ovaries (premenopausal), adipose tissue, and adrenal glands, and the latter are stimulated by pituitary adrenocorticotrophic hormone (ACTH).
Estrogen reduction by oophorectomy, adrenalectomy and hypophysectomy has been practiced for many years to retard the progression of advanced breast cancer and was effective in 1/3 of unselected patients. The use of the first generation, non-specific aromatase inhibitor aminoglutethamide replaced surgical adrenalectomy, and works by blocking adrenal steroid production including conversion of adrenal androgen to estrogen. Second generation aromatase inhibitors such as anastrozole specifically target the androgen to estrogen pathway and eliminate the need for steroid replacement. Aromatase inhibitors are not used for premenopausal women because the pituitary compensates for the decreased adrenal estrogen by stimulating the ovaries to produce more. Current hormone therapy utilizes selective hormone receptor modulators (SERMs) such as tamoxifen and raloxifene to specifically target hormone receptors. Because they are weaker estrogen agonists than native estrogen, they competitively inhibit the binding of estrogen to the receptor and result in reduced stimulation of breast tissue.
Hormone therapy is used therapeutically for recurrent breast cancer, as adjuvant therapy in localized disease to help treat potential occult micrometastases, and now prophylactically in high-risk patients. Distant metastatic breast cancer remains incurable with a natural history of 18-24 months survival, and the role of hormone therapy is to reduce the progression of disease. Patients with ER+ tumors have an 80% chance of response, ER- only a 10% chance. Patients who have primarily bone or soft tissue metastatic disease and who have had a long disease-free interval are good candidates for hormone therapy. About 10% of patients will experience transient tumor flare with initiation of hormone therapy with onset within hours to days and resolution within a few weeks.
Multiple trials, starting with the Swedes in 1975 using adjuvant hormonal therapy in patients with localized disease have demonstrated increased disease-free survival and a modest increase in overall survival. Patients who respond to one form of hormone therapy are likely to respond to another, but the degree of response decreases with each succeeding line of defense just as it does with chemotherapeutic agents. Recurrent tumors may also change their estrogen receptor status and should be rebiopsied to determine the probability of response.
Increasing public awareness and the widespread use of screening mammography have led to the majority of breast cancers being detected early. Only 5-10% of patients have metastatic disease at presentation. The National Surgical Adjuvant Breast Project (NSABP) protocol B-24 in 1991 assessed the use of the SERM tamoxifen (TAM) in 18,000 women who underwent breast-conserving resection (lumpectomy) and radiation for ductal carcinoma in situ (DCIS). Such patients have a natural history of recurrent invasive cancer in the same or opposite breast at a rate of 1% per year. The study demonstrated a 30% reduction in ipsilateral recurrence and a 52% reduction in the contralateral breast. Recent NSABP American chemoprevention trials in high-risk patients demonstrated a 49% decrease in risk of developing invasive breast cancer and a 50% decrease in the risk of non-invasive cancer.
Estrogen has a protective effect in maintaining bone mineral density. Women gradually lose bone density after age 30, and the process accelerates after menopause. The World Health Organization defines a bone mineral density between one and 2.5 standard deviations below that of the young adult mean as osteopenia, and below 2.5 as osteoporosis. The most common resulting fractures are vertebral compressions, Colle's wrist, and hip fracture. Twenty five percent of women over 50 have one or more vertebral compression fractures (2/3 of which are asymptomatic). Calcium and vitamin D supplementation, weight-bearing activity, smoking cessation and especially bisphosphonates help reduce bone loss.
Hormone replacement therapy aimed at avoiding bone demineralization by inhibiting osteoclast activity (as well as treating menopausal symptoms such as hot flashes, insomnia and vaginal dryness), also stimulates breast tissue and results in a 1.7 fold relative risk of developing breast cancer. The risk is increased to four fold with combination estrogen and progesterone therapy, and decreases with cessation. The development of SERMs targets reduction in breast stimulation while maintaining the beneficial cardiovascular and skeletal effects of estrogen.
Tamoxifen is the current first line hormonal agent approved for treatment of metastatic disease in postmenopausal women, for ER+, metastatic disease in premenopausal women, for metastatic disease in men, as well as adjuvant therapy for early disease. When bound to the estrogen receptor, TAM causes incomplete change in the tertiary structure of the receptor protein, rendering it incompletely active. The breast protective effects are achieved with a five-year course of 20 mg per day. TAM lowers cholesterol by 11%, increases lumbar spine density by 1.5%, and femoral neck density by 2%. The side effects of TAM, especially in premenopausal women include hot flashes and vaginal discharge. There is a modest increased risk of endometrial carcinoma (6/1000 v 1/1000) as well as deep venous thrombosis and pulmonary embolus (similar to that in hormone replacement therapy). The effect of TAM in patients with the BRCA1 and BRCA2 gene mutations is unknown, but most BRCA1 cancers are ER- and unlikely to be prevented.
Raloxifene, another SERM, developed for treatment of osteoporosis was observed to have cardiovascular and breast protective effects and unlike TAM, uterine protective effects. The current NIH study of tamoxifen and raloxifene (STAR) begun in 1999 will compare the effects of the two drugs in 20,000 women over a 5 year period.
There has been dramatic progress in the addition of hormonal agents for the treatment of all stages of breast cancer in the last decade. Selective aromatase inhibitors have become the first line agents and the progestin megestrol is used as a tertiary agent for advanced disease. Third generation agents act by down regulating the estrogen receptors, destroying them by non-competitive inhibition. Leutinizing hormone releasing hormone (LH-RH) antagonist overstimulates the anterior pituitary, resulting in the ultimate reduction of release of FSH and LH and the decreased output of estrogen by the ovaries. It is delivered as a continuous release subcutaneous implant. These agents are often used in combination with chemotherapeutic agents, especially the anthracyclines. Cyclophosphamide and doxorubicin are the most active and the first line agents of choice. The taxanes (paclitaxel, docetaxel) are used as single second line agents.
Abeloff: Clinical Oncology, 2nd ed., Copyright © 2000 Churchill Livingstone, Inc.
Townsend: Sabiston Textbook of Surgery, 16th ed., Copyright © 2001 W. B. Saunders Company. 569-589
Hormonal therapy for breast cancer. An update. Gradishar WJ - Hematol Oncol Clin North Am - 01-Apr-1999; 13(2): 435-55, vii
The biology of breast cancer. Nass SJ - Hematol Oncol Clin North Am - 01-Apr-1999; 13(2): 311-32
Lufkin EG, The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis. Rheumatic Diseases Clinics of North America Volume 27 o Number 1 o February 2001 Copyright © 2001 W. B. Saunders Company
Hellekson KL, NIH Statement on Adjuvant Therapy for Breast Cancer, American Family Physician
Volume 63 o Number 9 o May 1, 2001