Breast Cancer. Reproductive History. Estrogen Replacement Therapy.
Reproductive History
Certain reproductive characteristics–nulliparity, early age of menarche, older age at menopause, and older age at first full-term pregnancy–have been associated with increased risk of breast cancer. Oophorectomy at an early age has been considered protective in reducing the risk of breast cancer in reproductive-age women by almost 70%. It has been suggested that the period between the onset of menses and the age of first pregnancy provides a “window of initiation” for the development of breast cancer. This theory presents a paradox, at least in terms of the functional activity of the breast. Anatomically and functionally the breasts undergo atrophy with advancing age. Less than 25% of breast cancers occur in premenopausal women.
It has been widely believed that lactation has no effect on the incidence or the risk of breast cancer. According to a recent study, however, there is a reduction in the risk of breast cancer among premenopausal women who have lactated, but no reduction among postmenopausal women with a history of lactation. Thus, the role of lactation, specifically the biologic effect of lactation on breast cells, is unclear. The stronger effect of lactation as a protective factor at an early age suggests that decreased exposure to ovarian hormones at a younger age may be important. This theory is in keeping with the previous discussion concerning early age of menarche and the effect of ovarian hormones on developing breast parenchyma. Lactation is a behavior that can be altered; although the apparent effect of lactation is not great, any reduction in breast cancer incidence would be significant, especially in younger women.
Estrogen Replacement Therapy
Physicians should understand the rationale for estrogen replacement therapy, especially in terms of the prevention of cardiovascular disease and osteoporosis, and at the same time be aware of the lack of data to support the unequivocal recommendations for estrogen replacement therapy in patients treated for breast cancer.
There are a number of interesting observations that suggest a relationship between estrogen replacement therapy and breast cancer. It has been known for many years that oophorectomy before the age of 35 years reduces the risk of breast cancer by 70%. Patients with metastatic breast cancer treated with aminoglutethimide, an aromatase inhibitor, have a marked reduction in estradiol from 15-20 pg/mL to about 5 pg/mL because of the failure of conversion of hormones into estrogen. The level of estradiol is increased to 30-35 pg/mL with estrogen replacement therapy.
A number of clinical studies have reported that the risk of breast cancer is slightly elevated among users of estrogen replacement therapy. A meta-analysis concluded that women who had used estrogen in the past are not at an increased risk, but that current use may be associated with increased risk, although the relationship to breast cancer mortality was less clear.
There is no question that breast cancer is related to reproductive events. Increasing attention to the contemporary preventive approach to breast cancer focuses on the physiologic effects of the sex steroid hormones and their possible interaction with family history. Adding to the potential risks of estrogen replacement therapy is that current use of estrogen replacement therapy may be associated with lower specificity and lower sensitivity of screening mammography.
Successful treatment of breast cancer depends on local control, and there is always the potential for distant metastasis. If the patient is free of metastatic disease, the question is moot. Unfortunately, not all of the patients with breast cancer are cured even with the most effective treatment. The effect of estrogen replacement therapy on occult metastatic disease is the basis for the caution regarding the use of estrogen replacement therapy in these patients. The receptor data and other prognostic factors appear to be of little value, at the present time at least, in deciding for or against estrogen replacement therapy in these patients. Although the original tumor may be estrogen receptor negative, the subsequent metastases may be estrogen receptor positive. Finally, it is important to understand that if overt metastatic disease is discovered, treatment–how-ever aggressive–will be ineffective.
In considering estrogen replacement therapy, therefore, the physician should discuss benefits and the risks with the patient, including the uncertainty of the available data regarding risk. Vaginal administration of estrogen is not without concern. Estrogen is absorbed readily from the vaginal mucosa, especially if it is atrophic. There is decreased absorption with increasing vaginal cornification, but the absorption is perhaps sufficient to stimulate occult micrometastases.