Future possibilities in the prevention of breast cancer: Luteinizing hormone-releasing hormone agonists

More than a decade ago Pike et al [1] first suggested a potential role for agonists of LHRH to prevent breast cancer. The rationale for considering LHRH agonists is due to their ability to suppress ovarian function and sex steroid production; the reduction in sex steroids is predicted to lead to the prevention of breast cancer.Ovarian hormones (estrogens and progestogens) are critical factors in the genesis of human breast cancer. During the premenopausal years breast cancer risk increases steeply, but after cessation of ovarian function (menopause) it increases at a much lower rate. Epidemiologic studies have clearly demonstrated that early menopause, whether natural or artificial (bilateral oophorectomy), substantially reduces breast cancer risk. Menopause before age 35 years is associated with a 60-75% reduction in breast cancer risk [2,3,4,5,6]. The calculated effect of an early oophorectomy on the age-incidence curve of breast cancer is given in Figure 1; age at menopause determines the transition point from the steeply rising premenopausal slope to the more gentle postmenopausal slope. The protective effect of oophorectomy on breast cancer risk has recently been shown in women carrying BRCA1 germline mutations. Bilateral prophylactic oophorectomy (done to prevent ovarian cancer) is associated with a reduction in breast cancer risk [7]. The magnitude of the protection reported by Rebbeck et al [7] is substantial (hazard ratio of 0.53) and increased with increasing duration of follow up after the prophylactic surgery.The effect of ovarian hormones on breast cancer risk is predictable in light of the effects of these hormones on breast epithelial cell proliferation. Cell proliferation is central to the process of carcinogenesis, and agents that increase cell proliferation increase the incidence of random mutations and hence cancer risk [8]. In the normal human breast epithelial cell, both estrogens and progestogens are mitogens (for review [9]), hence oophorectom