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Women with a strong family history of breast and/or ovarian cancer have a greatly increased risk for the development of these diseases. The key question for these women is what they can do to ameliorate their cancer risk. Fortunately, there are now several interventions which clearly reduce breast and ovarian cancer risk in high-risk women. These include risk-reducing bilateral mastectomy, salpingo-oophorectomy and chemoprevention with tamoxifen or raloxifene. For those women who do not undergo risk-reducing bilateral mastectomy, screening is generally recommended in order to try and detect breast cancers at an early stage. Breast magnetic resonance imaging has an emerging role in such screening programs. Cancer screening does not reduce cancer risk and its impact on reduction of mortality in this group is uncertain. Women at high risk should be fully informed of their surgical, chemopreventive and screening options. A risk management plan should be tailored to each woman, particularly taking into account the level of her short-term (rather than lifetime) risk, her lifestyle plans (such as child-bearing), competing risks (particularly in women with a prior cancer) and her personal preferences. The risk management plan should be reviewed regularly and altered as the individual's short-term risk level and circumstances change, and as the evidence base for various interventions builds. Participation in appropriate clinical trials should be offered.

The story of deciphering the mechanisms that control the growth of sex-hormone-dependent cancers started more than a hundred years ago. Clinical observations of the apparently random responsiveness of breast cancer to endocrine ablation (hormonal withdrawal) provoked scientific enquiry in the laboratory that resulted in the development of effective strategies for targeting therapy to the estrogen receptor (ER) (or the androgen receptor in the case of prostate cancer), the development of antihormonal treatments that dramatically enhanced patient survival, and the fi rst successful testing of agents to reduce the risk of developing any cancer. Most importantly, elucidating the receptor-mediated mechanisms of sex-steroid-dependent growth and the clinical success of antihormones has had broad implications for medicinal chemistry with the synthesis of new selective hormone receptor modulators for numerous clinical applications. Indeed, the successful translational research on the ER was the catalyst for the current strategy for developing targeted therapies for the tumor and the start of “individualized medicine.” Over the past 50 years, ideas about the value of antihormones have translated effectively from the laboratory to improvement of clinical care, increase in national survival rates and signifi cant reduction in the burden of cancer.

The clinical fi nding that the rodent antifertility agent nonsteroidal antiestrogen clomiphene (a mixture of geometric isomers) was actually a profertility agent in subfertile women created the first practical method for enhancing fertility in women. A related compound, ICI 46,474, the pure trans isomer of a substituted triphenylethylene, was also a product of an industry fertility control program in the 1960s and it too was tested and then marketed in the United Kingdom as an inducer of ovulation in subfertile women, at the same time as an orphan drug for the treatment of metastatic breast cancer in postmenopausal women. Clomiphene has, however, remained the clinical gold standard for the induction of ovulation worldwide for 40 years. However, the fact that tamoxifen is a potent inducer of ovulation in premenopausal women remains an important consideration in breast cancer patients made infertile by combination cytotoxic chemotherapy. This chapter will trace the genesis of agents for the induction of ovulation and the current potential applications of tamoxifen for women with breast cancer who choose to preserve fertility.

Breast cancers that occur in women who carry mutations of the breast cancer susceptibility gene 1 (BRCA1) are mostly estrogen receptor (ER)–negative; while those that occur in BRCA2 mutation carriers are usually ER-positive, similar to sporadic breast cancers. Despite these phenotypic differences, the evidence suggests that hormonal factors affect the risk of breast cancer in both BRCA1 and BRCA2 mutation carriers. In particular, prophylactic oophorectomy reduces breast cancer risk and the antiestrogen tamoxifen reduces the occurrence of contralateral breast cancer in both BRCA1 and BRCA2 carriers. Interestingly, while both BRCA1 and BRCA2 exert important functions in DNA repair and the maintenance of genomic integrity, cell-biologic and animal studies indicate that BRCA1 exerts an additional function in the regulation of ER activity that may, in part, explain why BRCA1 mutation carriers develop hormonally infl uenced tumor types. Here, BRCA1 binds directly to the ER and inhibits its transcriptional activity, through a specifi c posttranslational modifi cation (monoubiquitination). BRCA1 also binds to the progesterone receptor (PR) and inhibits its activity; and, in mouse models, BRCA1 loss-of-function mutations confer enhanced proliferative responses to estrogen and progesterone and an increased incidence of ER-driven mammary cancers. Finally, recent studies suggest that BRCA1 may function in mammary epithelial cell differentiation by promoting the conversion of ER-negative stem cells to ER-positive cells. Together, these experimental fi ndings are beginning to shed light on the puzzling clinical observations that hormonal manipulations can alter breast cancer risk in BRCA1 mutation carriers even though a large majority of BRCA1-related breast cancers are ER-negative.

The development of effective, life-saving strategies for the adjuvant antihormone treatment of estrogen receptor (ER)–positive breast cancer is a major advance in medicine. The effectiveness of the long-term adjuvant tamoxifen therapy has saved perhaps millions of lives worldwide during the past 30 years. However, tamoxifen therapy for the postmenopausal patient has the concern of a small but significant increase in endometrial cancer and thromboembolic events. The innovation of blocking endogenous estrogen synthesis with aromatase inhibitors has not only reduced the side effects of tamoxifen with endometrial cancer and thromboembolic disorders but also enhanced survivorship. Tamoxifen remains the endocrine treatment of choice for the premenopausal patient.

The estrogen receptor (ER) has proved to be an excellent target for the treatment and prevention of breast cancer. Although the majority (80%) of breast cancer is ER positive, not all ER positive tumors respond to antihormone therapy. When an ER positive tumor does not respond at all to antihormone therapy it is described to have intrinsic resistance. This contrasts with acquired antihormone resistance where the tumor initially responds with regression but then cell populations expand that grow because of tamoxifen or despite estrogen deprivation. Based on laboratory studies using ER positive cell lines, the evolution of acquired antihormone resistance has been documented. Growth factor pathways expand and subvert the action of the ER at the genome. The new knowledge about molecular mechanisms of resistance has created new opportunities for combinations of antihormone therapies and inhibitors of growth factor pathways.

During the past four decades, the prospects of developing medicines to reduce the risk of breast cancer in healthy women have gone from a laboratory concept to a clinical reality. Tamoxifen, the pioneering selective estrogen receptor modulator (SERM), was initially shown to prevent rodent mammary carcinogenesis and the data were used to suggest prospective placebo-controlled clinical trials. Tamoxifen reduced the incidence of breast cancer by 50%; but, most importantly, this reduction versus placebo was maintained for a decade after stopping the drug. A small but significant increase in endometrial cancer in postmenopausal women taking tamoxifen, but not premenopausal women, makes tamoxifen the chemopreventive of choice for the high risk premenopausal woman. The finding that the SERM raloxifene maintains bone density in postmenopausal women but decreases breast cancer incidence without an increase in endometrial cancer makes raloxifene the chemopreventive of choice in postmenopausal women. A range of new and novel SERMs has completed clinical testing.