Hormonal prevention of breast cancer

Breast cancer prevention can be provided by using SERMs or aromatase inhibitors depending on the ovarian status, with a global risk reduction of 50 to 60%. Prophylactic annexectomy offered to reduce ovarian risk in BRCA mutation carriers also lowers breast cancer risk by 50%. Main side effects include deep vein thrombosis for SERMs, hot flushes and joint pain (although less frequently than initially suspected) with aromatase inhibitors. Other strategies based on progesterone, insulin or prolactin signaling modulation may be offered in the future. Criteria for candidate selection remain to be established.     

Hormonal therapy for metastatic male breast cancer

Forty-one men with metastatic breast cancer were treated with 70 trials of hormone therapy. These included 25 orchiectomies and 45 additive hormonal treatments. The overall response rate was 31%. The response rate was 32% to orchiectomy, 17% to estrogens, 43% to steroids, 25% to tamoxifen citrate, and 60% to androgens. The response to additive hormonal therapy was 31% and was not affected by prior orchiectomy (33% v 30%). Median overall response duration was 12 months, 17.5 months following orchiectomy, 8.5 months following additive hormonal therapy, five months following estrogens, 11 months following steroids, and eight months following androgens. Median survival from first metastasis was significantly prolonged in patients responding to orchiectomy and additive hormonal therapy. Patients with a disease-free interval (DFI) longer than 12 months had a 59% response rate to hormonal therapy compared with 9% of those with a DFI no more than 12 months. Response to one form of hormonal therapy did not predict later hormonal response. Ablative and additive hormonal therapy offer effective palliation to one third of male breast cancer patients, produce little toxic effects and morbidity, and improve survival duration after metastasis in responders.     

Hormonal therapy of breast cancer: new approaches and concepts.

The most useful new hormonal therapy against estrogen receptor-containing metastatic breast cancer is the development of antiestrogenic agents such as nafoxidine and tamoxifen. Both of these drugs possess antitumor activity comparable to that of other additive hormonal agents, and they are better tolerated for lack of any serious toxicity. The clinical usefulness of antiprolactin drugs in breast cancer is at present limited. Adrenal suppression using aminoglutethimide has been shown to induce useful remissions. We discuss the implications of new treatment modalities for the future management of disseminated breast cancer.     

The endocrine prevention of breast cancer

Breast cancer incidence is increasing in all parts of the world. Although in Western countries death rates are declining, there is a need to make attempts to prevent the disease in order to reduce the trauma of diagnosis and treatment. Endocrine approaches to breast cancer prevention have been the most successful approach to cancer prevention to date. Studies with tamoxifen were initiated when it was noted that, during adjuvant treatment after surgery to prevent relapse, the incidence of new contralateral cancers was reduced by half. Four trials of >or=5 years of tamoxifen compared with placebo in women at increased risk of breast cancer were initiated in the 1980s and showed a similar reduction in breast cancer, but only in oestrogen-receptor-positive disease. Recent follow-up indicated that there is a carry-over effect of tamoxifen after the completion of treatment at 5 years so that the preventive effect at 10 years is significantly great than at 5. The selective oestrogen receptor modulator (SERM) raloxifene has also been assessed as a preventive agent in two major international randomized trials compared with placebo and shows a protective effect similar to that of tamoxifen. An American study subsequently compared tamoxifen and raloxifene in a trial of nearly 20,000 women at increased risk (the STAR trial) and demonstrated that the two agents were equally effective but that the toxicity of raloxifene was less. Adjuvant trials comparing tamoxifen and the modern potent aromatase inhibitors (anastrozole, letrozole and exemestane) indicate that they are superior to tamoxifen and reduce contralateral breast cancer by approximately 70%. This observation has led to the initiation of two trials in postmenopausal women comparing anastrozole (the IBISII trial) or exemestane (the MAP-3 trial) with placebo. Currently it is recommended that tamoxifen is used to prevent breast cancer in premenopausal women and raloxifene for postmenopausal women (it is not effective in the premenopausal group),and we await the results of the aromatase inhibitor trials.     

Tamoxifen for breast cancer prevention.

Tamoxifen is of proven efficacy in the treatment of breast cancer. New data indicate that it might be able to reduce the occurrence of receptor positive breast cancer when taken as a preventative. However trade-offs for this reduction are an increased incidence of endometrial carcinomas and thromboembolic events. Therefore the use of tamoxifen as preventative ought to be restricted to clinical studies or a well defined high risk situation. Whether raloxifen is superior to tamoxifen remains to be shown.     

Hormonal cytology used in the therapy of breast cancer (author's transl)

More than 150 women have been under a long-time control provided by the Radium therapy Dpt. and by the Cytological Center. In all above mentioned cases the primary diagnosis was the breast cancer and in the majority the patients obtained radical surgery. The results of Co 60 castration and of hormonal therapy were evaluated by means of the hormonal cytology. In each case the cytological smears were taken several times during the therapy and after end of the therapy. The cytologist was not influenced by knowledge of the therapy. The optimal therapy was determined by the cytological results. The first results of selected method, which represents the effectivity of a hormonal-cytologically chosen therapy, were promising.     

Tamoxifen, raloxifene and the prevention of breast cancer

The recognition of a new group of drugs, now named selective estrogen receptor modulators (SERMs) has revolutionized prospects for the prevention of breast cancer. New agents will continue to be tested against tamoxifen, the first SERM and an established treatment of ER positive breast cancer. Raloxifene a related SERM is used to treat and prevent osteoporosis with the potential beneficial side effect of preventing breast cancer. The Study of Tamoxifen and Raloxifene (STAR) trial will establish whether raloxifene is an improvement over tamoxifen. Most importantly, emerging information about the molecular pharmacology of SERMs will be used to decipher the mechanism of action at specific target sites around a woman's body. This knowledge can be used to design new SERMs and advance the prospects for multifunctional medicine to prevent breast cancer, osteoporosis and coronary heart disease.     

SERMs for the treatment and prevention of breast cancer

Tamoxifen and raloxifene are both selective estrogen receptor modulators (SERMs). The medicines can block estrogen mediated breast cancer growth and development but will also maintain bone density in postmenopausal women and lower circulating cholesterol. Tamoxifen has remained the antihormonal therapy of choice for the treatment of ER positive breast cancer for the last 30 years. However, although adjuvant tamoxifen produces profound increases in disease-free and overall survival in patients with ER positive breast cancer, concerns about drug resistance, blood clots and endometrial cancer have resulted in a change to the use of aromatase inhibitors for the treatment of postmenopausal women. Nevertheless, tamoxifen remains the antihormonal treatment of choice for premenopausal women with ER positive breast cancer and for risk reduction in premenopausal women who are at high risk for developing breast cancer. The risk of endometrial cancer and thromboembolic disorders during tamoxifen therapy is not elevated in premenopausal women. It is important to note that aromatase inhibitors or raloxifene should not be used in premenopausal women. Raloxifene is used to prevent osteoporosis in postmenopausal women and, unlike tamoxifen, does not increase the risk of endometrial cancer. However, raloxifene does reduce breast cancer risk by 50–70% in both low risk and high risk postmenopausal women. Comparisons of raloxifene with tamoxifen show equal efficacy as a chemopreventive for breast cancer but there is a reduction in thromboembolic disorders, fewer endometrial cancers, hysterectomies, cataracts and cataract surgeries in women taking raloxifene. Overall, SERMs continue to fulfill their promise as appropriate medicines that target specific populations for the treatment and prevention of breast cancer.     

Leading the way in breast cancer screening and prevention

Journal of General Internal Medicine -     

Cyclooxygenase-2: a target for the prevention and treatment of breast cancer

Cyclooxygenase-2 (COX-2), an inducible prostaglandin synthase, is normally expressed in parts of the kidney and brain. Aberrant COX-2 expression was first reported in colorectal carcinomas and adenomas, and has now been detected in various human cancers, including those of the breast. Strikingly, COX-2 overexpression in murine mammary gland is sufficient to cause tumour formation. To date, the role of COX-2 in tumorigenesis has been most intensively studied in the colon. Thus, the relationship between COX-2 and neoplasia can best be illustrated with reference to intestinal tumorigenesis. Here we consider the potential utility of selective COX-2 inhibitors for the prevention and treatment of breast cancer. Data for cancers of the colon and breast are compared where possible. In addition, the mechanisms by which COX-2 is upregulated in cancers and contributes to tumorigenesis are discussed. Importantly, several recent studies of mammary tumorigenesis in animal models have found selective COX-2 inhibitors to be effective in the prevention and treatment of breast cancer. Clinical trials will be needed to determine whether COX-2 inhibition represents a useful approach to preventing or treating human breast cancer.     

Secondary prevention of breast cancer in older women

Periodic mammography is well studied and widely applied as a screening programme to reduce breast cancer-related mortality and morbidity in women aged 50 to 69 years. Despite the fact that age is a major risk factor for breast cancer, no evidence-based data are available on survival benefit of screening in women older than 69 years. The most commonly cited guidelines for screening in breast cancer disagree on the upper age limit of the target population. This age limit is a matter of cost-effectiveness and is influenced by active life expectancy, risk for breast cancer, comorbidity and functional status. Benefit of screening also depends on adherence rate of elderly women in screening programmes and optimal treatment of identified tumours. In a selected population of elderly women, screening for breast cancer might be cost-effective.     

A protective effect of morning radiotherapy on acute skin toxicity in patients with breast cancer: A prospective cohort study

The focus of this prospective cohort study was to evaluate the risk factors of severe acute skin toxicity (grade ≥2) in 100 patients with breast cancer (BC) during radiotherapy (RT).The patients were evaluated weekly during RT and 3 months after treatment. The endpoint included the occurrence of skin toxicity grade ≥2, according to Radiation Therapy Oncology Group (RTOG). Survival analysis was conducted by univariate and multivariate Cox regression analysis.In the multivariate analysis, RT in the afternoon (0–3 pm) (hazard ratios [HR] = 1.566, P = .042) was significantly associated with the early occurrence of skin toxicity, indicating a potential effect of chronotherapy related to this adverse event. In the univariate and multivariate analysis, skin phototype moderate brown (HR = 1.586, P = .042; HR = 1.706, P = .022, respectively) and dark brown or black (HR = 4.517, P < .001; HR = 5.336, P < 0.001, respectively) was significantly associated with the skin toxicity. Tangential field separation >21 cm (HR = 2.550, P = .009, HR = 2.923, P = .003), in women that were submitted to conservative surgery indicates indirectly that large breast size was also significantly associated with skin toxicity.Women with large breasts and dark brown or black skin should be followed more carefully during RT, which should be undergone in the morning, especially when submitted to conventional RT techniques, common in developing countries.