• The endocrine prevention of breast cancer.

      Howell, Anthony; CRUK Department of Medical Oncology, Christie Hospital, Manchester M20 4BX, UK. anthony.howell@christie.nhs.uk (2008-08)
      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.
    • Response and resistance to the endocrine prevention of breast cancer.

      Howell, Anthony; Bundred, Nigel J; Cuzick, Jack; Allred, D Craig; Clarke, Robert B; CRC Department Medical Oncology, University of Manchester Christie Hospital and Holt Radium Inst., Manchester, UK. (2008)
      The data from observational studies and clinical trials indicates that it is possible to prevent BC for prolonged periods using various endocrine manipulations. Ovarian suppression is thought to give lifelong protection and recent data indicate that the effectiveness of Tam continues after cessation of treatment at 5-8 years. It is clear from three randomised trials that SERMs prevent ERalpha+ tumors only in women at increased risk and at population risk of BC entered into these trials. The data from the Ral trials also suggests that this agent appears less effective than Tam in preventing DCIS. This is surprising since a large proportion of DCIS is ERalpha+. Equally surprising is the effectiveness of oophorectomy and Tam in mutation carriers, particularly BRCA1, which is associated with ERalpha+ tumors. The fact that ERT can be given without apparently abrogating the effect of oophorectomy and also to naturally postmenopausal women without increasing BC risk suggests that cyclical estrogen or estrogen + progestin are important for BC initiation and/or progression. The question arises whether the information we have concerning the responsiveness of ERalpha+ cells in TDLU, premalignant lesions, and invasive cancers give an indication of the targets for endocrine prevention. Data summarised in Table 1 indicate that TDLU are responsive to estrogen, ED, and SERMs/SERDs in premenopausal women and there may be the targets for the preventative effect of early oophorectomy particularly in BRCA1 carriers where we have demonstrated endocrine responsiveness of TDLU, which at this heterozygote stage are ERalpha+. The decline in numbers of atypical lobules in breasts without invasive cancer suggests that these are targets for the 'preventive' effect of the menopause, as suggested by Wellings. The data also suggest that ERalpha+ DCIS is responsive to estrogen and ED supporting premalignant lesions is a target as does the data from the NSABP P1 trial indicating a marked preventive effect of Tam in women previously diagnosed with atypical ductal hyperplasia and a preventative effect on CIS.