Breast Cancer Prevention Trial

In the Breast Cancer Prevention Trial (Fisher et al. 1998) a clinical survey aimed at determining the potential of tamoxifen for breast cancer prevention in women at increased risk, 13,338 pre- or postmenopausal women were monitored over 5 years. After randomization, women in the treatment group (n = 6681) were given a 20-mg daily dose of tamoxifen, while the remaining (n = 6707) received a placebo. Although the overall rate of fractures was about the same in both groups, tamoxifen-treated women sustained fewer hip, spine, and Colles fractures. Nevertheless, relevant data may have been biased, since in this trial there was an indiscriminate inclusion of pre- and postmenopausal women and no spinal radiographs were carried out. 

The effects of tamoxifen in women with and without CHD have been analyzed in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT). This randomized, placebo-controlled study included 13,388 women at increased risk for breast cancer. The conclusions of the trial are somewhat limited by the fact that it was designed to investigate the effect of tamoxifen as a chemopreventive for breast cancer, and not its effect on CVD risk. There was no indication that tamoxifen would modify the risk of CHD in women with or without heart disease (Reis et al. 2001). 

The most relevant study is the Breast Cancer Prevention Trial (BCPT, NSABP-P1) (Fisher et al. 1998). Initiated in the USA by the National Surgical Adjuvant Breast and Bowel Project, this study recruited 13,388 women considered at high risk for breast cancer based on Gail s probability algorithm (Gail et al. 1989). 

Cuzick J, Powles T, Veronesi U et al. (2003) Overview of the main outcomes in breast-cancer prevention trials. Lancet 361(9354) 296-300... 

Decensi A, Maisonneuve P, Rotmenz N et al. (2005) Effect of Tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 111 650-656... 

Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, et al. (1994) Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343 1318-1321... 

From a clinical perspective, tamoxifen is still the first and only SERM worth mentioning from the first- and second-generation compounds. The pharmacology of tamoxifen has been reviewed extensively [142]. The NSABP-11 adjuvant trial and the Breast Cancer Prevention Trial (BCPT-1) are some of the milestones in the history of tamoxifen [141]. 

In the Breast Cancer Prevention Trial (P-1), initiated by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in 1992, more than 13 000 eligible women were randomized to tamoxifen 20 mg/day or placebo for 5 years (26). During 69 months of follow-up tamoxifen reduced the risk of both invasive and non-invasive cancer... 

Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, Salvioni A, Travaglini R, Oliviero P, D Aiuto G, Gulisano M, Gucciardo G, Del Turco MR, Pizzichetta MA, Conforti S, Bonanni B, Boyle P, Veronesi U. Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 2005 111 650-6. 

STAR trial (Study of tamoxifen and raloxifene), which was completed in 2006, demonstrated additional utility of raloxifene in the prevention and treatment of breast cancer. In fact, the absence of associated uterotrophic effects with raloxifene suggests that it may be a safer agent than tamoxifen for use as a chemopreventative in high-risk postmenopausal women [3] therefore, raloxifene has very recently become a new option for breast cancer prevention now available for physicians and their patients. 

In addition to effects on bone, raloxifene may have effects in breast tissue and on the cardiovascular system. A secondary end point of the MORE trial evaluated the effects of raloxifene on the primary prevention of breast cancer and found a significant reduction in all types of breast cancer.33 Raloxifene decreases total and low-density lipoprotein (LDL) cholesterol,34 and studies are evaluating its effect on reducing the risk of cardiovascular disease.35... 

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

Tamoxifen has been widely used in the adjuvant treatment of invasive breast cancer associated to surgery and chemotherapy. It has been shown to be effective in preventing new contralateral tumors and local or peripheral recurrences (Nolvadex Adjuvant Trial Organization 1983 Cuzick and Baum 1985 Abe et al. 1998). The overview comprised 37,000 women from 55 randomized trials and included events occurring more than 5 years after randomization. The effects... 

The women were randomized to receive either tamoxifen (6681) or placebo (6707) for 5 years. However, the trial was stopped prematurely because the findings provided strong evidence of a reduction in breast cancer with tamoxifen therapy. The results have been released and made available at http //cancertrials.nci.nih.gov. These are the first available data supporting the hypothesis that breast cancer can be pharmacologically prevented in an at-risk female population. The administration of tamoxifen was effective in reducing by 69% the annual rate of ER(+) tumors, both invasive and in situ, but was ineffective in reducing the occurrence of ER(-) neoplasias (Young 1999). 

Three other studies were conducted to investigate the preventive potential of tamoxifen. One in Italy (Veronesi et al. 1998), one at the Royal Marsden Hospital, United Kingdom (Powles et al. 1998), and a multicentric international study (IBIS 2002). The British study was the smallest in size (2471 participants) but concentrated on women with a high incidence of family history and consequently presented a higher number of breast cancers. The Italian trial included only women with previous hysterectomy and, accordingly, around 50% had also undergone bilateral oophorectomy. The family risk was low only 15% had a first-degree relative affected by breast cancer. Both European studies permitted concurrent HRT, and 26% of the participants in the British trial received HRT while on study and 42% had ever received HT for menopausal symptoms. Neither of the studies showed any positive effect of the treatment with tamoxifen on the incidence of breast cancer. Reasons for this lack of effect can be different for each trial. 

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