Tamoxifen for the Prevention of Breast Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Journal of the National Cancer Institute (Impact Factor: 12.58). 12/2005; 97(22):1652-62. DOI: 10.1093/jnci/dji372
Source: PubMed

ABSTRACT Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor-positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical significance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings.
Women (n = 13,388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided.
After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to age, race, and level of breast cancer risk.
Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable subsets of individuals comprising 2.5 million women could derive a net benefit from the drug.

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Available from: Walter M Cronin, Jan 28, 2015
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    • "Antagonists to ERα such as tamoxifen can block the effects of E2 on breast cancer cells and thereby interfere with estrogen-induced cell proliferation. Although tamoxifen has been a great success and improves breast cancer survival rates considerably [4-6], a significant proportion of ERα-positive breast cancer is tamoxifen-unresponsive, and tamoxifen-resistant cases have been also reported [7,8]. The mechanism of E2/ERα signalling is not fully understood and a better understanding of the E2/ERα pathway will be essential for more effective and alternate treatments for breast cancer. "
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    ABSTRACT: Background Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) has been identified recently as a novel regulator of estrogen signalling in breast cancer cells. Despite being a potential target for new breast cancer treatment, its amino acid sequence suggests no association with any well-characterized protein family and provides little clues as to its molecular function. In this paper, we predicted the structure, function and interactions of BIG3 using a range of bioinformatic tools. Results Homology search results showed that BIG3 had distinct features from its paralogues, BIG1 and BIG2, with a unique region between the two shared domains, Sec7 and DUF1981. Although BIG3 contains Sec7 domain, the lack of the conserved motif and the critical glutamate residue suggested no potential guaninyl-exchange factor (GEF) activity. Fold recognition tools predicted BIG3 to adopt an α-helical repeat structure similar to that of the armadillo (ARM) family. Using state-of-the-art methods, we predicted interaction sites between BIG3 and its partner PHB2. Conclusions The combined results of the structure and interaction prediction led to a novel hypothesis that one of the predicted helices of BIG3 might play an important role in binding to PHB2 and thereby preventing its translocation to the nucleus. This hypothesis has been subsequently verified experimentally.
    BMC Research Notes 07/2014; 7(1):435. DOI:10.1186/1756-0500-7-435
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    • "Surgical interventions include bilateral prophylactic mastectomy, bilateral salpingo-oophorectomy or a combination of both procedures. Multiple chemoprevention trials examining the efficacy of tamoxifen (for example, NSABP-P1, IBIS-1), raloxifene (MORE, CORE, STAR) and aromatase inhibitors have been completed [3-9]. All chemopreventative agents identified to date, with a single exception, were introduced into the clinic as breast cancer treatments; a significant reduction in the rate of contralateral breast cancer in treated patients was used as an indication that these treatments also act to prevent breast cancer. "
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    ABSTRACT: Our efforts to prevent and treat breast cancer are significantly impeded by a lack of knowledge of the biology and developmental genetics of the normal mammary gland. In order to provide the specimens that will facilitate such an understanding, "The Susan G. Komen for the Cure(R) Tissue Bank at the IU Simon Cancer Center" (KTB) was established. The KTB is, to our knowledge, the only biorepository in the world prospectively established to collect normal, healthy breast tissue from volunteer donors. As a first initiative toward a molecular understanding of the biology and developmental genetics of the normal mammary gland, the effect of the menstrual cycle and hormonal contraceptives on DNA expression in the normal breast epithelium was examined. Using normal breast tissue from 20 premenopausal donors to KTB, the changes in the mRNA of the normal breast epithelium as a function of phase of the menstrual cycle and hormonal contraception were assayed using next-generation whole transcriptome sequencing (RNA-Seq). In total, 255 genes representing 1.4% of all genes were deemed to have statistically significant differential expression between the two phases of the menstrual cycle. The overwhelming majority (221; 87%) of the genes have higher expression during the luteal phase. These data provide important insights into the processes occurring during each phase of the menstrual cycle. There was only a single gene significantly differentially expressed when comparing the epithelium of women using hormonal contraception to those in the luteal phase. We have taken advantage of a unique research resource, The Komen Tissue Bank, to complete the first ever next-generation transcriptome sequencing of the epithelial compartment of 20 normal human breast specimens. This work has produced a comprehensive catalog of the differences in the expression of protein encoding genes as a function of the phase of the menstrual cycle. These data constitute the beginning of a reference data set of the normal mammary gland, which can be consulted for comparison with data developed from malignant specimens, or to mine the effects of the hormonal flux that occurs during the menstrual cycle.
    Breast cancer research: BCR 03/2014; 16(2):R26. DOI:10.1186/bcr3627 · 5.49 Impact Factor
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    • "It is classified as a benign condition, but it increases the risk of subsequent breast cancer by 4–5 times.16 The NSABP P-1 study reported a 75% reduction in the incidence of breast cancer in women with atypical hyperplasia who received tamoxifen rather than placebo.6 Shortly after closing of the NSABP P-1 trial, researchers continued to follow women whose breast tissue showed atypical hyperplasia or lobular carcinoma in situ.6 "
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    ABSTRACT: Tamoxifen has been used as a treatment for women who have been diagnosed with breast cancer for roughly four decades and has been approved as chemoprevention for over ten years. Although tamoxifen has been proven to be beneficial in preventing breast cancer in high-risk women, its use has not been widely embraced. To some extent, this is due to several of its side effects, including an increased risk of endometrial cancer and pulmonary embolism, but these serious side effects are rare. The risks and benefits of tamoxifen chemoprevention should be considered for each patient.
    Breast Cancer: Targets and Therapy 02/2014; 6:29-36. DOI:10.2147/BCTT.S43763
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