Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women

Veronesi, Umberto; Maisonneuve, Patrick; Costa, Alberto; Sacchini, Virgilio; Maltoni, Cesare; Robertson, Chris; Rotmensz, Nicole; Boyle, Peter

doi:10.1016/s0140-6736(98)85011-3

Cited by 644 publications

(248 citation statements)

References 10 publications

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“…These findings concur with the upregulation of aFGF, bFGF and ADM in premenopausal tissue. Increased vascular density in premenopausal tamoxifen exposed endometrium is an important consideration for premenopausal women using TAM as a chemopreventative agent, especially since the trial results have been divergent (Fisher et al, 1998;Powles et al, 1998;Veronesi et al, 1998). Our results, suggest these women may be at an increased risk of abnormal endometrial angiogenesis.…”

Section: Molecular and Cellular Pathologymentioning

confidence: 69%

Tamoxifen induction of angiogenic factor expression in endometrium

et al. 2002

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Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre-and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre-but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen.

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Section: Molecular and Cellular Pathologymentioning

confidence: 69%

Tamoxifen induction of angiogenic factor expression in endometrium

et al. 2002

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“…The trial subjects characteristics and main findings have already been published. 26,27 When this study was planned, 79 women had developed BC and no woman had died of BC. Two unaffected control women were matched by age, center and time on study for each case.…”

Section: Subjects and Samplesmentioning

confidence: 99%

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

et al. 2010

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The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P ¼ 0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P ¼ 0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmacogenomics in tailoring tamoxifen treatment.

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“…The trial showed a 49% reduction in breast cancer, but also showed that there were some life-threatening adverse effects associated with tamoxifen administration (Gail et al, 1999). Adding to the debate were the results of two European tamoxifen chemoprevention trials, which were unable to confirm the P-1 trial findings, but which also used different sample sizes and eligibility criteria (Powles et al, 1998;Veronesi et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

First do no harm: extending the debate on the provision of preventive tamoxifen

et al. 2001

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The Breast Cancer Prevention Trial (BCPT-P-1) demonstrated that tamoxifen could reduce the risk of invasive breast cancer in high-risk women by 49%, but that it could also increase the risk of endometrial cancer, vascular events and cataracts. This paper provides an estimate of the net health impacts of tamoxifen administration on high-risk Canadian women with no prior history of breast cancer. The results of the BCPT-P-1 were incorporated into the breast cancer and other modules of Statistics Canada’s microsimulation POpulation HEalth Model (POHEM). While the main intervention scenario conformed as closely as possible to the eligibility criteria for tamoxifen in the BCPT-P-1 protocol, 3 additional scenarios were simulated. Predicted absolute risks of breast cancer at 5 years of 1.66%, 3.32% and 4.15% were calculated for women 35 to 70 years of age. When the BCPT-P-1 results were incorporated into the simulation model, the analysis suggests no increase in life expectancy in this risk group. Tamoxifen appeared to be beneficial for women with a 5-year predicted risk of 3.32% or greater. The results of these simulations are particularly sensitive to the reduction in mortality observed in the BCPT-P-1, as well as being sensitive to other characteristics of the simulation model. Overall, the analysis raises questions about the use of tamoxifen in otherwise healthy women at high risk of breast cancer. © 2001 Cancer Research Campaign

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Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women

Cited by 644 publications

References 10 publications

Tamoxifen induction of angiogenic factor expression in endometrium

Tamoxifen induction of angiogenic factor expression in endometrium

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

First do no harm: extending the debate on the provision of preventive tamoxifen

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