A realistic clinical perspective of tamoxifen and endometrial carcinogenesis

Assikis, Vasilios J.; Neven, Patrick; Jordan, V. Craig; Vergote, Ignace

doi:10.1016/0959-8049(96)00184-0

Cited by 126 publications

(32 citation statements)

References 52 publications

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“…concomitant HRT including progestins might even affect the risk of endometrial cancers during tamoxifen. as the xero large majority of these cases were observed in post-menopausal xxomen (Assikis et al 1996).…”

Section: Discussionmentioning

confidence: 96%

Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial

et al. 1998

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Summary The combination of tamoxifen and transdermal hormone replacement therapy (HRT) may potentially reduce risks and side-effects of either agent, but an adverse interaction could attenuate their beneficial effects. We assessed the effects of their combination on cardiovascular risk factors within a prevention trial of tamoxifen. Baseline and 1 2-month measurements of total, low-density lipoprotein (LDL)-and high-density lipoprotein (HDL)-cholesterol, platelets and white blood cells were obtained in the following four groups: tamoxifen (n = 1117), placebo (n = 1112), tamoxifen and HRT (n = 68), placebo and HRT (n = 87). The analysis was further extended to women who were on HRT at randomization but discontinued it during the 12-month intervention period (n= 33 on tamoxifen and n = 35 on placebo) and to women who were not on HRT but started it during intervention (n = 36 in both arms of the study). Compared with small changes in the placebo group, tamoxifen was associated with changes in total, LDL-and HDL-cholesterol of approximately -90/, -19% and +0.2% in continuous HRT users compared with -9%/6, -14% and -0.8% in never HRT users. Similarly, there was no interaction on platelet count. In contrast, the decrease in total and LDL-cholesterol levels induced by tamoxifen was blunted by two-thirds in women who started HRT while on tamoxifen (P = 0.051 for the interaction term). We conclude that the beneficial effects of tamoxifen on cardiovascular risk factors are unchanged in current HRT users, whereas they may be attenuated in women who start transdermal HRT while on tamoxifen. Whereas a trial of tamoxifen in women already on transdermal HRT is warranted, prescription of HRT during tamoxifen may attenuate its activity.

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Section: Discussionmentioning

confidence: 96%

Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial

et al. 1998

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“…However, tamoxifen therapy is also associated with estrogen-like effects in the uterus with an increased incidence of endometrial cancer (13). Raloxifene is currently being compared with tamoxifen for the prevention of breast cancer in a large clinical trial called the Study of Tamoxifen and Raloxifene.…”

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confidence: 99%

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Liu¹,

Park²,

Bentrem³

et al. 2002

Journal of Biological Chemistry

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Amino acid Asp-351 in the ligand binding domain of estrogen receptor ␣ (ER␣) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ER␣ complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor ␣ target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ER␣. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ER␣ allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ER␣ complex with the complete loss of estrogenlike activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ER␣ expression vectors. Profound differences in the agonist and antagonist actions of Ral⅐ER␣ complexes were noted only in stable transfectants. The agonist activity of the Ral⅐ER␣ complex was enhanced with D351E and D351Y ER␣, but raloxifene lost its agonist activity with D351F ER␣. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ER␣. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ER␣ complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ER␣ complex.Raloxifene (Ral) 1 (see Fig. 1) is a polyhydroxyphenyl benzothiophene antiestrogen that has low estrogen agonist activity in the rodent uterus (1). The compound originally referred to as Ly156758 or keoxifene was abandoned for development as a treatment for breast cancer (2), because its bioavailability was less than 2% administered dose (3). However, the recognition that raloxifene maintains bone density (4, 5) and inhibits mammary carcinogenesis in the rat (6, 7) illustrates the concept of selective estrogen receptor modulation. Raloxifene is used for the prevention of osteoporosis in postmenopausal women (8), and treatment is associated with a reduced incidence of breast cancer (9).Tamoxifen is the prototype selective estrogen receptor modulator (SERM) that is used clinically for the treatment and prevention of breast cancer (10, 11) with the ability to maintain bone density in postmenopausal women (12). However, tamoxifen therapy is also associated with estrogen-like effects in the uterus with an increased incidence of endometrial cancer (13). Raloxifene is currently being ...

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“…Nowadays, more than 1 in 20 female cancers in Europe are of the endometrium. [1][2][3][4][5][6][7][8][9][10] Contrary to cervical carcinoma, no screening programs have been organized for the early detection of endometrial adenocarcinoma. The lack of screening programs may be related to the precocious presenting symptoms and to the relative good prognosis of the majority of endometrial adenocarcinomas.…”

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confidence: 99%

Liquid‐based endometrial cytology in the management of sonographically thickened endometrium

Buccoliero

Gheri

Castiglione

et al. 2007

Diagnostic Cytopathology

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Liquid-based cytology represents an opportunity to re-evaluate endometrial cytology. We evaluated the accuracy of liquid-based endometrial cytology as compared to biopsy in 670 women scheduled for histeroscopy because of thickened endometrium (>4 mm), as evaluated by transvaginal sonography. Endometrial biopsy detected pathology in 41 (6%) of cases (21 of which were adenocarcinomas). Cytologic study found pathology in 62 (9%) cases (19 of which were adenocarcinomas). Two hundred ninety-one biopsies (43%) and 28 (4%) cytologies were inadequate. The sensitivity and the specificity were estimated, respectively, at 95% and 98%; the positive and negative predictive values were estimated, respectively, at 83% and 99%. Cytology provided sufficient material more often than biopsy (P < 0.01). We consider endometrial cytology an efficacious diagnostic opportunity. It could be usefully applied in association with transvaginal sonography. The combination of these procedures might reduce more invasive and expensive diagnostic procedures. Diagn. Cytopathol. 2007;35:398-402. ' 2007 Wiley-Liss, Inc.Key Words: thin-layer; liquid-based; endometrial cytology; endometrial adenocarcinoma; endometrial hyperplasia Endometrial adenocarcinoma is the most common malignancy of the female genital tract. A significant increase in its frequency, both absolute and relative, has been observed during the last decades. This increase is considered the consequence of the extended life expectancy of women, the increase in the incidence of risk factors, and of the reduction of invasive cervical carcinomas. Nowadays, more than 1 in 20 female cancers in Europe are of the endometrium. [1][2][3][4][5][6][7][8][9][10] Contrary to cervical carcinoma, no screening programs have been organized for the early detection of endometrial adenocarcinoma. The lack of screening programs may be related to the precocious presenting symptoms and to the relative good prognosis of the majority of endometrial adenocarcinomas. Early abnormal uterine bleeding, the commonest presenting symptom for the 95% of women, allows diagnosis at stage I in 73% of cases. 11 Moreover, there has not been an endometrial test comparable to cervicovaginal cytology for diagnostic reliability, tolerability, and low cost.Several diagnostic procedures are used for investigating the endometrium, but there is no common agreement for the optimum approach in each circumstance (i.e. symptomatic vs. asymptomatic; with risk factors vs. without risk factors).Endometrial cytology has been hampered in its dissemination by the difficulty in its interpretation due to the common presence of excess blood and overlapping cells. Liquid-based cytology represents an opportunity to reexamine endometrial cytology. We conducted the current study to correlate the results of liquid-based endometrial cytology with the results of endometrial biopsy in a group of 670 women scheduled for hysteroscopy because of thick endometrium (>4 mm), as evaluated by transvaginal sonography (TVS). Our purpose was preliminarily to asce...

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A realistic clinical perspective of tamoxifen and endometrial carcinogenesis

Cited by 126 publications

References 52 publications

Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial

Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Liquid‐based endometrial cytology in the management of sonographically thickened endometrium

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