Descriptive Clinicopathologic Study of 17 Patients With Endometrial Cancer During or After Adjuvant Tamoxifen in Early Breast Cancer

Fornander, Tommy; Hellström, Ann‐Cathrin; Moberger, Birgitta

doi:10.1093/jnci/85.22.1850

Cited by 141 publications

(49 citation statements)

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“…Thus our data do not lend any support to the fear that antioestrogens increase the risk of endometrial carcinoma at least in the first 2-3 years of use. Our data seriously question the rationale of endometrial surveillance of antioestrogen users (Fornander et al, 1993;Tesoro et al, 1994;van Leeuwen et al, 1994).…”

Section: Discussionmentioning

confidence: 76%

“…This issue is important, since a history of breast cancer, alone, denotes a 1.6-fold risk of endometrial cancer (Adami et al, 1997). The risk of endometrial carcinoma in tamoxifen users has been shown to be increased in some (Fisher et al, 1994;Rutqvist et al, 1995;Fisher et al, 1998) although not all studies (Ribeiro and Swindell, 1988;Stewart et al, 1996), and close endometrial surveillance has been recommended to these patients (Fornander et al, 1993;van Leeuwen et al, 1994;Tesoro et al, 1999). We followed prospectively a rather large number of postmenopausal patients, whose endometrial status was carefully examined before and during the trial.…”

Section: Discussionmentioning

confidence: 99%

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Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women

et al. 2001

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To assess and compare the gynaecological consequences of the use of 2 antioestrogens we examined 167 postmenopausal breast cancer patients before and during the use of either tamoxifen (20 mg/day, n = 84) or toremifene (40 mg/day, n = 83) as an adjuvant treatment of stage II–III breast cancer. Detailed interview concerning menopausal symptoms, pelvic examination including transvaginal sonography (TVS) and collection of endometrial sample were performed at baseline and at 6, 12, 24 and 36 months of treatment. In a subgroup of 30 women (15 using tamoxifen and 15 toremifene) pulsatility index (PI) in an uterine artery was measured before and at 6 and 12 months of treatment. The mean (±SD) follow-up time was 2.3 ± 0.8 years. 35% of the patients complained of vasomotor symptoms before the start of the trial. This rate increased to 60.0% during the first year of the trial, being similar among patients using tamoxifen (57.1%) and toremifene (62.7%). Vaginal dryness, which was present in 6.0% at baseline, increased during the use of tamoxifen (26.2%) and toremifene (24.1%). Endometrial thickness increased from baseline (3.9 ± 2.7 mm) to 6.8 ± 4.2 mm at 6 months ( P < 0.001), and no difference emerged between the 2 regimens in this regard. Before the start of the antioestrogen regimen, the endometrium was atrophic in 71 (75.5%) and proliferative in 19 of 94 (20.2%) samples; 4 patients had benign endometrial polyps. During the use of antioestrogen altogether 339 endometrial samples were taken (159 in tamoxifen group, 180 in toremifene group). The endometrium was proliferative more often in the tamoxifen group (47.8%) than in the toremifene group (32.2%) ( P < 0.0001). 20 patients had a total of 24 polyps (17 in tamoxifen and 9 in toremifene group, P < 0.05) during the use of antioestrogens. One patient in the toremifene group developed endometrial adenocarcinoma at 12 months, and one patient had breast cancer metastasis on the endometrium. Tamoxifen failed to affect the PI in the uterine artery, but toremifene reduced it by 15.0% ( P < 0.05) by 12 months. In conclusion, tamoxifen and toremifene cause similarly vasomotor and vaginal symptoms. Neither regimen led to the development of premalignant endometrial changes. Our data suggest that so close endometrial surveillance as used in our study may not be mandatory during the first 3 years of use of antioestrogen treatment. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women

et al. 2001

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“…The full benefits of tamoxifen as a breast cancer therapeutic agent are compromised by its low incidence of endometrial cancer (Fornander et al, 1993;Kedar et al, 1994), and the formation of genotoxic tamoxifen-DNA adducts has been proposed to be a key step in this carcinogenic response (Shibutani et al, 1999). A major mechanism for this genotoxicity begins with the cytochrome P450-mediated oxidation of tamoxifen to a-hydroxytamoxifen (a-OHTAM), which then undergoes sulfation catalyzed by hSULT2A1 to form an electrophilic a-sulfooxy intermediate that reacts with DNA to form covalent adducts (Shibutani et al, 1998a).…”

Section: Discussionmentioning

confidence: 99%

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

2014

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Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use has been limited by the low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1 (hSULT2A1) catalyzes the formation of an a-sulfooxy metabolite of tamoxifen that is reactive toward DNA, and this has been implicated in its carcinogenicity. Also, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA, with K i values of 3.5 and 2.8 mM, respectively. In the hSULT2A1-catalyzed sulfation of PREG, 4-hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited K i values of 12.7 and 9.8 mM, respectively, whereas corresponding K i values of 19.4 and 17.2 mM were observed with DHEA as substrate. A K i value of 9.1 mM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 mM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules.

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“…There is, however, a reported increased risk of endometrial cancer in post-menopausal women (Fomander et al, 1993) not associated with any adducts in the endometrium (Carmichael et al, 1996) and indicating a non-genotoxic mechanism. At 20 mg day-' this increased risk of endometrial cancer is probably about two-to threefold (van Leeuwen et al, 1994), which is similar to the increased risk reported with unopposed oestrogen replacement therapy (ERT) associated with endometrial hyperplasia and atypia (Grady et al, 1995).…”

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confidence: 89%

The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo

Powles

Bourne²,

Athanasiou³

et al. 1998

Br J Cancer

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Summary Tamoxifen (tam) is used extensively for treatment of patients with breast cancer and is being evaluated for chemoprevention in healthy women. It has, however, been reported to increase the risk of endometrial cancer in post-menopausal women, probably by an oestrogenic effect on the endometrium. It also causes endometrial cysts and polyps. The aims of this study were to identify the incidence of endometrial thickening, polyps and cysts by transvaginal ultrasound (TVUS) screening of a population of post-menopausal healthy women in the Royal Marsden tamoxifen chemoprevention trial and to evaluate the possible benefit from the use of intermittent norethisterone (NE) in women with persistent changes. Since 1990, we have undertaken regular TVUS, using an endovaginal B mode probe, of the 463 postmenopausal women in the trial randomized to tam (20 mg day-') or placebo (plac), without breaking the randomization code. Endometrial thickening (ET) was defined as .8 mm at the widest point across the myometrial cavity in the longitudinal plane, including any stromal changes. Cystic changes were defined as more than one hypoechogenic area > 1 mm. Polyps were identified using saline hydrosonography. Oral NE (2.5 mg day-1) was used for 21 days out of 28 for three consecutive cycles by women with persistent endometrium . 8 mm, including cystic and polypoid changes. TVUS was repeated after the three courses to evaluate any change caused by NE and endometrial biopsies, including hysteroscopy, was performed on those women with persistent abnormalities. A persistent ET . 8 mm was identified in 56 (24%) of the 235 women on tamoxifen compared with only 5 (2%) of 228 women on placebo (P <0.0005). Stromal changes, including cysts, were detected in 36 (15%) and polyps in 26 (11%) of the women on tamoxifen compared with only two (<1%) of the women on placebo (P << 0.0005). After 3 months of cyclical norethisterone, 39 of 47 women (83%) on tamoxifen had persistent ultrasound changes. However, 45 (96%) had a progesterone withdrawal bleed. Hysteroscopy was performed in 39 women on tamoxifen (28 endometrial biopsy, 15 polypectomy), five of whom had histological evidence of a proliferative endometrium and a further three had an atypical hyperplastic endometrium (one of whom had a focus of invasive carcinoma). The cysts and polyps which were detected in women on tam could not be reversed by NE and were presumably stromal and not of malignant risk. However, 96% of the women had withdrawal NE bleeding, indicating an oestrogenically primed endometrium which could be a mechanism for an increased risk of endometrial cancer. Further studies are required to ascertain whether a progestin would protect against this risk. As in other studies, these results indicate that any increased risk of endometrial cancer caused by tamoxifen is low, and that TVUS screening is probably not justified for asymptomatic women on tamoxifen. Group, 1992). Based on these findings, it is now widely used and many millions of women have had, or are now receiving, such ...

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Descriptive Clinicopathologic Study of 17 Patients With Endometrial Cancer During or After Adjuvant Tamoxifen in Early Breast Cancer

Cited by 141 publications

References 0 publications

Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women

Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo

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