Prevention of breast cancer with tamoxifen—an update on the royal Marsden Hospital pilot programme

Powles, Trevor J.; Tillyer, C R; Jones, Alison; Ashley, S.; Treleaven, J; Davey, Jane B.; McKinna, J A

doi:10.1016/0277-5379(90)90116-b

Cited by 151 publications

(39 citation statements)

References 19 publications

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“…The details of the study design and eligibility criteria have been reported previously (Powles et al, 1989;Powles et al, 1990;Powles et al, 1994). Since 1990, regular screening using TVUS of the 463 post-menopausal women in this trial who have an intact uterus and are not on HRT, has identified 69 asymptomatic women with ET > 8 mm.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

“…We have previously reported abnormal endometrial cysts, polyps, hyperplasia and atypia in healthy post-menopausal women on tamoxifen in our breast cancer chemoprevention trial (Powles et al, 1990;Kedar et al, 1994). These abnormalities only occurred in women with an endometrial thickening (ET) of .…”

mentioning

confidence: 93%

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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“…It is currently being evaluated as a chemopreventive agent in young healthy women at high risk for breast cancer (Powles et al, 1990;Nay®eld et al, 1991). One of the most signi®cant complications of long term tamoxifen use is the development of endometrial cancer with up to a 7.5-fold increase in risk (Barakat, 1996;Fisher et al, 1994;Rutqvist et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

et al. 1998

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Tamoxifen is currently the most widely used drug for the treatment of breast cancer, but there now exists considerable evidence that tamoxifen can also induce endometrial hyperplasia in pre menopausal women. We have used PCR di erential display on primary human endometrial isolates in an attempt to identify genes induced by tamoxifen but not estrogen. Eight such di erentially expressed bands were cloned and sequenced, one of which was found to be the peptide adrenomedullin. We have shown that adrenomedullin is a novel growth factor for endothelial cells and is angiogenic in vivo in the chick chorioallantoic membrane assay. Immunohistochemical analysis of endometrial sections have shown that while macrophages in the endometrium express adrenomedullin at a low level, endometrial macrophages of women receiving tamoxifen strongly express adrenomedullin (P=0.008). We postulate that endometrial induction of the angiogenic factor adrenomedullin by tamoxifen is part of the mechanism by which tamoxifen results in endometrial hyperplasia.

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“…ErbB2 is overexpressed in a proportion of human tumours arising from several di erent sites (Berchuck et al, 1990;Hall et al, 1990;Kern et al, 1990;Yokota et al, 1986;Yonemura et al, 1991). In the breast, the 20 ± 25% of cancers which overexpress the gene have a poorer prognosis (Borg et al, 1990;Gasparini et al, 1992;Press et al, 1993;Slamon et al, 1987;Wright et al, 1989) and are relatively resistant to hormonal treatment (Wright et al, 1992) and chemotherapy (Gusterson et al, 1992;Muss et al, 1994). In vitro, ERBB2 is a transforming oncogene, both in rodent ®broblasts (Di Fiore et al, 1987) and immortalised breast epithelial cell lines (D'Souza et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…Tamoxifen is the leading hormonal treatment for breast cancer, producing objective disease responses in women with metastatic breast cancer (Hayward et al, 1977) and, in the adjuvant setting, increasing overall survival in post-menopausal women (Early Breast Cancer Trialists Collaborative Group, 1992a,b). In women at high risk of breast cancer, tamoxifen has been given prophylactically with the aim of reducing the incidence of the disease (Powles et al, 1990). The widespread use of tamoxifen, especially in healthy women, makes a clear understanding of its action particularly important.…”

Section: Introductionmentioning

confidence: 99%

An intron 1 enhancer element mediates oestrogen-induced suppression of ERBB2 expression

Bates

Hurst

1997

Oncogene

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Overexpression of the ERBB2 gene in human breast cancer is associated with a poor prognosis and resistance to hormonal treatment and chemotherapy. Oestrogen receptor (ER) positive tumour-derived cell lines are known to express relatively low levels of ERBB2 protein under oestrogenic conditions, but markedly higher levels following withdrawal of oestrogens or administration of tamoxifen. Expression of the closely related ERBB3 gene, which co-operates with ERBB2 in cellular transformation, is now shown to respond to oestrogenic manipulation in a similar way, both responses being mediated largely by transcriptional changes. Six previously undescribed DNase I hypersensitive sites occur within the ®rst intron of ERBB2 in cells that overexpress the gene. A 409 base pair DNA fragment containing one of these sites conferred ER dependent oestrogen inhibition on the ERBB2 promoter in two types of transient transfection assay. DNase I footprinting revealed four separate transcription factor binding sites within this fragment consistent with a role as a transcriptional enhancer. These ®ndings implicate intron 1 sequences in the control of ERBB2 expression for the ®rst time and demonstrate that one site within this region is involved in mediating the transcriptional response to oestrogens. Additionally, there is likely to be synergism between ERBB2 and ERBB3 signalling when both are overexpressed in response to oestrogen inhibition, thereby driving transformed cell behaviour.

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Prevention of breast cancer with tamoxifen—an update on the royal Marsden Hospital pilot programme

Cited by 151 publications

References 19 publications

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

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

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

An intron 1 enhancer element mediates oestrogen-induced suppression of ERBB2 expression

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