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Committee onGynecologic Practice

Reaffirmed 2008

ACOG

Number 336, June 2006 (Replaces No. 232, April 2000)

CommitteeOpinion

This document reflects emergingclinical and scientific advances as

of the date issued and is subject tochange. The information shouldnot be construed as dictating anexclusive course of treatment orprocedure to be followed.

Copyright June 2006by the American College ofObstetricians and Gynecologists.All rights reserved. No part of thispublication may be reproduced,stored in a retrieval system, post-ed on the Internet, or transmitted,in any form or by any means,electronic, mechanical, photo-

copying, recording, or otherwise,without prior written permissionfrom the publisher.

Requests for authorization tomake photocopies should bedirected to:

Copyright Clearance Center222 Rosewood DriveDanvers, MA 01923(978) 750-8400

ISSN 1074-861X

The American College of

Obstetricians and Gynecologists409 12th Street, SWPO Box 96920Washington, DC 20090-6920

Tamoxifen and uterine cancer.ACOG Committee Opinion No. 336.American College of Obstetriciansand Gynecologists. Obstet Gynecol2006;107:14758.

Tamoxifen and Uterine CancerABSTRACT: Tamoxifen may be associated with endometrial proliferation,

hyperplasia, polyp formation, invasive carcinoma, and uterine sarcoma. Anysymptoms of endometrial hyperplasia or cancer reported by a postmeno-

pausal woman taking tamoxifen should be evaluated. Premenopausal womentreated with tamoxifen have no known increased risk of uterine cancer and assuch require no additional monitoring beyond routine gynecologic care. Ifatypical endometrial hyperplasia develops, appropriate gynecologic manage-ment should be instituted, and the use of tamoxifen should be reassessed.

Tamoxifen, a nonsteroidal antiestrogen agent, is used widely as adjunctivetherapy for women with breast cancer. It has been approved by the U.S. Foodand Drug Administration for the following indications:

Adjuvant treatment of breast cancer

Metastatic breast cancer Reduction in breast cancer incidence in high-risk women

Because obstetriciangynecologists frequently treat women with breastcancer and women at risk for the disease, they may be consulted for adviceon the proper follow-up of women receiving tamoxifen. The purpose of thisCommittee Opinion is to review the risk and to recommend care to preventand detect uterine cancer in women receiving tamoxifen.

Tamoxifen is one of a class of agents known as selective estrogen recep-tor modulators (SERMs). Although the primary therapeutic effect of tamox-ifen is derived from its antiestrogenic properties, this agent also has modestestrogenic activity. In standard dosages, tamoxifen may be associated withendometrial proliferation, hyperplasia, polyp formation, invasive carcinoma,

and uterine sarcoma.Most studies have found that the increased relative risk of developing

endometrial cancer for women taking tamoxifen is two to three times high-er than that of an age-matched population (13). The level of risk of endome-trial cancer in women treated with tamoxifen is dose and time dependent.Studies suggest that the stage, grade, histology, and biology of tumors thatdevelop in individuals treated with tamoxifen (20 mg/d) are no differentfrom those that arise in the general population (3, 4). However, some reportshave indicated that women treated with a higher dosage of tamoxifen


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2 ACOG Committee Opinion No. 336

(40 mg/d) are more prone to develop more biologi-cally aggressive tumors (5).

In one early study of the National SurgicalAdjuvant Breast and Bowel Project (NSABP), therate of endometrial cancer occurrence among tamox-ifen users who were administered 20 mg/d was 1.6

per 1,000 patient years, compared with 0.2 per 1,000patient years among control patients taking a place-bo (3). In this study, the 5-year disease-free survivalrate from breast cancer was 38% higher in thetamoxifen group than in the placebo group, suggest-ing that the small risk of developing endometrialcancer is outweighed by the significant survival ben-efit provided by tamoxifen therapy for women withbreast cancer (3). The survival advantage with 5years of tamoxifen therapy continued with long-termfollow-up, but extending the duration of tamoxifenuse to 10 years failed to improve the survival benefit

gained from 5 years of tamoxifen use (6). In a morerecent update of all NSABP trials of patients withbreast cancer, the rate of endometrial cancer was1.26 per 1,000 patient years in women treated withtamoxifen versus 0.58 per 1,000 patient years in theplacebo group (7).

Uterine sarcomas consisting of malignant mixedmllerian tumors, leiomyosarcoma, and stroma cellsarcomas are a rare form of uterine malignancyoccurring in 25% of all patients with uterine malig-nancies (8). In a review of all NSABP breast cancertreatment trials, the rate of sarcoma in women treat-

ed with tamoxifen was 17 per 100,000 patient yearsversus none in the placebo group (7). Similarly, in aseparate trial of high-risk women without breast can-cer taking tamoxifen as part of a breast cancer pre-vention trial with a median follow-up of 6.9 years,there were four sarcomas (17 per 100,000 patientyears) in the tamoxifen group versus none in theplacebo group (7). This is compared with the inci-dence of one to two per 100,000 patient years in thegeneral population (9).

The NSABP prevention trial (P-1) data suggestthat the risk for both invasive and noninvasive breastcancer is reduced markedly with tamoxifen prophy-laxis. In this trial, however, the risk ratio for devel-oping endometrial cancer was 2.53 in women usingtamoxifen compared with women receiving a place-bo (10). In addition, the ability of tamoxifen toinduce endometrial malignancy as well as otherhistopathologic conditions appears to differ betweenpremenopausal and postmenopausal women. In theprevention trial of high-risk women, there was no

statistically significant difference in endometrialcancer rates between women treated with tamoxifenand those in the placebo group in the women aged49 years and younger; however, in women aged 50years and older, the risk ratio was 4.01 (95% confi-dence interval, 1.7010.90) for those treated with

tamoxifen versus those receiving placebo. Theannual rate was 3.05 malignancies per 1,000 womentreated with tamoxifen versus 0.76 malignancies per1,000 women receiving placebo (10). Another studyof women with breast cancer found that premeno-pausal women, treated or untreated, had no dif-ferences in endometrial thickness on ultrasoundexamination, uterine volume, or histopathologic find-ings, whereas postmenopausal women treated withtamoxifen had significantly more abnormalities (11).

Several approaches have been explored forscreening asymptomatic women using tamoxifen for

abnormal endometrial proliferation or endometrialcancer. Correlation is poor between ultrasono-graphic measurements of endometrial thickness andabnormal pathology in asymptomatic tamoxifenusers because of tamoxifen-induced subepithelialstromal hypertrophy (12). In asymptomatic womenusing tamoxifen, screening for endometrial cancerwith routine transvaginal ultrasonography, endome-trial biopsy, or both has not been shown to beeffective (1315). Although asymptomatic post-menopausal tamoxifen-treated women should nothave routine testing to diagnose endometrial pathol-

ogy, sonohysterography has improved the accuracyof ultrasonography in excluding or detectinganatomical changes, when necessary (16).

Other data suggest that low- and high-riskgroups of postmenopausal patients may be identifiedbefore the initiation of tamoxifen therapy for breastcancer (1719). Pretreatment screening identified 85asymptomatic patients with benign polyps in 510postmenopausal patients with newly diagnosedbreast cancer (16.7%). All polyps were removed. Atthe time of polypectomy, two patients had atypicalhyperplasias and subsequently underwent hysterec-tomies. The rest were treated with tamoxifen, 20mg/d, for up to 5 years. The incidence of atypicalhyperplasia was 11.7% in the group with initiallesions versus 0.7% in the group without lesions(P


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findings of pelvic ultrasound examination and endome-trial biopsy in asymptomatic breast cancer patients. BreastCancer Res Treat 1998;47:416.

14. Fung MF, Reid A, Faught W, Le T, Chenier C, Verma S, etal. Prospective longitudinal study of ultrasound screeningfor endometrial abnormalities in women with breast can-cer receiving tamoxifen. Gynecol Oncol 2003;91:1549.

15. Love CD, Muir BB, Scrimgeour JB, Leonard RC, DillonP, Dixon JM. Investigation of endometrial abnormalitiesin asymptomatic women treated with tamoxifen and anevaluation of the role of endometrial screening. J ClinOncol 1999;17:20504.

16. Markovitch O, Tepper R, Aviram R, Fishman A, ShapiraJ, Cohen I. The value of sonohysterography in the predic-

tion of endometrial pathologies in asymptomatic post-menopausal breast cancer tamoxifen-treated patients.Gynecol Oncol 2004;94:7549.

17. Berliere M, Charles A, Galant C, Donnez J. Uterine sideeffects of tamoxifen: a need for systematic pretreatmentscreening. Obstet Gynecol 1998;91:404.

18. Berliere M, Radikov G, Galant C, Piette P, Marbaix E,

Donnez J. Identification of women at high risk of devel-oping endometrial cancer on tamoxifen. Eur J Cancer2000;36(suppl 4):S356.

19. Vosse M, Renard F, Coibion M, Neven P, Nogaret JM,Hertens D. Endometrial disorders in 406 breast cancerpatients on tamoxifen: the case for less intensive monitor-ing. Eur J Obstet Gynecol Reprod Biol 2002;101:5863.

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