www.elsevier.com/locate/ebhc

EVIDENCE-BASED CLINICAL PRACTICE

Hormone replacement therapy is not safe forbreast cancer survivors$

Rena Vassilopoulou-Sellin, MD (Commentary Author)

Department of Endocrinology, University of Texas, M.D. Anderson Cancer Center, Houston, TX77030, USA

Summary

Question Is hormone replacement therapy safe for women with previous breastcancer?

Study design Randomised controlled trial (interim analysis).

Main results In 345 women surviving breast cancer, there were more new breastcancer events in women taking HRT for menopausal symptoms compared withwomen receiving symptomatic treatment without hormones at a median of 2 yearsfollow-up (absolute risk for new breast cancer: 26/174 [14%] with HRT vs 8/171 [5%]with no HRT; relative hazard 3.5, 95% CI 1.5 to 8.1).

Authors’ conclusions In women surving breast cancer, those who received HRT formenopausal symptoms were at a higher risk of developing new breast cancerscompared with those who received symptomatic treatment without hormones.These findings led to the termination of the trial.& 2004 Elsevier Ltd. All rights reserved.

Commentary

The HABITS trial, the largest prospective, multi-national randomised clinical trial to ascertain thesafety of hormone replacement therapy (HRT) forwomen with breast cancer was stopped earlybecause interim safety analysis demonstrated anexcessive rate of breast cancer events in the HRTarm. The significance of the trial and the resultsmust be viewed in the broader context of the role

of HRT in menopausal women in general and breastcancer survivors in particular.

‘‘Menopause’’ describes the cessation of ovarianoestrogen production; it usually occurs sponta-neously around the age of 50 years but may developprematurely after surgery or chemotherapy. Healthprofessionals have debated for decades whethersuch oestrogen decrease should be prevented withexogenous supplementation (HRT). The crux of theargument: is menopause a desired physiologictransition or is it an acquired oestrogen deficiencystate? Does HRT guard against age-related healthdeterioration and very importantly is it safe? WhileHRT was thought to prevent not only climactericsymptoms but also heart disease, osteoporosis and

ARTICLE IN PRESS

KEYWORDS

Breast cancer;

HRT;

Risk factors;

Survival;

Randomised controlled

trial

$Abstracted from: Holmberg L, Anderson H, HABITS SteeringData Monitoring Co. HABITS (hormonal replacement therapyafter breast cancerFis it safe?), a randomised comparison: trialstopped. Lancet 2004; 363: 453–5.

1462-9410/$ - see front matter & 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.ehbc.2004.05.004

Evidence-based Healthcare (2004) 8, 224–226

perhaps mental deterioration, a significant shift ofopinion evolved during the late 1990s, so much sothat in the summer of 2003 the US PreventiveServices Task Force1 recommended against theroutine use of oestrogen for the prevention ofchronic conditions in postmenopausal women.Given the unquestionable superiority of HRT forthe relief of, often debilitating, climacteric symp-toms, the discussion appropriately shifted to thesafety of HRT.

The possibility that prolonged oestrogen supple-mentation is associated with higher rates of breastcancer has been an early and persistent concernmade more prominent in recent studies.2–4 Studiesfocused on breast cancer survivors have beenextremely limited and generally small and retro-spective. The HABITS trial was designed to remedythe problem by providing prospective data withsufficient power to answer the question. The earlystopping of the trial is therefore very significantand will probably signal the end of such investiga-tions. It should be noted, though, that the patientselection and the HRT regimens were so variablethat we cannot determine whether subgroups ofbreast cancer survivors may safely take HRT.Indeed, a recent prospective, randomized trial thatexcluded women with ER(þ ) tumours and re-stricted HRT to oestrogen alone demonstrated avery favourable effect of oestrogen on disease-freesurvival.5

At this time, HRT is mainly advocated for short-term relief of menopausal symptoms. A smallincrease in breast cancer is a general concern,especially in progesterone containing regimens.The HABITS report carries the same cautionregarding breast cancer survivors; however, inbreast cancer survivors as in all menopausalwomen, oestrogen utilisation for individually se-lected criteria also remains viable.

Study parameters

Question Is hormone replacement therapysafe for women with previousbreast cancer?

Study design Randomised controlled trial (in-terim analysis).

Setting Two centres in Sweden; recruitmentfrom May 1997 to September 2003.

Participants 345 (of 434 originally randomised)women who had previously re-

ceived treatment for stage I orstage II breast cancer (fewer thanfour positive nodes). Women wereincluded if they were free ofrecurrence, had no other canceror significant disease and hadmenopausal symptoms that weredeemed to require treatment.Treatment with adjuvant tamox-ifen was permitted.

Intervention Women were randomised to hor-mone replacement therapy (HRT) orbest symptomatic treatment with-out hormones for 2 years. A cyclicoestrogen–progestagen combina-tion was recommended for womenwith an intact uterus and lastbleeding within 2 years, a contin-uous combined oestrogen–progesta-gen combination was recommendedfor women with last bleeding morethan 2 years ago, and mediumpotency oestrogen only was recom-mended for women with a hyster-ectomy. Follow up was intended for5 years although the trial wasterminated early (see Notes).

Main outcomes Any new breast cancer event.

Notes The data monitoring committeeperformed an interim analysis onthe 345 women with at least onefollow-up by September 2003. Itwas decided to terminate the trialafter a median follow-up of 2.1years when there was a significantrelative hazard of HRT comparedwith no HRT (RH 3.3, 95% CI 1.5 to7.4). More women randomised toreceive HRT were hormone recep-tor positive compared with womenrandomised to receive no HRT (86/154 [56%] vs-73/151 [48%]; p valuenot reported).

Sources of funding: This study was funded by Novo-Nordisk, the Nordic Cancer Union and the SwedishCancer Society.

Summary prepared by Bazian Ltd, London.

References

1. NIH news release www.nhlbi.nih.gov/new/press/04-03-02.

ARTICLE IN PRESS

Commentary on: Hormone replacement therapy is not safe for breast cancer survivors 225

2. Collaborative Group on Hormonal Factors in BrestCancer. Breast cancer and hormone replacementtherapy: collaborative reanalysis of data from 51 epidemio-logical studies of 52,705 women with breast cancer and108,411 women without breast cancer. Lancet 1997; 350:1047–59.

3. Roussouw JE, Anderson GL, Prentice RL, et al. Risks andbenefits of estrogen plus progestin in healthy postmenopausal

women: principal results from the women’s health initiativerandomized controlled trial. JAMA 2002; 288: 321–33.

4. Beral V. Million Women Study Collaborators. Breast cancerand hormone-replacement therapy in the Million WomenStudy. Lancet 2003;362:419–27.

5. Vassilopoulou-Sellin R, Cohen DS, Hortobagyi GN, et al.Estrogen replacement therapy for menopausal women witha history of breast carcinoma. Cancer 2002;95:1817–26.

ARTICLE IN PRESS

226 R. Vassilopoulou-Sellin