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T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 360;6 nejm.org february 5, 2009 573

original article

Breast Cancer after Use of Estrogen plus

Progestin in Postmenopausal WomenRowan T. Chlebowski, M.D., Ph.D., Lewis H. Kuller, M.D., Dr.P.H.,

Ross L. Prentice, Ph.D., Marcia L. Stefanick, Ph.D., JoAnn E. Manson, M.D., Dr.P.H.,Margery Gass, M.D., Aaron K. Aragaki, M.S., Judith K. Ockene, Ph.D.,

Dorothy S. Lane, M.D., Gloria E. Sarto, M.D., Aleksandar Rajkovic, M.D., Ph.D.,Robert Schenken, M.D., Susan L. Hendrix, D.O., Peter M. Ravdin, M.D., Ph.D.,

Thomas E. Rohan, M.B., B.S., Ph.D., Shagufta Yasmeen, M.D.,and Garnet Anderson, Ph.D., for the WHI Investigators*

From the Los Angeles Biomedical Re-search Institute at HarborUCLA Medi-cal Center, Torrance, CA (R.T.C.); the Uni-versity of Pittsburgh, Pittsburgh (L.H.K.);the Fred Hutchinson Cancer ResearchCenter, Seattle (R.L.P., A.K.A., G.A.); theStanford Prevention Research Center,Stanford, CA (M.L.S.); Brigham and Wom-ens Hospital and Harvard Medical School,Boston (J.E.M.); the University of Cincin-nati, Cincinnati (M.G.); the University ofMassachusetts, Fallon Clinic, Worcester

(J.K.O.); the State University of New Yorkat Stony Brook, Stony Brook (D.S.L.); theUniversity of Wisconsin, Madison (G.E.S.);Baylor College of Medicine, Houston(A.R.); the University of Texas Health Sci-ence Center at San Antonio, San Antonio(R.S.); Wayne State University School ofMedicine and Hutzel Hospital, Detroit(S.L.H.); the University of Texas M.D. An-derson Cancer Center, Houston (P.M.R.);the Albert Einstein College of Medicine,Bronx, NY (T.E.R.); and the University ofCalifornia at Davis, Sacramento (S.Y.).Address reprint requests to Dr. Chlebow-ski at the Los Angeles Biomedical Re-search Institute at HarborUCLA Medi-

cal Center, 1124 W. Carson St., Torrance,CA 90502, or at [email protected].

*A complete list of the Womens HealthInitiative (WHI) investigators appears inthe Appendix.

N Engl J Med 2009;360:573-87.Copyright 2009 Massachusetts Medical Society.

A b s t r a ct

Background

Following the release of the 2002 report of the Womens Health Initiative (WHI)trial of estrogen plus progestin, the use of menopausal hormone therapy in theUnited States decreased substantially. Subsequently, the incidence of breast canceralso dropped, suggesting a cause-and-effect relation between hormone treatmentand breast cancer. However, the cause of this decrease remains controversial.

Methods

We analyzed the results of the WHI randomized clinical trial in which one studygroup received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxy-

progesterone acetate daily and another group received placebo and examinedtemporal trends in breast-cancer diagnoses in the WHI observational-study cohort.Risk factors for breast cancer, frequency of mammography, and time-specific inci-dence of breast cancer were assessed in relation to combined hormone use.

Results

In the clinical trial, there were fewer breast-cancer diagnoses in the group receivingestrogen plus progestin than in the placebo group in the initial 2 years of the study,but the number of diagnoses increased over the course of the 5.6-year interventionperiod. The elevated risk decreased rapidly after both groups stopped taking thestudy pills, despite a similar frequency of mammography. In the observational study,the incidence of breast cancer was initially about two times as high in the group

receiving menopausal hormones as in the placebo group, but this difference in inci-dence decreased rapidly in about 2 years, coinciding with year-to-year reductions incombined hormone use. During this period, differences in the frequency of mam-mography between the two groups were unchanged.

Conclusions

The increased risk of breast cancer associated with the use of estrogen plus proges-tin declined markedly soon after discontinuation of combined hormone therapyand was unrelated to changes in frequency of mammography.

The New England Journal of Medicine

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Copyright 2009 Massachusetts Medical Society. All rights reserved.

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Th e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 360;6 nejm.org february 5, 2009574

The Womens Health Initiative (whi)trial of conjugated equine estrogens plusmedroxyprogesterone acetate was stopped

when health risks were shown to exceed the ben-efits of combined hormone therapy.1 The incidenceof breast cancer was higher in the hormone-ther-apy group, and the cancers were larger and more

advanced2; in addition, the frequency of abnor-malities on mammograms and of breast biopsieswas increased in the hormone-therapy group.3

After the release of our initial WHI report, in2002,1 menopausal hormone use decreased con-siderably in the United States.4,5 Approximatelya year later, a substantial drop in the incidenceof breast cancer was observed.6,7 Although sev-eral countries subsequently reported similar de-creases,8-10 others did not,11,12 and the cause ofthe decline remains controversial.13,14 The tempo-ral relation between decreased use of menopausal

hormones and the drop in the incidence of breastcancer suggested causality, although changes inthe frequency of mammographic screening aswell as other factors were recognized as possiblecontributors.6,7 When the WHI trial was stopped,more breast cancers were seen in the follow-upperiod (mean, 2.4 years) among women who hadreceived estrogen plus progestin than in the pla-cebo group,15 and it appeared that hormone ther-apy hindered the detection of breast cancer.2,3

Methods

Details of the WHI study have been describedelsewhere.16-18 Briefly, postmenopausal womenbetween the ages of 50 and 79 years with an an-ticipated survival of at least 3 years were eligible.Additional criteria for eligibility were the absenceof a history of invasive breast cancer or hysterec-tomy and a baseline mammogram and clinicalbreast examination with no suggestion of breastcancer. Women using menopausal hormone ther-apy were eligible after a 3-month washout period.

Subjects were randomly assigned to receive a dailydose of conjugated equine estrogens (0.625 mg)plus medroxyprogesterone acetate (2.5 mg) (Prem-pro, Wyeth-Ayerst Pharmaceuticals) or an identi-cal-appearing placebo. Randomization was per-formed by the WHI Clinical Coordinating Center.Study pills were distributed at clinical centers,with the use of a bar-code system to ensure thatboth staff and participants were unaware of thegroup assignments. The initial study population

consisted of 16,608 women, with the first ran-domization on October 29, 1993; postinterven-tion follow-up data were available for 15,387women, none of whom had received a diagnosisof breast cancer, and these women were thereforeincluded in the postintervention analyses.

We also analyzed data collected for 41,449

women enrolled in another WHI investigation,an observational study with eligibility criteriasimilar to those of the clinical trial: no history ofa hysterectomy or breast cancer and normal find-ings on a mammogram obtained within 2 yearsbefore study enrollment; 25,328 of the partici-pants reported no use of menopausal hormonetherapy and 16,121 reported use of estrogen plusprogestin at baseline. The first enrollment oc-curred on September 19, 1994, and data wereincluded through December 31, 2005. Thesewomen received no instruction from the WHI

regarding menopausal hormone use but were senta letter outlining the results of the estrogen-plus-progestin trial several weeks after the initialpublication of the study findings.

All women in both studies gave written in-formed consent, and the protocols were approvedby the institutional review board at each insti-tution.

Data Collection

All participants in both studies provided informa-tion on demographic characteristics, risk factorsfor breast cancer, medical and family histories,and lifestyle using standardized self-reportinginstruments. Information on past use of hor-mones was obtained by trained interviewers usingstructured questionnaires. Ongoing use of hor-mone therapy in the observational study was de-termined annually by means of questionnaires.Mammography was performed at WHI clinicalcenters and at community sites,19 and the reportswere coded in accordance with radiologists rec-ommendations. Mammographic findings were

considered to be abnormal if a physician-directedintervention was recommended (either follow-upafter a short interval or further evaluation be-cause of a finding that was suspicious or highlysuggestive of cancer).

Follow-up and Termination Procedures

Clinical outcomes were reported in a self-admin-istered questionnaire at 6-month intervals for theclinical trial and annually for the observational




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breast cancer after use of estrogen plus progestin in postmenopausal women


study. Breast cancers were confirmed by a reviewof pathology reports performed by local physicianadjudicators, followed by adjudication at the Clini-cal Coordinating Center.3 In the clinical trial,mammograms and breast examinations were re-quired annually, and the administration of studypills was continued only after adherence to the

regimen during the previous year had been docu-mented. In the observational study, mammogra-phy use was not defined by the protocol. Deci-sions regarding diagnostic procedures for breastcancer were made by community physicians. Rec-ommendations to perform breast biopsies werebased on clinical findings.

The intervention phase of the trial was termi-nated when an excessive net risk of combinedhormone therapy was identified.1 All participantswere instructed to stop taking the study pills (ac-tive or placebo) immediately, in a letter that was

intended for receipt on the day before the trialresults were published (July 8, 2002). This letterinitiated the postintervention phase of the trial.The originally specified date of trial completion(March 31, 2005) was the end date for the cur-rent analyses. During the postintervention phase,participants were followed on the same scheduleand were encouraged to continue having annualmammograms. Information on the frequency ofmammography and on clinical outcomes wascollected for the observational study during asimilar time period.

Statistical Analysis

Baseline characteristics of participants in the clin-ical trial were compared with the use of the chi-square test, Fishers exact test, or Students t-test.Hazard ratios for the intervention and postinter-vention phases of the trial were estimated fromCox proportional-hazards analysis, stratif ied ac-cording to age and randomized assignment inthe dietary-modification trial, a concurrent WHIclinical trial that participants could also enter.15

Additional analyses of the influence of meno-pausal hormones on the risk of invasive breastcancer depict linear, time-varying hazard ratiosover the period of the intervention and postinter-vention phases. To determine whether temporaltrends differed between the two phases, the equal-ity of the slopes between the two linear estimateswas tested. To confirm that the linear fits werereasonable, hazard ratios for the hormone-therapyand placebo groups were determined for sequen-

tial 6-month intervals and were visually comparedwith the linear hazard-ratio estimates. Sensitivityanalyses for adherence were conducted after cen-soring of data for events that occurred 6 monthsafter a woman became nonadherent (i.e., was us-ing

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Results

Clinical Trial

For the 15,387 participants in the clinical trialwho had not previously received a diagnosis of

invasive breast cancer and for whom any follow-up data during the postintervention phase wereavailable, risk factors for breast cancer were bal-anced between the two randomized study groups(Table 1) (P>0.10 for all tests of association). As

Table 1. Characteristics of the Participants in the Postintervention Phase of the Clinical Trial.*

CharacteristicHormone-Therapy Group

(N = 7854)Placebo Group

(N = 7533)

no./total no. (%)

Age at screening

50 to 59 yr 2663 (33.9) 2506 (33.3)

60 to 69 yr 3566 (45.4) 3425 (45.5)

70 to 79 yr 1625 (20.7) 1602 (21.3)

Race or ethnic group

White 6619 (84.3) 6351 (84.3)

Black 502 (6.4) 524 (7.0)

Hispanic 423 (5.4) 379 (5.0)American Indian 23 (0.3) 27 (0.4)

Asian or Pacific Islander 172 (2.2) 155 (2.1)

Unknown 115 (1.5) 97 (1.3)

Education

0 to 8 yr 174/7812 (2.2) 160/7475 (2.1)

Some high school 326/7812 (4.2) 337/7475 (4.5)

High-school diploma or GED 1501/7812 (19.2) 1501/7475 (20.1)

Some schooling after high school 3090/7812 (39.6) 2810/7475 (37.6)

College degree or higher 2721/7812 (34.8) 2667/7475 (35.7)

Gail-model estimate of 5-yr breast-cancer risk

1.75 2607 (33.2) 2483 (33.0)

Age at menarche

11 yr 1582/7833 (20.2) 1546/7501 (20.6)

12 to 13 yr 4252/7833 (54.3) 4038/7501 (53.8)

14 yr 1999/7833 (25.5) 1917/7501 (25.6)

Interval since menopause

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breast cancer after use of estrogen plus progestin in postmenopausal women


Table 1. (Continued.)



(N = 7533)

no./total no. (%)

Age at birth of first child

Never had term pregnancy or was never pregnant 795/7116 (11.2) 759/6768 (11.2)

12 mo 1335/7767 (17.2) 1285/7445 (17.3)

Use of oral contraceptives

No 4396 (56.0) 4291 (57.0)

Yes 3458 (44.0) 3242 (43.0)

Duration of use

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Table 1. (Continued.)



(N = 7533)

no./total no. (%)

No. of first-degree relatives with breast cancer

0 6436/7351 (87.6) 6226/7045 (88.4)

1 840/7351 (11.4) 744/7045 (10.6)

2 75/7351 (1.0) 75/7045 (1.1)

No. of second-degree relatives with breast cancer

0 6639/6929 (95.8) 6408/6674 (96.0)

1 280/6929 (4.0) 263/6674 (3.9)

2 10/6929 (0.1) 3/6674 (0.0)

History of benign breast disease

No 5881/7034 (83.6) 5839/7022 (83.2)

Yes, 1 biopsy 881/7034 (12.5) 912/7022 (13.0)

Yes, 2 biopsies 272/7034 (3.9) 271/7022 (3.9)

Body-mass index

1 drink/day 964/7824 (12.3) 976/7510 (13.0)

SmokingNever smoked 3920/7773 (50.4) 3756/7437 (50.5)

Past smoker 3080/7773 (39.6) 2925/7437 (39.3)

Current smoker 773/7773 (9.9) 756/7437 (10.2)

Use of NSAIDs 2628/7773 (33.5) 2569/7437 (34.1)

* Because of rounding, percentages may not total 100. GED denotes general equivalency diploma, METS metabolicequivalents, and NSAID nonsteroidal antiinflammatory drug.

Race or ethnic group was self-reported. The body-mass index is the weight in kilograms divided by the square of the height in meters.




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Table2.Year-to-YearBreast-CancerIncidenceandMeansofDetectionbefo

reandafterInterventionEnded,According

toStudyGroup.*

Variable

IntervalbeforeInterventionEnded

IntervalafterInterventionEn

ded

2to

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