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Hormonal replacement therapy (HRT) andbreast cancerRelated Summaries

Breast cancer in womenHormonal replacement therapy (HRT) for overview of HRTHormonal replacement therapy (HRT) and cardiovascular diseaseHormonal replacement therapy (HRT) and osteoporosisHormonal replacement therapy (HRT) and venous thromboembolism

Overview

combined estrogen and progestin (hormone replacement therapy [HRT]) associated with increasedrisk for breast cancer, but evidence for ongoing risk after stopping treatment is conflicting

hormone replacement therapy associated with increased risk for invasive breast cancer (level2 [mid­level] evidence)current use of HRT associated with increased risk of breast cancer incidence and mortality(level 2 [mid­level] evidence)conflicting evidence for ongoing risk of breast cancer after stopping HRT

long­term use of estrogen alone may increase risk for breast cancerestrogen alone does not appear to increase risk for invasive breast cancer but may increaserisk for abnormalities on follow­up mammograms (level 2 [mid­level] evidence)estradiol alone for > 5 years associated with increased risk for breast cancer (level 2 [mid­level] evidence)use of unopposed estrogen for > 20 years might be associated with increased risk of invasivebreast cancer (level 2 [mid­level] evidence)

HRT may increase risk for recurrent breast cancer in breast cancer survivors, but evidence isconflicting

HRT appears to increase risk of recurrent breast cancer (level 2 [mid­level] evidence) in 2randomized trialsHRT does not appear to increase risk for recurrent breast cancer based on systematic reviewof observational studiesHRT associated with nonsignificant increase in risk of new breast cancer event andcontralateral breast cancer after 10 years (level 2 [mid­level] evidence)among women with breast cancer, prediagnostic use of hormone therapy may be associatedwith decreased breast cancer mortality (level 2 [mid­level] evidence)

use of HRT may reduce sensitivity of mammography screening

Women's Health Initiative (WHI) Trial

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Combination HRT

Women's Health Initiative (WHI) is largest randomized trial of HRT, and was stopped early due toincreased risk of invasive breast cancer hormone replacement therapy associated with increased risk for invasive breast cancer(level 2 [mid­level] evidence)

based on randomized trial with early termination and low patient adherence16,608 postmenopausal women aged 50­79 years were randomized to HRT (equineestrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg [Prempro]) vs. placebo orally dailyfor mean 5.2 years (range 3.5­8.5 years)discontinuation of study drug occurred in 42% HRT and 38% placebo patients, whileaddition of HRT through personal clinician was started in 6.2% HRT and 10.7% placebopatientstrial was stopped early due to increased risk of invasive breast cancer with HRTintention­to­treat analysis was performed, so results likely underestimate "per protocol"resultsno differences in overall mortality or endometrial cancer0.38% HRT patients/year vs. 0.3% placebo patients/year developed invasive breast cancer(NNH 1,250 per year), but borderline statistical significance and not significant in adjustedanalysiseffect on breast cancer mortality not established as breast cancer mortality only occurred in 3HRT patients and 2 placebo patientsReference ­ Women's Health Initiative (WHI) Trial (JAMA 2002 Jul 17;288(3):321)editorial can be found in JAMA 2002 Jul 17;288(3):366, commentary can be found in BMJ2008 May 10;336(7652):1033 (commentary can be found in BMJ 2008 May24;336(7654):1148) increased risk of invasive breast cancer (cumulative risk) continued with longerfollow­up of WHI trial (level 2 [mid­level] evidence)

based on 2 follow­up trials of randomized trial above16,608 postmenopausal women aged 50­79 years randomized to HRT (equineestrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg [Prempro]) vs. placeboorally daily for mean 5.2 years (range 3.5­8.5 years)

comparing combined HRT vs. placebo after mean follow­up 5.6 years245 vs. 185 cases of total breast cancer (2.88% vs. 2.28%, p < 0.001,NNH 166)199 vs. 150 cases of invasive breast cancer (2.34% vs. 1.85%, p = 0.003,NNH 204)among invasive breast cancers, 25.4% vs. 16% were at more advancedstage (regional or metastatic) (p = 0.04)9.4% vs. 5.4% women had abnormal mammograms after 1 year (p <0.001, NNH 25)Reference ­ JAMA 2003 Jun 25;289(24):3243 full­text, editorial can befound in JAMA 2003 Jun 25;289(24):3304, commentary can be found inACP J Club 2003 Nov­Dec;139(3):61

12,788 women with no prior hysterectomy from WHI trial followed for mean 11 yearscomparing HRT vs. placebo

invasive breast cancer occurred in 4.5% vs. 3.6% (NNH 111)invasive breast cancer incidence 0.42% per year vs. 0.34% per year(hazard ratio [HR] 1.25, 95% CI 1.07­1.46)breast cancer mortality 0.03% per year vs. 0.01% per year (HR 1.9, 95%

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CI 1­4.04)all­cause mortality after breast cancer diagnosis 0.05% per year vs. 0.03%per year (HR 1.57, 95% CI 1.01­2.48)

HRT associated with increased risk of node­positive breast cancer (HR 1.78,95% CI 1.23­2.58)Reference ­ JAMA 2010 Oct 20;304(15):1684, editorial can be found in JAMA2010 Oct 20;304(15):1719

estrogen plus progestin associated with increased risk of breast cancer compared with nohormone use (level 2 [mid­level] evidence)

based on cohort study41,449 postmenopausal women with no prior hysterectomy and negative mammogramwithin 2 years followed for mean 11.3 years39% used estrogen plus progestinestrogen plus progestin use associated with increased risk of breast cancer compared to nohormone use (adjusted hazard ratio 1.55, 95% CI 1.41­1.7)no significant difference in survival following breast cancer diagnosisReference ­ J Natl Cancer Inst 2013 Apr 17;105(8):526

HRT combination therapy associated with higher rates of mammogram abnormalities andbreast biopsies in WHI trial (level 2 [mid­level] evidence)

comparing combined HRT vs. placebo at 5.6 years35% vs. 23% cumulative frequency of mammograms with abnormalities (p < 0.001,NNH 8)10% vs. 6.1% cumulative frequency of breast biopsy (p < 0.001, NNH 25)23.2% vs. 33.2% positive predictive value for mammography

Reference ­ Arch Intern Med 2008 Feb 25;168(4):370, correction can be found in ArchIntern Med 2008 May 12;168(9):935

conflicting evidence for ongoing risk of breast cancer after stopping HRTbased on secondary analyses of WHI trial using different methods breast cancer risk reported to return to baseline after HRT discontinued

relative risk increase with HRT gradually decreased back to 1 (implying no furtherincrease in risk) in analysis over time after HRT discontinuationReference ­ N Engl J Med 2009 Feb 5;360(6):573, commentary can be found in NEngl J Med 2009 May 28;360(22):2366

breast cancer risk may continue to be higher than baseline in HRT group with longerfollow­up of WHI trial

12,788 women with no prior hysterectomy followed for mean 11 yearscomparing HRT vs. placebo

incidence of invasive breast cancer at mean 11 years was 4.5% vs. 3.6% (NNH111)incidence of invasive breast cancer at mean 5.6 years (from data above) 2.34%vs. 1.85% (NNH 204)incidence of invasive breast cancer occurring between these timepoints (derivedindirectly with assumption of representing time off HRT in both groups) 2.16%vs. 1.75% (NNH 244)

Reference ­ JAMA 2010 Oct 20;304(15):1684, editorial can be found in JAMA 2010Oct 20;304(15):1719

higher rates of cancer (but not specifically breast cancer) associated with HRT 3 yearsafter halt of WHI trial (level 2 [mid­level] evidence)

based on postintervention phase of randomized trial

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15,730 women from WHI trial were followed for mean 2.4 years after halt of trial8,052 women from HRT group7,678 women from placebo group

comparing HRT vs. placebo during postintervention phaseall­cause mortality 2.9% vs. 2.6% (not significant)malignancies (including invasive breast cancer, endometrial or colorectalcancer) in 3.5% vs. 2.8% (p < 0.05, NNH 142, 95% CI 74­893)invasive breast cancer in 0.09% vs. 0.08% (not significant)

Reference ­ JAMA 2008 Mar 5;299(9):1036, commentary can be found in JAMA2008 Jun 18;299(23):2744, ACP J Club 2008 Aug 19;149(2):11

new­onset breast tenderness after starting combination HRT associated with increased riskof breast cancer

based on cohort of 14,538 women from WHI trial without baseline breast tendernessin women taking combination HRT, new­onset breast tenderness was associated withincreased risk for breast cancer (hazard ratio 1.48, 95% CI 1.08­2.03)new­onset breast tenderness not associated with breast cancer risk in placebo groupReference ­ Arch Intern Med 2009 Oct 12;169(18):1684

combined estrogen and testosterone use associated with nonsignificant increase in breastcancer risk after 3 years in cohort of 31,842 women from Women's Health Initiativeobservational study (Arch Intern Med 2009 Jan 12;169(1):41 full­text)

Estrogen alone

estrogen alone does not appear to increase risk for invasive breast cancer but may increaserisk for abnormalities on follow­up mammograms (level 2 [mid­level] evidence)

based on randomized trial with early trial termination10,739 postmenopausal women aged 50­79 years with prior hysterectomy randomized toconjugated equine estrogen 0.625 mg (Premarin) vs. placebo orally daily for mean of almost7 yearsstudy stopped early by NIH since there was no benefit in primary outcome of reducingcardiovascular diseaseinvasive breast cancer in 1.77% with estrogen vs. 2.28% with placebo (not significant)Reference ­ JAMA 2004 Apr 14;291(14):1701, editorial can be found in JAMA 2004 Apr14;291(14):1769, results noted earlier in NIH News Release 2004 Mar 2, commentary can befound in JAMA 2004 Aug 11;292(6):683, summary can be found in Am Fam Physician2005 Jan 15;71(2):371estrogen treatment associated with increased rate of mammography screening requiringfollow­up

annualized rate of invasive breast cancer 0.28% with estrogen vs. 0.34% with placebo(not statistically significant)mammograms with abnormalities requiring follow­up at 1 year 9.2% estrogen groupvs. 5.5% placebo group had (p < 0.001)mammograms with abnormalities requiring follow­up at 2 years 9.4% estrogen groupvs. 6.7% placebo group had (p < 0.001)Reference ­ JAMA 2006 Apr 12;295(14):1647, commentary can be found in Am FamPhysician 2006 Aug 15;74(4):651

Observational Studies

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Cohort studies

current use of HRT associated with increased risk of incident breast cancer and breastcancer mortality (level 2 [mid­level] evidence)

based on prospective cohort study1,084,110 women aged 50­64 years followed for several years (mean 2.6 years for incidence,mean 4.1 years for mortality)all types of HRT associated with increased risk, but magnitude greatest with combinationestrogen/progestinReference ­ Lancet 2003 Aug 9;362(9382):419, editorial can be found in Lancet 2003 Aug9;362(9382):414, correction can be found in Lancet 2003 Oct 4;362(9390):1160,commentary can be found in Lancet 2003 Oct 18;362(9392):1328, Am Fam Physician 2004Mar 15;69(6):1547

estradiol alone for > 5 years associated with increased risk for breast cancer (level 2 [mid­level] evidence)

based on cohort study110,984 Finnish women > 50 years old who used oral or transdermal estradiol, oral estriol orvaginal estrogens for at least 6 months during 1994­20012,171 (2%) developed breast canceroral or transdermal estradiol for > 5 years associated with standardized incidence ratio 1.44(95% CI 1.29­1.59), or 2­3 extra cases per 1,000 women followed for 10 years (NNH 333­500)no significant association with estradiol use < 5 years, oral estriol, or vaginal estrogensReference ­ Obstet Gynecol 2006 Dec;108(6):1354, editorial can be found in Obstet Gynecol2006 Dec;108(6):1352 (correction can be found in Obstet Gynecol 2007 Mar;109(3):788),commentary can be found in BMJ 2007 Jan 6;334(7583):3434 and in Am Fam Physician2007 May 15;75(10):1560

estrogen alone and estrogen with progestin associated with increased incidence of breastcancer in United States black women (level 2 [mid­level] evidence)

based on Black Women's Health Study 1995­2003 with 32,559 women > 40 years oldfollowed for mean 5.6 years with 615 (1.9%) cases of breast cancer reportedReference ­ Arch Intern Med 10;166(7):760

HRT associated with increased risk of breast cancer in postmenopausal women (level 2[mid­level] evidence)

based on prospective cohort study122,000 female registered nurses followed from 1976­1992 with 1,935 newly diagnosedcases of breast cancerrisk of breast cancer was increased in women using monotherapy with conjugated estrogens(relative risk (RR) 1.32) and in women taking progestins alone (RR 2.24), RR of breastcancer was similar for women taking estrogen plus progestin (RR 1.41) as in women takingestrogen aloneincreased RR of breast cancer disappeared when HRT had been stopped for > 2 yearsamong current users of HRT, increased RR only after use for > 5 yearshighest risk was among women 60­64 who had used HRT for > 5 years (RR 1.71)short­term estrogen use (< 7 years) in women < 55 is considered safewomen > 55 who have been on HRT > 5 years should consider benefits and risksReference ­ N Engl J Med 1995 Jun 15;332(24):1589, commentary can be found in J FamPract 1995 Nov;41(5):501use of estrogen­progesterone therapy associated with increased risk of breast cancerbased on cohort study of 221,551 Finnish women > 50 years old using E2­progestogen for ≥

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6 months Obstet Gynecol 2009 Jan;113(1):65 use of unopposed estrogen for > 20 years might be associated with increased risk of invasivebreast cancer (level 2 [mid­level] evidence)

based on prospective cohort study28,835 women who became postmenopausal after hysterectomy934 developed invasive breast canceruse of estrogen for < 10 years not associated with increased riskReference ­ Arch Intern Med 2006 May 8;166(9):1027, commentary can be found in AmFam Physician 2006 Oct 15;74(8):1420

use of estrogen slightly increases risk of breast cancer, use of estrogen/progestin slightlyincreases risk over that of estrogen alone, no increased risk found > 4 years after stoppinghormone replacement therapy (level 2 [mid­level] evidence)

based on cohort study46,355 postmenopausal women followed for mean 10 years (median 12 years)relative risks for breast cancer varied from 0.6­1.4 based on use of estrogen orestrogen/progestin and years of last usehigher risks were associated with more recent or current use of HRTmost subgroup analyses were not statistically significant but overall trend is prominentReference ­ JAMA 2000 Jan 26;283(4):485, editorial can be found in JAMA 2000 Jan26;283(4):534increased risks primarily associated with long­term use of cyclic therapy and may not applyto continuous combined HRT (Dear Health Care Professional letter 2000 Feb 22 fromWyeth­Ayerst Laboratories), commentary can be found in J Fam Pract 2000 Apr;49(4):301,commentary can be found in JAMA 2000 Aug 9;284(6):691DynaMed commentary ­ actual increase in risk relatively small, results subject to multiplebiases, many subjects initially enrolled in study based on having undergone breast surgerywith no evidence of malignant disease so these patients may be different than generalpopulation

increased risk of breast cancer greater for estrogen combined with progestogens other thanprogesterone or dydrogesterone (level 2 [mid­level] evidence)

based on cohort study of 80,377 postmenopausal women2,354 cases of invasive breast cancer occurred during mean 8.1 year follow­uprelative risk of breast cancer 1.29 (95% CI 1.02­1.65) with estrogen alone vs. HRT never­usersrelative risk of breast cancer with estrogen­progestogen combinations varied with type ofprogestogen

1 (95% CI 0.83­1.22) for estrogen­progesterone1.16 (95% CI 0.94­1.43) for estrogen­dydrogesterone1.69 (95% CI 1.5­1.91) for estrogen combined with other progestogens

Reference ­ Breast Cancer Res Treat 2008 Jan;107(1):103 full­text, correction can be foundin Breast Cancer Res Treat 2008 Jan;107(2):307

combined estrogen and testosterone use associated with increased risk of breast cancerbased on nested case­control studyNurses' Health Study identified 4,610 incident cases of invasive breast cancer amongpostmenopausal women during 24 years of follow­up (1,359,232 person­years)among women with natural menopause, multivariate relative risk for breast cancer was 2.48(95% CI 1.53­4.04) for current users of estrogen plus testosterone than never users ofpostmenopausal hormonesrisk with estrogen plus testosterone significantly greater than with estrogen alone (p = 0.007)and marginally greater than with estrogen plus progestin (p = 0.11)

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Reference ­ Arch Intern Med 2006 Jul 24;166(14):1483 full­text, commentary can be foundin Arch Intern Med 2007 Jan 22;167(2):205

HRT not associated with increased risk of breast cancer overall, but associated withincreased risk of invasive breast cancer "with favorable prognosis" (level 2 [mid­level]evidence)

based on population­based cohort study37,105 healthy postmenopausal women aged 55­69 years followed for up to 11 years1520 (4%) developed breast cancer of whom only 82 (5%) had "invasive carcinoma withfavorable histology"no association found for HRT with invasive lobular or ductal tumors of ductal carcinoma insitueditorial suggests that original article placed too much emphasis on positive association andnot enough on overall lack of association between HRT and breast cancerReference ­ JAMA 1999 Jun 9;281(22):2091, commentary can be found in JAMA 1999 Jun9;281(22):2140

HRT increased risk of breast cancer while lowering mortality in patients with family historyof breast cancer (level 2 [mid­level] evidence)

based on prospective cohort study of 35,919 women in Iowa followed 8 years12% had family history of breast cancer (mother, sister or daughter)HRT increased risk of breast cancer (from 46 to 61 per 10,000 person­years, not statisticallysignificant)while lowering mortality (statistically significant, from 80 to 46 per 10,000 person­years)Reference ­ Ann Intern Med 1997 Dec 1;127:973 full­text in J Watch 1998 Jan 15;18(2):15and in Hosp Pract 1998 Mar;33(3):49

among women with breast cancer, prediagnostic use of hormone therapy may be associatedwith decreased breast cancer mortality (level 2 [mid­level] evidence)

based on prospective cohort study12,269 women ≥ 50 years old with incident invasive breast cancer followed for mean 10.3years1,690 breast cancer deaths occurredreduced risk of death from breast cancer associated with

any use of hormone therapy (adjusted hazard rate ratio 0.87, 95% CI 0.78­0.98)current hormone therapy use at time of diagnosis (adjusted hazard rate ratio 0.85, 95%CI 0.73­0.98)exclusive use of estrogen­progestin therapy (adjusted hazard rate ratio 0.73, 95% CI0.59­0.91)current exclusive use of estrogen­progestin at diagnosis (adjusted hazard rate ratio0.69, 95% CI 0.55­0.88)estrogen­progestin use ≥ 5 years (adjusted hazard rate ratio 0.60, 95% CI 0.43­0.84)

Reference ­ Cancer Epidemiol Biomarkers Prev 2008 Apr;17(4):864risk of breast cancer was higher with HRT use > 2 years than with HRT use < 6 months(level 2 [mid­level] evidence) (hazard ratio 1.34, 95% CI 1.13­1.58) in record linkage study of73,505 women aged 45­75 years who received at least one HRT prescription and were followed 5­7 years Ann Oncol 2008 Jan;19(1):150qualitative review of 45 studies comparing ever­users and never­users of estrogen foundinconsistent results regarding risk of breast cancer (Obstet Gynecol 2001 Sep;98(3):498 in BMJ2001 Sep 15;323(7313):642), summary can be found in Am Fam Physician 2002 Mar 1;65(5):947

Case­control studies

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studies reporting increased risk for breast cancerHRT use > 4 years associated with increased risk of breast cancer by 2%/year (level 2[mid­level] evidence)

based on case­control study with 52,705 women with invasive breast cancer and108,411 controls2.3%/year increased risk of breast cancer for HRT use > 4 years, but risk no longerpresent with cessation of HRT > 5 yearsReference ­ Lancet 1997 Oct 11;350(9084):1047 in J Watch 1997 Nov 15;17(22):174only 12% women using HRT in these studies used progestogens, so results mainlyapply to estrogen alone (Evidence­Based Medicine 1998 May/Jun;3(3):93)

continuous combined HRT associated with increased risk of breast cancer, but noapparent risk with estrogen alone or sequential estrogen and progestin (level 2 [mid­level] evidence)

based on comparison of 1,870 cases and 1,953 controls aged 35­64 years andpostmenopausalReference ­ Obstet Gynecol 2002 Dec;100(6):1148 in J Watch Online 2003 Jan 14,summary can be found in Am Fam Physician 2003 Mar 1;67(5):1059

combined HRT (sequential or continuous) associated with 1.7 times risk of invasivebreast cancer (level 2 [mid­level] evidence)

based on study of 975 cases and 1,007 controls among women aged 65­79 yearsReference ­ JAMA 2003 Jun 25;289(24):3254, editorial can be found in JAMA 2003Jun 25;289(24):3304

recent long­term use of HRT associated with increased risk of breast cancer (level 2[mid­level] evidence)

based on case­control study with 705 postmenopausal women aged 50­74 years withinvasive breast cancer and 692 controlsReference ­ JAMA 2002 Feb 13;287(6):734, commentary can be found in JAMA 2002May 8;287(18):2360

conjugated estrogen plus progestin use associated with increased risk of breast cancer,particularly after ≥ 4 years of use (level 2 [mid­level] evidence)

based on case­control study 4,515 women aged 50­64 years with breast cancer whoused hormone replacement therapy compared to 18,058 controlsincreased risk of breast cancer with conjugated estrogen plus progestin use of ≥ 48months (odds ratio 3.10, p < 0.05)Reference ­ Obstet Gynecol 2009 Jan;113(1):74

studies reporting no increase in risk for breast cancer long­term use (> 8 years) of combined estrogen and progestin HRT does not appear toincrease risk of breast cancer in postmenopausal middle­aged women (level 2 [mid­level] evidence)

based on case­control study involving 537 patients with incident breast cancer and 492randomly selected controlsReference ­ JAMA 1995 Jul 12;274(2):137, editorial can be found in J Fam Pract 1995Nov;41(5):501, JAMA 1995 Jul 12;274(2):178, commentary can be found in ACP JClub 1996 Jan­Feb;124(1):21, JAMA 1996 Apr 17;275(15):1159

HRT does not appear to be associated with increased risk of breast cancer inpostmenopausal women with BRCA1 mutation (level 2 [mid­level] evidence)

based on case­control study236 women postmenopausal women with BRCA1 mutation and breast cancer werematched to 236 postmenopausal women with BRCA1 mutation and no breast cancerwomen with HRT exposure had reduced risk for breast cancer (adjusted odds ratio

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0.58, 95% CI 0.35­0.96) compared to women without HRT exposureanalysis by type of HRT exposure found inverse association with estrogen alone (oddsratio 0.51, 95% CI 0.27­0.98) and no significant association with estrogen plusprogesterone (odds ratio 0.66, 95% CI 0.34­1.27)Reference ­ J Natl Cancer Inst 2008 Oct 1;100(19):1361 full­text

HRT and Recurrent Breast Cancer

HRT might increase risk for recurrent breast cancer in breast cancer survivors, but evidence isconflicting

HRT appears to increase risk of recurrent breast cancer (level 2 [mid­level] evidence)based on 2 randomized trials with early termination434 women with previous breast cancer randomized in 2 open trials to HRT vs. noHRTtrials ended early because interim analysis showed unacceptable risk with HRT345 women had at least 1 follow­up report, median follow­up 2.1 years26 women assigned to HRT vs. 8 assigned to no HRT had new breast cancer event(14.9% vs. 4.7%, NNH 9)1 new breast cancer event in control group was subsequently excluded due to lack ofverification, all 26 in HRT group and 2 in no­HRT group who had new breast cancerevent used HRTReference ­ HABITS trial (Lancet 2004 Feb 7;363(9407):453), editorial can be foundin Lancet 2004 Feb 7;363(9407):410, commentary can be found in Lancet 2004 May1;363(9419):14764­year follow­up of HABITS trial supports recurrent breast cancer risk

447 women with previous breast cancer randomized in 2 open trials to HRT vs.no HRT (DynaMed commentary ­­ lower numbers in report above likely due toit being an interim report generated before trial closed)442 women followed for median 4 yearsnew breast cancer events occurred in 18% HRT vs. 8% control women duringfollow­up (p < 0.05, NNH 10)5­year cumulative incidence 22.2% with HRT vs. 8% with controlReference ­ J Natl Cancer Inst 2008 Apr 2;100(7):475

HRT does not appear to increase risk for recurrent breast cancer based on systematicreview of observational studies

based on systematic review of mostly observational studiessystematic review of 10 prospective studies (only 1 randomized trial) comparing 717estrogen users and 2,545 nonusers after diagnosis of breast cancerbreast cancer survivors using estrogen had no increased risk of recurrence (relativerisk 0.72, 95% CI 0.47­1.1) and reduced mortality (3% vs. 11.4%, relative risk 0.18,95% CI 0.1­0.31)Reference ­ J Fam Pract 2002 Dec;51(12):1056

HRT associated with nonsignificant increase in risk of new breast cancer event andcontralateral breast cancer after 10 years (level 2 [mid­level] evidence)

based on follow­up of randomized trial with early termination378 women with prior breast cancer were randomized to HRT vs. no HRT andfollowed for median 10.8 yearstrial terminated after median 4.1 years due to increased risk of recurrence in pooledanalysis with HABITS trial but no significant difference in recurrence excludingHABITS trial

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comparing HRT vs. no HRTnew breast cancer event (defined as any recurrence, contralateral breast cancer,other cancer, or death) in 32% vs. 25% (not significant)locoregional recurrence in 6% vs. 8% (not significant)distant metastasis in 6% vs. 6% (not significant)contralateral breast cancer in 8% vs. 2% (p = 0.016, NNH 16)

Reference ­ Eur J Cancer 2013 Jan;49(1):52

HRT and Mammography

HRT use may reduce accuracy of mammography

HRT use associated with lower sensitivity (more false negative mammograms), based on studyof 1,557 breast cancers (Cancer Epidemiol Biomarkers Prev 2005 May;14(5):1060)HRT use may reduce sensitivity of mammography screening, based on study of 103,770women in Australia (Lancet 2000 Jan 22;355(9200):270), commentary can be found in Lancet2000 May 13;355(9216):1726HRT use associated with increased breast density on mammography based on study of 5,212postmenopausal women (JAMA 2001 Jan 10;285(2):171), commentary can be found in JAMA2001 Apr 11;285(14):1839

bazedoxifene­conjugated estrogens not associated with increased breast density onmammography (level 2 [mid­level] evidence)

based on breast density substudy from randomized trial940 healthy postmenopausal women aged 40­65 years with intact uterus seeking treatmentfor menopausal symptoms randomized to once­daily oral dose of 1 of the following 5regimens for 1 year, and digital mammograms at baseline and 1 year evaluated for change inpercent dense breast tissue

bazedoxifene 20 mg and conjugated estrogens 0.45 mgbazedoxifene 20 mg and conjugated estrogens 0.625 mgbazedoxifene 20 mgconjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg (aconventional estrogen­progestin therapy)placebo

81% completed substudycompared with placebo

no significant difference in change in breast density with bazedoxifene 20 mg andconjugated estrogens 0.45 and 0.625 mgconjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg associatedwith increased breast density (p < 0.001)

Reference ­ Obstet Gynecol 2013 May;121(5):959DynaMed commentary ­­ bazedoxifene not available in United States as of February 28,2013, but is marketed in Italy and Spain; bazedoxifene/conjugated estrogen combination notcommercially available as of February 28, 2013

HRT use does not independently predict accuracy of screening mammography, butincreased breast density reduces accuracy

based on study of 463,372 screening mammograms in 329,495 women aged 40­89 years,2,223 women had diagnosis of breast canceradjusted sensitivity and specificity was 87% and 96.9% in women with almost entirely fatty

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breasts and decreased to 62.9% and 89.1% in women with extremely dense breastsadjusted sensitivity and specificity was 83.3% and 94.4% in women aged 80­89 years anddecreased to 68.6% and 91.4% in women aged 40­44Reference ­ Ann Intern Med 2003 Feb 4;138(3):168), correction can be found in Ann InternMed 2003 May 6;138(9):771, summary can be found in Am Fam Physician 2003 Sep15;68(6):1198

HRT associated with higher false positive recall rates from screening mammography among87,967 postmenopausal women aged 50­64 years (BMJ 2004 May 29;328(7451):1291)

Additional Information

HRT use not associated with histology indicating poorer prognosis among breast cancerpatients

based on study of 1,113 women aged 50­64 years with breast cancer, 14.9% had HRT use atdiagnosisno differences in type, size or grade of tumors; lymph nodes were positive in 23% HRTusers and 33% nonusersReference ­ BMJ 2000 Feb 5;320(7231):348 in J Watch 2000 Mar 15;20(6):46

discussion of estimating individual risk of breast cancer with HRT can be found in BMJ 2005 Aug6;331(7512):347

Guidelines and Resources

Guidelines

Society of Obstetricians and Gynaecologists of Canada (SOGC) guideline on hormone therapy andbreast cancer (menopause and osteoporosis update 2009) can be found at SOGC 2009 Jan PDF

Review articles

AHRQ comparative effectiveness review on menopausal symptoms: comparative effectiveness oftherapies can be found at AHRQ Comparative Effectiveness Review 2015 Mar:147 PDF

review of urogenital consequences of estrogen deprivation therapy in breast cancer patients andestrogen replacement therapy can be found in Oncologist 2008 Mar;13(3):222review of consensus conference III on image­detected breast cancer; state­of­the­art diagnosis andtreatment can be found in J Am Coll Surg 2009 Oct;209(4):504

References

DynaMed editorial process

DynaMed topics are created and maintained by the DynaMed Editorial Team.Over 500 journals and evidence­based sources (DynaMed Content Sources) are monitored directlyor indirectly using a 7­Step evidence­based method for systematic literature surveillance.DynaMed topics are updated daily as newly discovered best available evidence is identified.The participating members of the DynaMed Editorial Team have declared that they have nofinancial or other competing interests related to this topic.

20/12/2015 DynaMed Plus: Hormonal replacement therapy (HRT) and breast cancer

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How to cite

National Library of Medicine, or "Vancouver style" (International Committee of Medical JournalEditors):

DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 ­ . Record No.115361, Hormonal replacement therapy (HRT) and breast cancer; [updated 2014 Mar 11,cited place cited date here]; [about 9 screens]. Available fromhttp://www.dynamed.com/login.aspx?direct=true&site=DynaMed&id=115361. Registrationand login required.