DynaMed Plus_ Hormonal replacement therapy (HRT) and breast cancer.pdf
Content
20/12/2015
DynaMed Plus: Hormonal replacement therapy (HRT) and breast cancer
Hormonal replacement therapy (HRT) and
breast cancer
Related Summaries
Breast cancer in women
Hormonal replacement therapy (HRT) for overview of HRT
Hormonal replacement therapy (HRT) and cardiovascular disease
Hormonal replacement therapy (HRT) and osteoporosis
Hormonal replacement therapy (HRT) and venous thromboembolism
Overview
combined estrogen and progestin (hormone replacement therapy [HRT]) associated with increased
risk for breast cancer, but evidence for ongoing risk after stopping treatment is conflicting
hormone replacement therapy associated with increased risk for invasive breast cancer (level
2 [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 cancer
estrogen alone does not appear to increase risk for invasive breast cancer but may increase
risk for abnormalities on followup mammograms (level 2 [midlevel] evidence)
estradiol alone for > 5 years associated with increased risk for breast cancer (level 2 [mid
level] evidence)
use of unopposed estrogen for > 20 years might be associated with increased risk of invasive
breast cancer (level 2 [midlevel] evidence)
HRT may increase risk for recurrent breast cancer in breast cancer survivors, but evidence is
conflicting
HRT appears to increase risk of recurrent breast cancer (level 2 [midlevel] evidence) in 2
randomized trials
HRT does not appear to increase risk for recurrent breast cancer based on systematic review
of observational studies
HRT associated with nonsignificant increase in risk of new breast cancer event and
contralateral breast cancer after 10 years (level 2 [midlevel] evidence)
among women with breast cancer, prediagnostic use of hormone therapy may be associated
with 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 to
increased 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 adherence
16,608 postmenopausal women aged 5079 years were randomized to HRT (equine
estrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg [Prempro]) vs. placebo orally daily
for mean 5.2 years (range 3.58.5 years)
discontinuation of study drug occurred in 42% HRT and 38% placebo patients, while
addition of HRT through personal clinician was started in 6.2% HRT and 10.7% placebo
patients
trial was stopped early due to increased risk of invasive breast cancer with HRT
intentiontotreat analysis was performed, so results likely underestimate "per protocol"
results
no differences in overall mortality or endometrial cancer
0.38% 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 adjusted
analysis
effect on breast cancer mortality not established as breast cancer mortality only occurred in 3
HRT patients and 2 placebo patients
Reference 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 BMJ
2008 May 10;336(7652):1033 (commentary can be found in BMJ 2008 May
24;336(7654):1148)
increased risk of invasive breast cancer (cumulative risk) continued with longer
followup of WHI trial (level 2 [midlevel] evidence)
based on 2 followup trials of randomized trial above
16,608 postmenopausal women aged 5079 years randomized to HRT (equine
estrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg [Prempro]) vs. placebo
orally daily for mean 5.2 years (range 3.58.5 years)
comparing combined HRT vs. placebo after mean followup 5.6 years
245 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 advanced
stage (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 be
found in JAMA 2003 Jun 25;289(24):3304, commentary can be found in
ACP J Club 2003 NovDec;139(3):61
12,788 women with no prior hysterectomy from WHI trial followed for mean 11 years
comparing 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 JAMA
2010 Oct 20;304(15):1719
estrogen plus progestin associated with increased risk of breast cancer compared with no
hormone use (level 2 [midlevel] evidence)
based on cohort study
41,449 postmenopausal women with no prior hysterectomy and negative mammogram
within 2 years followed for mean 11.3 years
39% used estrogen plus progestin
estrogen plus progestin use associated with increased risk of breast cancer compared to no
hormone use (adjusted hazard ratio 1.55, 95% CI 1.411.7)
no significant difference in survival following breast cancer diagnosis
Reference J Natl Cancer Inst 2013 Apr 17;105(8):526
HRT combination therapy associated with higher rates of mammogram abnormalities and
breast biopsies in WHI trial (level 2 [midlevel] evidence)
comparing combined HRT vs. placebo at 5.6 years
35% 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 Arch
Intern Med 2008 May 12;168(9):935
conflicting evidence for ongoing risk of breast cancer after stopping HRT
based 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 further
increase in risk) in analysis over time after HRT discontinuation
Reference N Engl J Med 2009 Feb 5;360(6):573, commentary can be found in N
Engl J Med 2009 May 28;360(22):2366
breast cancer risk may continue to be higher than baseline in HRT group with longer
followup of WHI trial
12,788 women with no prior hysterectomy followed for mean 11 years
comparing HRT vs. placebo
incidence of invasive breast cancer at mean 11 years was 4.5% vs. 3.6% (NNH
111)
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 (derived
indirectly 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 2010
Oct 20;304(15):1719
higher rates of cancer (but not specifically breast cancer) associated with HRT 3 years
after 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 trial
8,052 women from HRT group
7,678 women from placebo group
comparing HRT vs. placebo during postintervention phase
allcause mortality 2.9% vs. 2.6% (not significant)
malignancies (including invasive breast cancer, endometrial or colorectal
cancer) 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 JAMA
2008 Jun 18;299(23):2744, ACP J Club 2008 Aug 19;149(2):11
newonset breast tenderness after starting combination HRT associated with increased risk
of breast cancer
based on cohort of 14,538 women from WHI trial without baseline breast tenderness
in women taking combination HRT, newonset breast tenderness was associated with
increased risk for breast cancer (hazard ratio 1.48, 95% CI 1.082.03)
newonset breast tenderness not associated with breast cancer risk in placebo group
Reference Arch Intern Med 2009 Oct 12;169(18):1684
combined estrogen and testosterone use associated with nonsignificant increase in breast
cancer risk after 3 years in cohort of 31,842 women from Women's Health Initiative
observational 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 increase
risk for abnormalities on followup mammograms (level 2 [midlevel] evidence)
based on randomized trial with early trial termination
10,739 postmenopausal women aged 5079 years with prior hysterectomy randomized to
conjugated equine estrogen 0.625 mg (Premarin) vs. placebo orally daily for mean of almost
7 years
study stopped early by NIH since there was no benefit in primary outcome of reducing
cardiovascular disease
invasive 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 Apr
14;291(14):1769, results noted earlier in NIH News Release 2004 Mar 2, commentary can be
found in JAMA 2004 Aug 11;292(6):683, summary can be found in Am Fam Physician
2005 Jan 15;71(2):371
estrogen treatment associated with increased rate of mammography screening requiring
followup
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 group
vs. 5.5% placebo group had (p < 0.001)
mammograms with abnormalities requiring followup at 2 years 9.4% estrogen group
vs. 6.7% placebo group had (p < 0.001)
Reference JAMA 2006 Apr 12;295(14):1647, commentary can be found in Am Fam
Physician 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 breast
cancer mortality (level 2 [midlevel] evidence)
based on prospective cohort study
1,084,110 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 combination
estrogen/progestin
Reference Lancet 2003 Aug 9;362(9382):419, editorial can be found in Lancet 2003 Aug
9;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 2004
Mar 15;69(6):1547
estradiol alone for > 5 years associated with increased risk for breast cancer (level 2 [mid
level] evidence)
based on cohort study
110,984 Finnish women > 50 years old who used oral or transdermal estradiol, oral estriol or
vaginal estrogens for at least 6 months during 19942001
2,171 (2%) developed breast cancer
oral 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 333
500)
no significant association with estradiol use < 5 years, oral estriol, or vaginal estrogens
Reference Obstet Gynecol 2006 Dec;108(6):1354, editorial can be found in Obstet Gynecol
2006 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 Physician
2007 May 15;75(10):1560
estrogen alone and estrogen with progestin associated with increased incidence of breast
cancer in United States black women (level 2 [midlevel] evidence)
based on Black Women's Health Study 19952003 with 32,559 women > 40 years old
followed for mean 5.6 years with 615 (1.9%) cases of breast cancer reported
Reference 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 study
122,000 female registered nurses followed from 19761992 with 1,935 newly diagnosed
cases of breast cancer
risk 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 breast
cancer was similar for women taking estrogen plus progestin (RR 1.41) as in women taking
estrogen alone
increased RR of breast cancer disappeared when HRT had been stopped for > 2 years
among current users of HRT, increased RR only after use for > 5 years
highest 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 safe
women > 55 who have been on HRT > 5 years should consider benefits and risks
Reference N Engl J Med 1995 Jun 15;332(24):1589, commentary can be found in J Fam
Pract 1995 Nov;41(5):501
use of estrogenprogesterone therapy associated with increased risk of breast cancer
based 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 invasive
breast cancer (level 2 [midlevel] evidence)
based on prospective cohort study
28,835 women who became postmenopausal after hysterectomy
934 developed invasive breast cancer
use of estrogen for < 10 years not associated with increased risk
Reference Arch Intern Med 2006 May 8;166(9):1027, commentary can be found in Am
Fam Physician 2006 Oct 15;74(8):1420
use of estrogen slightly increases risk of breast cancer, use of estrogen/progestin slightly
increases risk over that of estrogen alone, no increased risk found > 4 years after stopping
hormone replacement therapy (level 2 [midlevel] evidence)
based on cohort study
46,355 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 or
estrogen/progestin and years of last use
higher risks were associated with more recent or current use of HRT
most subgroup analyses were not statistically significant but overall trend is prominent
Reference JAMA 2000 Jan 26;283(4):485, editorial can be found in JAMA 2000 Jan
26;283(4):534
increased risks primarily associated with longterm use of cyclic therapy and may not apply
to continuous combined HRT (Dear Health Care Professional letter 2000 Feb 22 from
WyethAyerst 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):691
DynaMed commentary actual increase in risk relatively small, results subject to multiple
biases, many subjects initially enrolled in study based on having undergone breast surgery
with no evidence of malignant disease so these patients may be different than general
population
increased risk of breast cancer greater for estrogen combined with progestogens other than
progesterone or dydrogesterone (level 2 [midlevel] evidence)
based on cohort study of 80,377 postmenopausal women
2,354 cases of invasive breast cancer occurred during mean 8.1 year followup
relative risk of breast cancer 1.29 (95% CI 1.021.65) with estrogen alone vs. HRT never
users
relative risk of breast cancer with estrogenprogestogen combinations varied with type of
progestogen
1 (95% CI 0.831.22) for estrogenprogesterone
1.16 (95% CI 0.941.43) for estrogendydrogesterone
1.69 (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 found
in Breast Cancer Res Treat 2008 Jan;107(2):307
combined estrogen and testosterone use associated with increased risk of breast cancer
based on nested casecontrol study
Nurses' Health Study identified 4,610 incident cases of invasive breast cancer among
postmenopausal 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 of
postmenopausal hormones
risk 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 found
in Arch Intern Med 2007 Jan 22;167(2):205
HRT not associated with increased risk of breast cancer overall, but associated with
increased risk of invasive breast cancer "with favorable prognosis" (level 2 [midlevel]
evidence)
based on populationbased cohort study
37,105 healthy postmenopausal women aged 5569 years followed for up to 11 years
1520 (4%) developed breast cancer of whom only 82 (5%) had "invasive carcinoma with
favorable histology"
no association found for HRT with invasive lobular or ductal tumors of ductal carcinoma in
situ
editorial suggests that original article placed too much emphasis on positive association and
not enough on overall lack of association between HRT and breast cancer
Reference JAMA 1999 Jun 9;281(22):2091, commentary can be found in JAMA 1999 Jun
9;281(22):2140
HRT increased risk of breast cancer while lowering mortality in patients with family history
of breast cancer (level 2 [midlevel] evidence)
based on prospective cohort study of 35,919 women in Iowa followed 8 years
12% 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 statistically
significant)
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):15
and in Hosp Pract 1998 Mar;33(3):49
among women with breast cancer, prediagnostic use of hormone therapy may be associated
with decreased breast cancer mortality (level 2 [midlevel] evidence)
based on prospective cohort study
12,269 women ≥ 50 years old with incident invasive breast cancer followed for mean 10.3
years
1,690 breast cancer deaths occurred
reduced 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% CI
0.590.91)
current exclusive use of estrogenprogestin at diagnosis (adjusted hazard rate ratio
0.69, 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):864
risk 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 of
73,505 women aged 4575 years who received at least one HRT prescription and were followed 5
7 years Ann Oncol 2008 Jan;19(1):150
qualitative review of 45 studies comparing everusers and neverusers of estrogen found
inconsistent results regarding risk of breast cancer (Obstet Gynecol 2001 Sep;98(3):498 in BMJ
2001 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 cancer
HRT 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 and
108,411 controls
2.3%/year increased risk of breast cancer for HRT use > 4 years, but risk no longer
present with cessation of HRT > 5 years
Reference Lancet 1997 Oct 11;350(9084):1047 in J Watch 1997 Nov 15;17(22):174
only 12% women using HRT in these studies used progestogens, so results mainly
apply to estrogen alone (EvidenceBased Medicine 1998 May/Jun;3(3):93)
continuous combined HRT associated with increased risk of breast cancer, but no
apparent risk with estrogen alone or sequential estrogen and progestin (level 2 [mid
level] evidence)
based on comparison of 1,870 cases and 1,953 controls aged 3564 years and
postmenopausal
Reference 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 invasive
breast cancer (level 2 [midlevel] evidence)
based on study of 975 cases and 1,007 controls among women aged 6579 years
Reference JAMA 2003 Jun 25;289(24):3254, editorial can be found in JAMA 2003
Jun 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 with
invasive breast cancer and 692 controls
Reference JAMA 2002 Feb 13;287(6):734, commentary can be found in JAMA 2002
May 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 who
used hormone replacement therapy compared to 18,058 controls
increased risk of breast cancer with conjugated estrogen plus progestin use of ≥ 48
months (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 to
increase risk of breast cancer in postmenopausal middleaged women (level 2 [mid
level] evidence)
based on casecontrol study involving 537 patients with incident breast cancer and 492
randomly selected controls
Reference JAMA 1995 Jul 12;274(2):137, editorial can be found in J Fam Pract 1995
Nov;41(5):501, JAMA 1995 Jul 12;274(2):178, commentary can be found in ACP J
Club 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 in
postmenopausal women with BRCA1 mutation (level 2 [midlevel] evidence)
based on casecontrol study
236 women postmenopausal women with BRCA1 mutation and breast cancer were
matched to 236 postmenopausal women with BRCA1 mutation and no breast cancer
women 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 exposure
analysis by type of HRT exposure found inverse association with estrogen alone (odds
ratio 0.51, 95% CI 0.270.98) and no significant association with estrogen plus
progesterone (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 is
conflicting
HRT appears to increase risk of recurrent breast cancer (level 2 [midlevel] evidence)
based on 2 randomized trials with early termination
434 women with previous breast cancer randomized in 2 open trials to HRT vs. no
HRT
trials ended early because interim analysis showed unacceptable risk with HRT
345 women had at least 1 followup report, median followup 2.1 years
26 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 of
verification, all 26 in HRT group and 2 in noHRT group who had new breast cancer
event used HRT
Reference HABITS trial (Lancet 2004 Feb 7;363(9407):453), editorial can be found
in Lancet 2004 Feb 7;363(9407):410, commentary can be found in Lancet 2004 May
1;363(9419):1476
4year 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 to
it being an interim report generated before trial closed)
442 women followed for median 4 years
new breast cancer events occurred in 18% HRT vs. 8% control women during
followup (p < 0.05, NNH 10)
5year cumulative incidence 22.2% with HRT vs. 8% with control
Reference J Natl Cancer Inst 2008 Apr 2;100(7):475
HRT does not appear to increase risk for recurrent breast cancer based on systematic
review of observational studies
based on systematic review of mostly observational studies
systematic review of 10 prospective studies (only 1 randomized trial) comparing 717
estrogen users and 2,545 nonusers after diagnosis of breast cancer
breast cancer survivors using estrogen had no increased risk of recurrence (relative
risk 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 and
contralateral breast cancer after 10 years (level 2 [midlevel] evidence)
based on followup of randomized trial with early termination
378 women with prior breast cancer were randomized to HRT vs. no HRT and
followed for median 10.8 years
trial terminated after median 4.1 years due to increased risk of recurrence in pooled
analysis with HABITS trial but no significant difference in recurrence excluding
HABITS trial
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comparing HRT vs. no HRT
new 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 study
of 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 103,770
women in Australia (Lancet 2000 Jan 22;355(9200):270), commentary can be found in Lancet
2000 May 13;355(9216):1726
HRT use associated with increased breast density on mammography based on study of 5,212
postmenopausal women (JAMA 2001 Jan 10;285(2):171), commentary can be found in JAMA
2001 Apr 11;285(14):1839
bazedoxifeneconjugated estrogens not associated with increased breast density on
mammography (level 2 [midlevel] evidence)
based on breast density substudy from randomized trial
940 healthy postmenopausal women aged 4065 years with intact uterus seeking treatment
for menopausal symptoms randomized to oncedaily oral dose of 1 of the following 5
regimens for 1 year, and digital mammograms at baseline and 1 year evaluated for change in
percent dense breast tissue
bazedoxifene 20 mg and conjugated estrogens 0.45 mg
bazedoxifene 20 mg and conjugated estrogens 0.625 mg
bazedoxifene 20 mg
conjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg (a
conventional estrogenprogestin therapy)
placebo
81% completed substudy
compared with placebo
no significant difference in change in breast density with bazedoxifene 20 mg and
conjugated estrogens 0.45 and 0.625 mg
conjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg associated
with increased breast density (p < 0.001)
Reference Obstet Gynecol 2013 May;121(5):959
DynaMed commentary bazedoxifene not available in United States as of February 28,
2013, but is marketed in Italy and Spain; bazedoxifene/conjugated estrogen combination not
commercially available as of February 28, 2013
HRT use does not independently predict accuracy of screening mammography, but
increased 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 cancer
adjusted 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 breasts
adjusted sensitivity and specificity was 83.3% and 94.4% in women aged 8089 years and
decreased to 68.6% and 91.4% in women aged 4044
Reference Ann Intern Med 2003 Feb 4;138(3):168), correction can be found in Ann Intern
Med 2003 May 6;138(9):771, summary can be found in Am Fam Physician 2003 Sep
15;68(6):1198
HRT associated with higher false positive recall rates from screening mammography among
87,967 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 cancer
patients
based on study of 1,113 women aged 5064 years with breast cancer, 14.9% had HRT use at
diagnosis
no differences in type, size or grade of tumors; lymph nodes were positive in 23% HRT
users and 33% nonusers
Reference 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 Aug
6;331(7512):347
Guidelines and Resources
Guidelines
Society of Obstetricians and Gynaecologists of Canada (SOGC) guideline on hormone therapy and
breast 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 of
therapies can be found at AHRQ Comparative Effectiveness Review 2015 Mar:147 PDF
review of urogenital consequences of estrogen deprivation therapy in breast cancer patients and
estrogen replacement therapy can be found in Oncologist 2008 Mar;13(3):222
review of consensus conference III on imagedetected breast cancer; stateoftheart diagnosis and
treatment can be found in J Am Coll Surg 2009 Oct;209(4):504
References
DynaMed editorial process
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The participating members of the DynaMed Editorial Team have declared that they have no
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DynaMed Plus: Hormonal replacement therapy (HRT) and breast cancer
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12/12
DynaMed Plus: Hormonal replacement therapy (HRT) and breast cancer
Hormonal replacement therapy (HRT) and
breast cancer
Related Summaries
Breast cancer in women
Hormonal replacement therapy (HRT) for overview of HRT
Hormonal replacement therapy (HRT) and cardiovascular disease
Hormonal replacement therapy (HRT) and osteoporosis
Hormonal replacement therapy (HRT) and venous thromboembolism
Overview
combined estrogen and progestin (hormone replacement therapy [HRT]) associated with increased
risk for breast cancer, but evidence for ongoing risk after stopping treatment is conflicting
hormone replacement therapy associated with increased risk for invasive breast cancer (level
2 [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 cancer
estrogen alone does not appear to increase risk for invasive breast cancer but may increase
risk for abnormalities on followup mammograms (level 2 [midlevel] evidence)
estradiol alone for > 5 years associated with increased risk for breast cancer (level 2 [mid
level] evidence)
use of unopposed estrogen for > 20 years might be associated with increased risk of invasive
breast cancer (level 2 [midlevel] evidence)
HRT may increase risk for recurrent breast cancer in breast cancer survivors, but evidence is
conflicting
HRT appears to increase risk of recurrent breast cancer (level 2 [midlevel] evidence) in 2
randomized trials
HRT does not appear to increase risk for recurrent breast cancer based on systematic review
of observational studies
HRT associated with nonsignificant increase in risk of new breast cancer event and
contralateral breast cancer after 10 years (level 2 [midlevel] evidence)
among women with breast cancer, prediagnostic use of hormone therapy may be associated
with 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 to
increased 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 adherence
16,608 postmenopausal women aged 5079 years were randomized to HRT (equine
estrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg [Prempro]) vs. placebo orally daily
for mean 5.2 years (range 3.58.5 years)
discontinuation of study drug occurred in 42% HRT and 38% placebo patients, while
addition of HRT through personal clinician was started in 6.2% HRT and 10.7% placebo
patients
trial was stopped early due to increased risk of invasive breast cancer with HRT
intentiontotreat analysis was performed, so results likely underestimate "per protocol"
results
no differences in overall mortality or endometrial cancer
0.38% 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 adjusted
analysis
effect on breast cancer mortality not established as breast cancer mortality only occurred in 3
HRT patients and 2 placebo patients
Reference 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 BMJ
2008 May 10;336(7652):1033 (commentary can be found in BMJ 2008 May
24;336(7654):1148)
increased risk of invasive breast cancer (cumulative risk) continued with longer
followup of WHI trial (level 2 [midlevel] evidence)
based on 2 followup trials of randomized trial above
16,608 postmenopausal women aged 5079 years randomized to HRT (equine
estrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg [Prempro]) vs. placebo
orally daily for mean 5.2 years (range 3.58.5 years)
comparing combined HRT vs. placebo after mean followup 5.6 years
245 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 advanced
stage (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 be
found in JAMA 2003 Jun 25;289(24):3304, commentary can be found in
ACP J Club 2003 NovDec;139(3):61
12,788 women with no prior hysterectomy from WHI trial followed for mean 11 years
comparing 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 JAMA
2010 Oct 20;304(15):1719
estrogen plus progestin associated with increased risk of breast cancer compared with no
hormone use (level 2 [midlevel] evidence)
based on cohort study
41,449 postmenopausal women with no prior hysterectomy and negative mammogram
within 2 years followed for mean 11.3 years
39% used estrogen plus progestin
estrogen plus progestin use associated with increased risk of breast cancer compared to no
hormone use (adjusted hazard ratio 1.55, 95% CI 1.411.7)
no significant difference in survival following breast cancer diagnosis
Reference J Natl Cancer Inst 2013 Apr 17;105(8):526
HRT combination therapy associated with higher rates of mammogram abnormalities and
breast biopsies in WHI trial (level 2 [midlevel] evidence)
comparing combined HRT vs. placebo at 5.6 years
35% 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 Arch
Intern Med 2008 May 12;168(9):935
conflicting evidence for ongoing risk of breast cancer after stopping HRT
based 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 further
increase in risk) in analysis over time after HRT discontinuation
Reference N Engl J Med 2009 Feb 5;360(6):573, commentary can be found in N
Engl J Med 2009 May 28;360(22):2366
breast cancer risk may continue to be higher than baseline in HRT group with longer
followup of WHI trial
12,788 women with no prior hysterectomy followed for mean 11 years
comparing HRT vs. placebo
incidence of invasive breast cancer at mean 11 years was 4.5% vs. 3.6% (NNH
111)
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 (derived
indirectly 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 2010
Oct 20;304(15):1719
higher rates of cancer (but not specifically breast cancer) associated with HRT 3 years
after 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 trial
8,052 women from HRT group
7,678 women from placebo group
comparing HRT vs. placebo during postintervention phase
allcause mortality 2.9% vs. 2.6% (not significant)
malignancies (including invasive breast cancer, endometrial or colorectal
cancer) 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 JAMA
2008 Jun 18;299(23):2744, ACP J Club 2008 Aug 19;149(2):11
newonset breast tenderness after starting combination HRT associated with increased risk
of breast cancer
based on cohort of 14,538 women from WHI trial without baseline breast tenderness
in women taking combination HRT, newonset breast tenderness was associated with
increased risk for breast cancer (hazard ratio 1.48, 95% CI 1.082.03)
newonset breast tenderness not associated with breast cancer risk in placebo group
Reference Arch Intern Med 2009 Oct 12;169(18):1684
combined estrogen and testosterone use associated with nonsignificant increase in breast
cancer risk after 3 years in cohort of 31,842 women from Women's Health Initiative
observational 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 increase
risk for abnormalities on followup mammograms (level 2 [midlevel] evidence)
based on randomized trial with early trial termination
10,739 postmenopausal women aged 5079 years with prior hysterectomy randomized to
conjugated equine estrogen 0.625 mg (Premarin) vs. placebo orally daily for mean of almost
7 years
study stopped early by NIH since there was no benefit in primary outcome of reducing
cardiovascular disease
invasive 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 Apr
14;291(14):1769, results noted earlier in NIH News Release 2004 Mar 2, commentary can be
found in JAMA 2004 Aug 11;292(6):683, summary can be found in Am Fam Physician
2005 Jan 15;71(2):371
estrogen treatment associated with increased rate of mammography screening requiring
followup
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 group
vs. 5.5% placebo group had (p < 0.001)
mammograms with abnormalities requiring followup at 2 years 9.4% estrogen group
vs. 6.7% placebo group had (p < 0.001)
Reference JAMA 2006 Apr 12;295(14):1647, commentary can be found in Am Fam
Physician 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 breast
cancer mortality (level 2 [midlevel] evidence)
based on prospective cohort study
1,084,110 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 combination
estrogen/progestin
Reference Lancet 2003 Aug 9;362(9382):419, editorial can be found in Lancet 2003 Aug
9;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 2004
Mar 15;69(6):1547
estradiol alone for > 5 years associated with increased risk for breast cancer (level 2 [mid
level] evidence)
based on cohort study
110,984 Finnish women > 50 years old who used oral or transdermal estradiol, oral estriol or
vaginal estrogens for at least 6 months during 19942001
2,171 (2%) developed breast cancer
oral 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 333
500)
no significant association with estradiol use < 5 years, oral estriol, or vaginal estrogens
Reference Obstet Gynecol 2006 Dec;108(6):1354, editorial can be found in Obstet Gynecol
2006 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 Physician
2007 May 15;75(10):1560
estrogen alone and estrogen with progestin associated with increased incidence of breast
cancer in United States black women (level 2 [midlevel] evidence)
based on Black Women's Health Study 19952003 with 32,559 women > 40 years old
followed for mean 5.6 years with 615 (1.9%) cases of breast cancer reported
Reference 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 study
122,000 female registered nurses followed from 19761992 with 1,935 newly diagnosed
cases of breast cancer
risk 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 breast
cancer was similar for women taking estrogen plus progestin (RR 1.41) as in women taking
estrogen alone
increased RR of breast cancer disappeared when HRT had been stopped for > 2 years
among current users of HRT, increased RR only after use for > 5 years
highest 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 safe
women > 55 who have been on HRT > 5 years should consider benefits and risks
Reference N Engl J Med 1995 Jun 15;332(24):1589, commentary can be found in J Fam
Pract 1995 Nov;41(5):501
use of estrogenprogesterone therapy associated with increased risk of breast cancer
based 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 invasive
breast cancer (level 2 [midlevel] evidence)
based on prospective cohort study
28,835 women who became postmenopausal after hysterectomy
934 developed invasive breast cancer
use of estrogen for < 10 years not associated with increased risk
Reference Arch Intern Med 2006 May 8;166(9):1027, commentary can be found in Am
Fam Physician 2006 Oct 15;74(8):1420
use of estrogen slightly increases risk of breast cancer, use of estrogen/progestin slightly
increases risk over that of estrogen alone, no increased risk found > 4 years after stopping
hormone replacement therapy (level 2 [midlevel] evidence)
based on cohort study
46,355 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 or
estrogen/progestin and years of last use
higher risks were associated with more recent or current use of HRT
most subgroup analyses were not statistically significant but overall trend is prominent
Reference JAMA 2000 Jan 26;283(4):485, editorial can be found in JAMA 2000 Jan
26;283(4):534
increased risks primarily associated with longterm use of cyclic therapy and may not apply
to continuous combined HRT (Dear Health Care Professional letter 2000 Feb 22 from
WyethAyerst 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):691
DynaMed commentary actual increase in risk relatively small, results subject to multiple
biases, many subjects initially enrolled in study based on having undergone breast surgery
with no evidence of malignant disease so these patients may be different than general
population
increased risk of breast cancer greater for estrogen combined with progestogens other than
progesterone or dydrogesterone (level 2 [midlevel] evidence)
based on cohort study of 80,377 postmenopausal women
2,354 cases of invasive breast cancer occurred during mean 8.1 year followup
relative risk of breast cancer 1.29 (95% CI 1.021.65) with estrogen alone vs. HRT never
users
relative risk of breast cancer with estrogenprogestogen combinations varied with type of
progestogen
1 (95% CI 0.831.22) for estrogenprogesterone
1.16 (95% CI 0.941.43) for estrogendydrogesterone
1.69 (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 found
in Breast Cancer Res Treat 2008 Jan;107(2):307
combined estrogen and testosterone use associated with increased risk of breast cancer
based on nested casecontrol study
Nurses' Health Study identified 4,610 incident cases of invasive breast cancer among
postmenopausal 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 of
postmenopausal hormones
risk 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 found
in Arch Intern Med 2007 Jan 22;167(2):205
HRT not associated with increased risk of breast cancer overall, but associated with
increased risk of invasive breast cancer "with favorable prognosis" (level 2 [midlevel]
evidence)
based on populationbased cohort study
37,105 healthy postmenopausal women aged 5569 years followed for up to 11 years
1520 (4%) developed breast cancer of whom only 82 (5%) had "invasive carcinoma with
favorable histology"
no association found for HRT with invasive lobular or ductal tumors of ductal carcinoma in
situ
editorial suggests that original article placed too much emphasis on positive association and
not enough on overall lack of association between HRT and breast cancer
Reference JAMA 1999 Jun 9;281(22):2091, commentary can be found in JAMA 1999 Jun
9;281(22):2140
HRT increased risk of breast cancer while lowering mortality in patients with family history
of breast cancer (level 2 [midlevel] evidence)
based on prospective cohort study of 35,919 women in Iowa followed 8 years
12% 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 statistically
significant)
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):15
and in Hosp Pract 1998 Mar;33(3):49
among women with breast cancer, prediagnostic use of hormone therapy may be associated
with decreased breast cancer mortality (level 2 [midlevel] evidence)
based on prospective cohort study
12,269 women ≥ 50 years old with incident invasive breast cancer followed for mean 10.3
years
1,690 breast cancer deaths occurred
reduced 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% CI
0.590.91)
current exclusive use of estrogenprogestin at diagnosis (adjusted hazard rate ratio
0.69, 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):864
risk 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 of
73,505 women aged 4575 years who received at least one HRT prescription and were followed 5
7 years Ann Oncol 2008 Jan;19(1):150
qualitative review of 45 studies comparing everusers and neverusers of estrogen found
inconsistent results regarding risk of breast cancer (Obstet Gynecol 2001 Sep;98(3):498 in BMJ
2001 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 cancer
HRT 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 and
108,411 controls
2.3%/year increased risk of breast cancer for HRT use > 4 years, but risk no longer
present with cessation of HRT > 5 years
Reference Lancet 1997 Oct 11;350(9084):1047 in J Watch 1997 Nov 15;17(22):174
only 12% women using HRT in these studies used progestogens, so results mainly
apply to estrogen alone (EvidenceBased Medicine 1998 May/Jun;3(3):93)
continuous combined HRT associated with increased risk of breast cancer, but no
apparent risk with estrogen alone or sequential estrogen and progestin (level 2 [mid
level] evidence)
based on comparison of 1,870 cases and 1,953 controls aged 3564 years and
postmenopausal
Reference 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 invasive
breast cancer (level 2 [midlevel] evidence)
based on study of 975 cases and 1,007 controls among women aged 6579 years
Reference JAMA 2003 Jun 25;289(24):3254, editorial can be found in JAMA 2003
Jun 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 with
invasive breast cancer and 692 controls
Reference JAMA 2002 Feb 13;287(6):734, commentary can be found in JAMA 2002
May 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 who
used hormone replacement therapy compared to 18,058 controls
increased risk of breast cancer with conjugated estrogen plus progestin use of ≥ 48
months (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 to
increase risk of breast cancer in postmenopausal middleaged women (level 2 [mid
level] evidence)
based on casecontrol study involving 537 patients with incident breast cancer and 492
randomly selected controls
Reference JAMA 1995 Jul 12;274(2):137, editorial can be found in J Fam Pract 1995
Nov;41(5):501, JAMA 1995 Jul 12;274(2):178, commentary can be found in ACP J
Club 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 in
postmenopausal women with BRCA1 mutation (level 2 [midlevel] evidence)
based on casecontrol study
236 women postmenopausal women with BRCA1 mutation and breast cancer were
matched to 236 postmenopausal women with BRCA1 mutation and no breast cancer
women 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 exposure
analysis by type of HRT exposure found inverse association with estrogen alone (odds
ratio 0.51, 95% CI 0.270.98) and no significant association with estrogen plus
progesterone (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 is
conflicting
HRT appears to increase risk of recurrent breast cancer (level 2 [midlevel] evidence)
based on 2 randomized trials with early termination
434 women with previous breast cancer randomized in 2 open trials to HRT vs. no
HRT
trials ended early because interim analysis showed unacceptable risk with HRT
345 women had at least 1 followup report, median followup 2.1 years
26 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 of
verification, all 26 in HRT group and 2 in noHRT group who had new breast cancer
event used HRT
Reference HABITS trial (Lancet 2004 Feb 7;363(9407):453), editorial can be found
in Lancet 2004 Feb 7;363(9407):410, commentary can be found in Lancet 2004 May
1;363(9419):1476
4year 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 to
it being an interim report generated before trial closed)
442 women followed for median 4 years
new breast cancer events occurred in 18% HRT vs. 8% control women during
followup (p < 0.05, NNH 10)
5year cumulative incidence 22.2% with HRT vs. 8% with control
Reference J Natl Cancer Inst 2008 Apr 2;100(7):475
HRT does not appear to increase risk for recurrent breast cancer based on systematic
review of observational studies
based on systematic review of mostly observational studies
systematic review of 10 prospective studies (only 1 randomized trial) comparing 717
estrogen users and 2,545 nonusers after diagnosis of breast cancer
breast cancer survivors using estrogen had no increased risk of recurrence (relative
risk 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 and
contralateral breast cancer after 10 years (level 2 [midlevel] evidence)
based on followup of randomized trial with early termination
378 women with prior breast cancer were randomized to HRT vs. no HRT and
followed for median 10.8 years
trial terminated after median 4.1 years due to increased risk of recurrence in pooled
analysis with HABITS trial but no significant difference in recurrence excluding
HABITS trial
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comparing HRT vs. no HRT
new 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 study
of 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 103,770
women in Australia (Lancet 2000 Jan 22;355(9200):270), commentary can be found in Lancet
2000 May 13;355(9216):1726
HRT use associated with increased breast density on mammography based on study of 5,212
postmenopausal women (JAMA 2001 Jan 10;285(2):171), commentary can be found in JAMA
2001 Apr 11;285(14):1839
bazedoxifeneconjugated estrogens not associated with increased breast density on
mammography (level 2 [midlevel] evidence)
based on breast density substudy from randomized trial
940 healthy postmenopausal women aged 4065 years with intact uterus seeking treatment
for menopausal symptoms randomized to oncedaily oral dose of 1 of the following 5
regimens for 1 year, and digital mammograms at baseline and 1 year evaluated for change in
percent dense breast tissue
bazedoxifene 20 mg and conjugated estrogens 0.45 mg
bazedoxifene 20 mg and conjugated estrogens 0.625 mg
bazedoxifene 20 mg
conjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg (a
conventional estrogenprogestin therapy)
placebo
81% completed substudy
compared with placebo
no significant difference in change in breast density with bazedoxifene 20 mg and
conjugated estrogens 0.45 and 0.625 mg
conjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg associated
with increased breast density (p < 0.001)
Reference Obstet Gynecol 2013 May;121(5):959
DynaMed commentary bazedoxifene not available in United States as of February 28,
2013, but is marketed in Italy and Spain; bazedoxifene/conjugated estrogen combination not
commercially available as of February 28, 2013
HRT use does not independently predict accuracy of screening mammography, but
increased 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 cancer
adjusted sensitivity and specificity was 87% and 96.9% in women with almost entirely fatty
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DynaMed Plus: Hormonal replacement therapy (HRT) and breast cancer
breasts and decreased to 62.9% and 89.1% in women with extremely dense breasts
adjusted sensitivity and specificity was 83.3% and 94.4% in women aged 8089 years and
decreased to 68.6% and 91.4% in women aged 4044
Reference Ann Intern Med 2003 Feb 4;138(3):168), correction can be found in Ann Intern
Med 2003 May 6;138(9):771, summary can be found in Am Fam Physician 2003 Sep
15;68(6):1198
HRT associated with higher false positive recall rates from screening mammography among
87,967 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 cancer
patients
based on study of 1,113 women aged 5064 years with breast cancer, 14.9% had HRT use at
diagnosis
no differences in type, size or grade of tumors; lymph nodes were positive in 23% HRT
users and 33% nonusers
Reference 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 Aug
6;331(7512):347
Guidelines and Resources
Guidelines
Society of Obstetricians and Gynaecologists of Canada (SOGC) guideline on hormone therapy and
breast 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 of
therapies can be found at AHRQ Comparative Effectiveness Review 2015 Mar:147 PDF
review of urogenital consequences of estrogen deprivation therapy in breast cancer patients and
estrogen replacement therapy can be found in Oncologist 2008 Mar;13(3):222
review of consensus conference III on imagedetected breast cancer; stateoftheart diagnosis and
treatment can be found in J Am Coll Surg 2009 Oct;209(4):504
References
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The participating members of the DynaMed Editorial Team have declared that they have no
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DynaMed Plus: Hormonal replacement therapy (HRT) and breast cancer
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related to this topic, unless otherwise indicated.
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