REVIEW

Estrogens and breast cancer

J. Kim1
& P. N. Munster2
1
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer
Center, Indianapolis; 2Department of Medicine, Center for BRCA Research, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San
Francisco, USA

Available online 8 November 2024

Estrogens have been associated with an increase in breast cancer risk. Yet emerging clinical and experimental evidence
points to progestogens [endogenous progesterone or synthetic progesterone (progestin)] as the primary hormonal
driver underlying seemingly estrogen-associated breast cancer risk. Estrogens may contribute to breast cancer risk
indirectly by induction of the progesterone receptor and thus amplifying progesterone signaling. Large studies of
hormonal contraceptives suggest that the small increase in breast cancer risk from hormonal contraceptives is
mainly attributable to progestins, not estrogens. Estrogen-plus-progestin hormone replacement therapy (HRT) has
consistently shown an increase in breast cancer risk among postmenopausal women, whereas estrogen-alone HRT
has little impact on breast cancer risk in naturally or surgically menopausal women. In particular, the long-term
follow-up of the Women’s Health Initiative (WHI) randomized trials suggests a benefit of estrogen alone. Recent
data further indicate that endogenously elevated estrogen during assisted reproductive technology (ART) exhibits
little adverse effect on or potentially a reduction in breast cancer risk and recurrence. Also, accumulating evidence
suggests that inhibition of progesterone signaling is a critical mechanism underlying the risk-reducing and
therapeutic effects of antiestrogens. Estrogen HRT has shown an array of proven benefits, including ameliorating
menopausal symptoms and improving bone health. Collective evidence thus suggests that estrogen HRT is likely to
offer health benefits to perimenopausal or postmenopausal women, including breast cancer survivors, as well as
young BRCA1/2 carriers with prophylactic oophorectomy for ovarian cancer prevention.
Key words: estrogen, progesterone, progestin, progestogen, breast cancer, hormone replacement therapy

Estrogen and progesterone are principal hormones in a ovarian cancer and endometrial cancer.6,7 Despite the
woman’s life. Before menopause, women are exposed to intended medical effects and additional health benefits,
regularly varying levels of endogenous estrogens and pro- these hormonal agents, especially estrogens, remain a
gesterone released during repeated menstrual cycles and lingering concern for breast cancer risk.8-11
potentially to more sustained levels of these hormones In this review, we have aimed to comprehensively eval-
during pregnancy. Reproductive-age women may be further uate the association between estrogens and breast cancer.
exposed to these hormones via oral contraceptives, Given the expansive scope of scientific investigations per-
composed of a progestin with or without an estrogen, and taining to this topic, we focus on findings from randomized
other forms of hormonal contraception.1 Near or after clinical trials (RCTs), prospective cohort studies, and meta-
menopause, hormone replacement therapy (HRT)destro- analyses with rigor and a large sample size, as well as
gen alone or combined with a progestindmay be offered to preclinical mechanistic studies. To be inclusive on the topic
mitigate menopausal symptoms arising from precipitous with depth, we examined vast evidence, via extensive
declines in endogenous estrogen production and to reduce search on PubMed, from clinical and basic experimental
the risk of bone fractures.2-5 Women with prior use of oral studies, which include hormonal contraceptives, HRT,
contraceptive pills show a significantly reduced risk of estrogen-elevating fertility treatments such as in vitro
fertilization (IVF), reproductive factors, steroid hormone
*Correspondence to: Dr Jaeyeon Kim, Department of Biochemistry and Mo- synthesis and metabolism, breast cancer therapies, basic
lecular Biology, Indiana University School of Medicine, Indiana University experimental studies, and animal research. Ultimately, we
Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
46202, USA. Tel: þ1-317-278-9740 have sought to connect the dots by critically assessing and
E-mail: jaeyeonk@iu.edu (J. Kim). cohesively integrating wide-ranging, oft-incongruent find-
0923-7534/© 2024 The Author(s). Published by Elsevier Ltd on behalf of ings into the conclusions based on the totality of current
European Society for Medical Oncology. This is an open access article under the evidence.
CC BY license (http://creativecommons.org/licenses/by/4.0/).

134 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025

J. Kim & P. N. Munster Annals of Oncology

Emerging from this comprehensive review is a new elevated levels of estrogens and increased breast cancer risk
perspective on the role of hormones in breast cancer risk. in postmenopausal women.26 In premenopausal women,
What initially appeared to be estrogen-associated breast however, obesity is linked to a reduced risk of breast cancer
cancer risk may actually be driven by progestogens. with lower levels of progesterone.27 It remains unclear
Emerging evidence suggests that progestins, not estrogens, whether progesterone levels are elevated in postmenopausal
from hormonal contraceptives are most likely responsible for women with obesity as are estrogen levels.26 Owing to the
the small increase in breast cancer risk. Combined evidence limited sensitivity of progesterone assay, it has been chal-
suggests that progestogens are likely the primary oncogenic lenging to measure accurate concentrations of progesterone
hormonal factor that underlies the increased breast cancer in postmenopausal women.23 Studies indicate that the ovary
risk associated with estrogen-containing HRT, while estro- and adrenal gland are likely to be primary sources of post-
gens may contribute to breast cancer risk by augmenting menopausal progesterone.28,29
progesterone signaling. Additionally, suppression of proges-
terone signaling may be a key mechanism underlying the
risk-reducing and therapeutic effects of antiestrogen breast HISTORICAL PERSPECTIVE ON ESTROGENS AND BREAST
cancer therapies. Also, vastly elevated levels of endogenous CANCER
estrogens induced by fertility treatments, such as IVF/ART, Even before the discovery of estrogen, ovarian hormones
appear to have no adverse effect on breast cancer risk or were speculated to be involved in breast cancer. In 1896,
recurrence. Collective evidence suggests that estrogen the British surgeon George Beatson observed a regression
therapy, coupled with minimal use of a progestogen, might of metastatic breast cancer in premenopausal women after
be a safe option for women in need of HRT. oophorectomies.30 Together with animal studies linking
estrogen to mammary tumor development, estrogen was
postulated to increase breast cancer risk in humans.31
ENDOGENOUS HORMONE PRODUCTION E1 was the first estrogen discovered through purification
During the menstrual cycle, estradiol (E2) is the predomi- from pregnant women’s urine in 1929.32 In the 1930s and
nant ovarian estrogen produced by ovarian follicles and the early 1940s, other natural estrogens, including conjugated
corpus luteum. E2 levels gradually increase from 20-50 pg/ equine estrogens (CEEs), were extracted from the urine of
ml to 50-80 pg/ml during the early- to mid-follicular phase, pregnant women or pregnant mares.33 Estrogens were also
rapidly rise to peak at w250 pg/ml (130-400 pg/ml) before synthesizeddnotably, diethylstilbestrol (DES) and ethinyles-
the luteinizing hormone (LH) surge, and remain around 120 tradiol (EE).33 These natural and synthetic estrogens were
pg/ml (<20-241 pg/ml) during the luteal phase before used for menopausal symptoms and gained broad popularity
dropping to 30-50 pg/ml during menses.12-16 Estrone (E1) in the late 1960s.33,34 There was a brief decrease in use
levels vary from <15 to w200 pg/ml14-16 and estriol (E3) between 1975 and 1980 due to reports of increased endo-
levels remain low yet steady at 7-11 pg/ml during the metrial cancer risk associated with estrogen-only formula-
menstrual cycle.17 Menstrual progesterone levels are low at tions.35-37 With the addition of a progestin to counteract the
<1.5 ng/ml before the LH surge and rapidly rise to 10-20 risk of endometrial cancer,38 HRT use had continued to rise
ng/ml in the luteal phase.12,16 During pregnancy, proges- through the 1980s and 1990s, coupled with the Food and
terone is produced by the corpus luteum of the ovary for Drug Administration (FDA) approval for osteoporosis pre-
the first 6-8 weeks of pregnancy and thereafter by the vention in 1988.34,39,40 Following a peak in the late 1990s,
placenta for the remainder of pregnancy ranging from 10 to HRT use had sharply declined worldwide in the aftermath of
40 ng/ml in the first trimester and progressively increasing the reports of the Women’s Health Initiative (WHI) trials in
to reach 150-175 ng/ml at term.13,18-21 In addition to high 2002 and 2004, which, at that time, indicated that excess
levels of E2 during pregnancy (200-20 000 pg/ml), E3 be- health risks of HRT would outweigh its benefits.3,41-43 Despite
comes the major estrogen produced by the placenta to a series of follow-up WHI studies reversing the health con-
reach as high as 8000-13 000 pg/ml at term.18-22 E1 levels cerns of HRT,4,44,45 HRT use has remained controversial, pri-
are also progressively elevated, ranging from <1000 pg/ml marily owing to the concern of breast cancer.11
in the first trimester to 6000-11 000 pg/ml at term.18,21,22 It was a serendipitous contamination that introduced
Even after menopause, women continue to produce low estrogen into oral contraceptives during the birth control
levels of estrogens and progesterone (<0.5 ng/ml).13,23 pill trials in the 1950s.46 The ‘birth control pill’ was originally
Postmenopausal estrogens consist of E1 (25-42 pg/ml), the based on the observations that high levels of exogenous
dominant estrogen after menopause, and also E2 (10-25 pg/ progesterone would mimic pregnancy and thereby block
ml).24,25 E3 levels remain low at w6 pg/ml.17 These estrogens ovulation and conception.46 Though effective in preventing
are primarily synthesized by peripheral conversion of andro- pregnancy, the ‘pill’ composed of a purified progestin alone
stenedione (0.53 ng/ml) and testosterone (22.2 ng/dl), the also caused bleeding in the uterus, which resulted from
androgens produced from postmenopausal ovaries and ad- irregular shedding of the endometrium.46,47 Fortuitously, it
renal glands.25 Postmenopausal androgen biosynthesis, albeit was discovered that norethynodrel, one of progestin com-
slightly reduced after menopause, remains comparable to pounds of interest at that time, did not cause uterine
premenopausal levels of androstenedione (0.83 ng/ml) and breakthrough bleeding and was later found to be contam-
testosterone (25.8 ng/dl).15 Obesity is also associated with inated with mestranol, a synthetic estrogen.46 This

Volume 36 - Issue 2 - 2025 https://doi.org/10.1016/j.annonc.2024.10.824 135

Annals of Oncology J. Kim & P. N. Munster

observation paved the way for adding an estrogen to proliferation is increased in postmenopausal women taking
maintain endometrial stability and thus reduce the risk of estrogen-containing HRT,76 as well as in mice and primates
uterine breakthrough bleeding.48 Moreover, it was later treated with estrogen,77-80 supporting estrogen as an
recognized that estrogen contributed to the contraceptive oncogenic factor for breast cancer.8,81 Current evidence
effects of the pill.1,47,48 thus appears to support the encompassing oncogenic and
Early formulations of high-dose contraceptive estrogens tumor-promoting role of estrogen in breast cancer risk,
caused multiple undesirable side effects, including venous recurrence, and growth/progression.
thromboembolism,1 prompting a dose reduction in estro- Yet a more careful look reveals a complex, counterintuitive
gens. Estrogen doses were reduced from mestranol 150 mg relationship between estrogens and breast cancer. Estrogens,
in an original formulation to estrogen <50 mg by the early such as DES and E2 given at high doses (1.5-1500 mg/day),
1980s.49 Most modern oral contraceptives now typically had been used to treat ER-positive advanced breast cancer
contain 20-35 mg EE.50 Progestins have also changed over until the introduction of tamoxifen,82-86 an ER antagonist in
the years to newer formulations to minimize androgenic breast tissue. After a failed development as a contraceptive,
side effects.51 The original formulation of norethynodrel 10 tamoxifen was reborn as a therapy for estrogen-driven breast
mg was reduced in subsequent generations of progestins, cancer with an FDA approval in 1977.63,87 The efficacy of DES
such as levonorgestrel (LNG) 100-250 mg and desogestrel therapy in postmenopausal women with metastatic breast
150 mg.48 Following the FDA approval in 1960 of the first cancer was comparable to or higher than that of tamoxifen
combination pill (norethynodrel 5 mg and mestranol 75 mg), (response rates, 41% versus 33%),84 yet tamoxifen was more
a progestin-only pill was also introduced in 1973 to avoid tolerable.83-85 E2 treatment results in growth arrest and
the adverse effects of estrogen.49 A progestin-only pill apoptosis in estrogen-deprived cultured ER-positive breast
typically contains lower progestin doses (‘minipill’) than cancer cells and may thus explain its therapeutic effect.86,88
progestineestrogen combination products.52 Similarly, high doses of progestins, such as medrox-
Unlike its secondary role in oral contraceptives, estrogen yprogesterone acetate (MPA, 500-1500 mg/day) and meges-
was the main component of HRT, aimed to counteract for trol acetate (60-180 mg/day), showed response rates (28%)
the sharp decline of menstrual estrogens after menopause.4 analogous to tamoxifen (31%, 20 mg/day) in postmenopausal
While relieving menopausal symptoms, the stimulatory ef- women with ER-positive metastatic breast cancer.89-92
fect of estrogen-alone HRT on endometrial proliferation and This may be in part through partial agonistic activity for the
cancer risk required the addition of a progestin in post- glucocorticoid receptor93,94 and the androgen receptor.81,95
menopausal women with an intact uterus.3,53,54 Endogenous estrogensdE2 and E1dare hydroxylated
Once hailed as the ‘fountain of youth’, exogenous estro- and further conjugated to form various metabolites,
gens began to raise concerns for breast cancer risk.34 To including 2-hydroxyestrone, 2-hydroxyestradiol, 4-
address these concerns, large national and international hydroxyestrone, 16a-hydroxyestrone, 2-methoxyestrone,
studiesdnotably, the Nurses’ Health Study in 1976, the and quinones.96,97 Epidemiologic studies have consistently
Collaborative Group on Hormonal Factors in Breast Cancer shown that endogenous estrogens or collective estrogen
(CGHFBC) in 1992, and the WHI in 1992dwere launched to metabolites are associated with an increased risk of breast
examine the impacts of hormonal contraceptives and HRT cancer among postmenopausal women.8,97-101 In contrast,
on breast cancer risk. Overall, these studies reported a small the association between individual estrogen metabolites
increase in breast cancer risk among users of hormonal and breast cancer risk appears to be inconsistent.97,100,101 It
contraceptives.55-58 Initial reports of HRT studies generally is possible that individual estrogen metabolites may func-
indicated that estrogen therapy, particularly when given in tion as oncogenic or onco-protective in breast cancer.96 The
combination with a progestin, was associated with a causal connection between estrogen metabolites and
moderately increased risk of breast cancer in post- breast cancer risk remains to be established.
menopausal women.3,40,44,59-62

BREAST CANCER RISK FROM CURRENT HORMONAL

ESTROGEN AND BREAST CANCERdINTRICATE CONTRACEPTIVES IN PREMENOPAUSAL WOMEN
COMPLEXITY Overall, hormonal contraceptives are associated with a small
Multiple lines of evidence have suggested a link between increase in breast cancer risk in young women under age 50
estrogen and breast cancer.8,9 Inhibiting estrogen signaling years55-58,102-104 (Table 1). A nationwide study of all women
with the selective estrogen receptor (ER) modulator (1.8 million) aged 15-45 years in Denmark reported a 20%
tamoxifen, degrading the ER by fulvestrant, and blocking relative increase in breast cancer risk among current and
estrogen biosynthesis by aromatase inhibitors reduce the recent users of hormonal contraception compared with
risk of recurrence or progression in patients with ER- nonusers [relative risk (RR) 1.20, 95% confidence interval (CI)
positive breast cancer.63-68 Blocking ER signaling by anties- 1.14-1.26, P ¼ 0.002].105 A 20% increase in the RR of breast
trogens, such as tamoxifen and aromatase inhibitors, was cancer should be taken into perspective because absolute
also shown to reduce breast cancer risk.69-74 Additionally, breast cancer risks are quite low among young women who
high blood levels of estrogens have been linked to an use hormonal contraceptives. In the general population, the
increased risk of breast cancer.8,75 Breast epithelial cell risks of developing invasive breast cancer over the

136 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025

 Table 1. Hormonal contraceptives and breast cancer risk
Volume 36

J. Kim & P. N. Munster

CGHFBC US Nurses’ Health II Denmark UK CPRD BRCA1/2 carriers
Study type Meta-analysis of 54 epidemiological Prospective Nationwide prospective cohort Nested case-control study Review
studies and meta-analysis (12 studies) (10 BC studies)
HC type COCP (P + E) (formulations from COCP/POP distinction not COCP (P + E); P only (POP, I-P, P only (POP, I-P, P-Imp, P-IUD); COCP (P + E)
P-Imp, P-IUD); COCP, w90% of
-

1960s to 1980s) provided; likely most use from COCP (P + E)

COCP HC use
Issue 2

HC formulation E (EE, < or 50 mg/day; M, 50 mg/ Formulations from 1980s and Formulations since 1995; Formulations since 1990s; P BC risk
day); P (LNG, < or >250 mg/day; 1990s E (EE, 20-50 mg/day); P (CPT, (CPT, DRSP, DSG, GSD, LNG, NET,
NET, < or >1000 mg/day) DRSP, DSG, GSD, LNG, NET, NGM, NGT), dose varied
-

NGM), dose varied

<1 to 15; <1 to 8 <1 to >10 <1 to 5
2025

HC BRCA1 BRCA2
duration, Median, 3
years
Participants 153 536 (total): 53 297 (BC cases), 116 608 (total): 1344 (BC cases), 1 797 932 (total): 11 517 (BC 27 669 (total); 1.09 1.15
100 239 (controls) 115 264 (controls) cases), 1 786 415 (controls); 9498 [BC cases: 4195 (0.77-1.54) (0.61-2.18)
from HC (53% P only)]; RR (95% CI) RR (95% CI)
18 171 [controls: 7092
from HC (52% P only)]
Mean age (SD), Median age and year at BC Age range at enrollment (1989): Age range at BC diagnosis: 15- Mean age at BC diagnosis 1.49 2.58
years diagnosis, 49, 1984; Median age for 25-42 49 (1996-2017), 43 (5); (1.05-2.11) (1.21-5.49)
HC use, 26 (range: early teens to Age range at BC diagnosis, 20-49 HR (95% CI) HR (95% CI)
early 40s)
Observation Original studies published from w12 (1989-2001) Mean, 10.9 (SD 5.8); Before BC diagnosis; 1.08 1.03
period, years 1980 to1995 1995-2012 mean, 7.3 (SD 4.6) (0.94-1.25) (0.81-1.32)
OR (95% CI) OR (95% CI)
BC riska 1.24 1.07 1.33 1.12 1.20 1.25 Meta-analysis 1.19 1.36
overall (1.15-1.33) (SD 0.02) (1.03-1.73) (0.95-1.33) (1.14-1.26) (1.18-1.33) OR RR (95% CI) (0.92-1.55) (0.89-2.10)
RR (95% CI) ever use RR (95% CI) RR (95% CI) RR (95% CI) (95% CI) OR (95% CI) OR (95% CI)
current use current use past use Case ctrl
BC risk 1.18 1.16 1.16 1.42 1.21 1.08 1.23 N/A 1.45 d
by age/HC (SD 0.122) (1.08-1.23) (0.80-1.69) (1.05-1.94) (1.11-1.33) (1.03-1.13) (1.14-1.32) (1.20-1.75)
type/HC 1 year 1-4 years after >0-8 years ‡8 years LNG-IUDb Past HC use COCP OR (95% CI)
duration current use last use current use current use >6 months
1.27 1.07 0.81 0.50 1.09 1.00 1.26 1.29 0.78 1.04
(SD 0.079) (1.02-1.13) (0.45-1.45) (0.18-1.35) (0.80-1.50) (0.80-1.25) (1.16-1.37) (1.21-1.37) (0.59-1.04) (0.81-1.32)
https://doi.org/10.1016/j.annonc.2024.10.824

1-4 years 5-9 years after NET (P) T-NET (P) NET (P) NET (P) POP POP ES (95% CI) ES (95% CI)
current use last use current use current use COCP POP
1.21 1.01 0.86 3.05 1.33 1.93 1.25 1.18 1.24 0.71
(SD 0.061) (0.96-1.05) (0.32-2.34) (2.00-4.66) (1.20-1.48) (1.18-3.16) (1.07-1.45) (1.07-1.30) (0.45-3.40) (0.21-2.37)
5-9 years 10 years after LNG (P) T-LNG (P) LNG (P) LNG (P) I-P I-P HR (95% CI) HR (95% CI)
current use last use current use current use COCP POP
1.29 1.34 1.22 1.12 1.18 1.22 1.28 1.08 1.75
(SD 0.060) (0.79-2.28) (0.45-3.32) (1.01-1.25) (0.87-1.60) (0.93-1.59) (1.08-1.51) (0.75-1.5) (1.03-2.9)
10 years NETA (P) ED (P) DSG (P) DSG (P) P-Imp P-Imp HR (95% CI) HR (95% CI)
current use current use current use COCP POP

Annals of Oncology
1.30 1.23 1.89 1.01-1.62 1.00-1.93 1.32 1.21 1.7
(SD 0.089) (SD 0.042) (1.05-3.41) (RR range (RR range (1.17-1.49) (1.14-1.28) (1.1-2.05)
current use current use NGT (P) by P type) by P type) LNG-IUD LNG-IUD HR (95% CI)
nulliparous parous current use COCP POP
References Lancet and Contraception. Cancer Epidemiol Biomarkers N Engl J Med. 2017105 PLoS Med. 2023107 Arch Gynecol Obstet. 2020104
1996102,103 Prev. 201057
Progestin-only contraceptives are highlighted in light orange. Statistically significant risk is represented in boldface.
BC, breast cancer; Case ctrl, case-control study; CGHFBC, Collaborative Group on Hormonal Factors in Breast Cancer; CI, confidence interval; COCP, combined oral contraceptive pill; CPRD, Clinical Practice Research Datalink; CPT, cyproterone; DSG,
desogestrel; DRSP, drospirenone; E, estrogen; ED, ethynodiol diacetate; EE, ethinylestradiol; ES, effect estimate; GSD, gestodene; HC, hormonal contraceptive(s); HR, hazard ratio; I-P, injected progestin; LNG, levonorgestrel; M, mestranol; N/A,
137

information not available; NET, norethisterone; NETA, norethisterone acetate; NGT, norgestrel; NGM, norgestimate; OR, odds ratio; P, progestin; P-Imp, progestin implant; LNG-IUD, progestin LNG-releasing intrauterine device; POP, P-only pill; RR,
relative risk; SD, standard deviation; T-LNG, triphasic LNG; T-NET, triphasic NET.
a
BC risk estimated using cases of invasive breast cancer.
b
An updated analysis of LNG-IUD showed an HR of 1.4 (95 CI 1.2-1.5) for breast cancer risk in 78,595 LNG-IUD users regardless of duration of use, compared with the matched nonuser control group. Numerically, this resulted in an excess of 14 breast
cancer diagnoses per 10,000 users.116
Annals of Oncology J. Kim & P. N. Munster

subsequent 10 years for women ages 20, 30, and 40 years those in hormonal contraceptives.3 The progestin compo-
are estimated to be 0.07%, 0.5%, and 1.6%, respectively.106 nent was added to reduce the risk of endometrial hyper-
A 20% increase with hormonal contraception in these age plasia in women with an intact uterus.3,53,54 Hence,
groups would therefore elevate their respective 10-year estrogen-alone HRT is generally used in women with prior
breast cancer risks to 0.08%, 0.6%, and 1.9%. hysterectomy.
Importantly, it appears that breast cancer risk from oral Overall, as summarized in Table 2, initial observational
contraceptive use may be primarily attributed to progestins. studies of HRT showed that estrogen-alone therapy was
Large clinical trials, comparing breast cancer risks between associated with smaller increases (6%-37%) in breast
progestineestrogen combined contraceptives and cancer risk than was estrogen-plus-progestin therapy
progestin-only contraceptives, indicate that estrogens in (17%-131%) in postmenopausal women (aged 50 years)
hormonal contraceptives may have little or no impact on compared with never-users.40,59-61 In contrast with the
breast cancer risk.105,107 A Swedish study of 1.5 million observational studies, several placebo-controlled RCTs,
women aged 15-34 years reported a significant increase in including the WHI trial, have shown that estrogen-alone
breast cancer risk with progestin-only contraception [inci- HRT has little or no impact on elevating breast cancer
dent rate ratio (IRR) 1.32, 95% CI 1.20-1.45], which was not risk in postmenopausal women.44,121-123 Notably, with
observed with combined hormonal contraceptives (IRR longer than 20 years of follow-up, the WHI study showed
1.03, 95% CI 0.91-1.16).108 Notably, the progestin LNG that estrogen-alone HRT had significantly and durably
exhibited a higher risk of breast cancer in progestin-only reduced breast cancer risk by 22% (range 21%-69%)
pills (RR 1.93, 95% CI 1.18-3.16) than did in LNGe [hazard ratio (HR) 0.78, 95% CI 0.65-0.93, P ¼ 0.005] as
estrogen combined pills (RR 1.33, 95% CI 1.20-1.48) well as breast cancer mortality by 40% (HR 0.60, 95% CI
(nationwide Danish study) (Table 1),105 despite the fact that 0.37-0.97, P ¼ 0.04) in postmenopausal women with
LNG doses range from 100 to 150 mg for combined for- hysterectomy.43,44,124 Consistent with the observational
mulations and 30 mg in progestin-only pills.48,52 studies, however, the WHI RCT affirmed that estrogen plus
Some studies and a meta-analysis have shown a 20%-30% progestin increased the risk for breast cancer by 28%
increase of breast cancer risk associated with use of (range 22%-36%) (HR 1.28, 95% CI 1.13-1.45, P <
progestin-releasing intrauterine devices (IUDs), which 0.001).3,44
release a constant low dose of progestin (Table 1).105,107 In The inconsistency or discrepancy in the breast cancer
contrast, such an increase was not found in a meta-analysis risks of estrogen-alone HRT found between observational
of 190 475 women who used LNG-IUDs.109 The contracep- studies and RCTs may be due to a difference in baseline
tive effects of progestin-only pills (30-350 mg/day) and breast cancer risks between exposure and control groups
progestin-releasing IUDs (6-20 mg LNG release/day) are pri- in observational studies.125 In RCTs, randomization would
marily achieved by acting directly on the cervix to increase make baseline breast cancer risks similar between
the viscosity of cervical mucus, preventing sperm migra- estrogen-alone HRT and placebo groups, whereas the
tion.110-112 Yet some of these progestin-only contraceptives absence of randomization may make observational studies
were reported to inhibit ovulation in up to 40%-60% of subject to potentially different baseline risks for breast
users,113-115 indicating a potential systemic effect. A recent cancer between users of estrogen-alone HRT and never-
large study of LNG-IUDs showed an HR of 1.4 (95 CI 1.2-1.5) users (control group).125 If true breast cancer risk from
for breast cancer risk in 78,595 LNG-IUD users, compared estrogen-alone HRT were small or absent, the baseline risk
with the matched 78,595 nonuser control group.116 difference in observational studies could have a sizable
Numerically, this increased risk resulted in an excess of 14 impact on the risk difference measured in RCTs.125,126
breast cancer diagnoses per 10,000 users. Larger prospective From observational studies to WHI RCTs, there were
studies may be needed to truly determine the effect of IUDs overall decreases in breast cancer risks for estrogen-alone
and their extent on the risk of breast cancer. HRT (6%-37% increase to 22% decrease) and estrogen-
Use of combined oral contraceptive pills is associated plus-progestin HRT (17%-131% increase to 22%-36% in-
with markedly reduced risks (30%-50%) of ovarian and crease), suggesting a baseline risk difference between HRT
endometrial cancers.6,117-120 Thus, juxtaposed with the ef- users and never-users in non-randomized, observational
ficacy and safety for contraception as well as the significant studies. When this baseline risk difference in breast cancer
risk reduction in ovarian and endometrial cancers, the was removed or mitigated by randomization, the weak
breast cancer risk posed by hormonal contraceptives is association of estrogen-alone HRT with increased breast
small and does not appear to increase mortality in pre- cancer risk did not appear to remain.43,44,124 Even after
menopausal women.67 randomization, however, estrogen-plus-progestin HRT,
which exhibited a robust association with increased breast
cancer risk in observational studies, still showed a signif-
ESTROGEN-CONTAINING HRT AND BREAST CANCER RISK icant increase in breast cancer risk.3,44
IN POSTMENOPAUSAL WOMEN Collectively, these findings support a causative role of
HRT contains much higher doses of an estrogen (e.g. CEEs, progestins from HRT, with minimal effect from estrogen, in
0.625 mg/day) and a progestin (e.g. MPA, 2.5 mg/day) than elevating breast cancer risk.

138 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025

Volume 36

J. Kim & P. N. Munster

Table 2. Hormone replacement therapy (HRT) and breast cancer risk

WHI CGHFBC QResearch/CPRD Million Women BRCA1 carriers

Meta-analysis
-

E alone E+P E alone E+P E alone E+P E alone E+P E alone E+P
Issue 2

Study type RCT Prospective (24 studies) and Retrospective Prospective Prospective
retrospective (34 studies) (case control) (longitudinal cohort)
HRT constituent CEE (E); placebo CEE (E) + MPA CEE or E2 (E) (E) + MPA, NETA, CEE or E2 (E) (E) + NETA, LNG, CEE or EE (E) (E) + MPA, NET, N/A N/A
-

(P); placebo or LNG (P) MP, or DDG (P) NGT, or LNG (P)
CEE, 0.625 CEE,  or >
2025

HRT dose 0.625 mg/day CEE, 0.625 CEE, 0.3 to N/A N/A N/A N/A N/A
mg/day; >0.625 mg/day; mg/d; E2, 1 0.625 mg/day;
MPA, 2.5 E2, 1-2 mg/day mg/d; E2 gel, EE,  or > 1 mg/
mg/day 50 mg day
HRT 7.2 5.6 <1 to 15 <1 to 10 <1 to 10 0.5 to 19
duration, years Mean, 10 (SD 6) Mean, 3.9
Participants 10 739; 5310 (E 16 608; 8506 568 859 (total); 143 887 (BC cases), 556 109 (total); 98 611 (BC cases), 828 923 (total); 872 BRCA1 carriers with BO (total);
alone), 5429 (E + P), 8102 424 972 (controls); 37 213 (E alone), 457 498 (controls); 51 659 (E alone), 115 383 (E alone), 377 (HRT), 495 (no HRT); 259 (E alone,
(placebo) (placebo) 37 951 (E + P) 124 435 (E + P); 380 015 (No HRT) 142 870 (E + P), 392 757 (no HRT) 69%), 66 (E + P, 18%), 40 (P alone,
11%)
Mean age (SD) at 63.6 63.2-63.3 55-72 50-67 Mean age (SD) at BC diagnosis: 55.9 HRT, mean 40.3 (range, 21-67); no
recruitment, (7.3) (7.1) cases, 63.4 (8.3); controls, 63.3-63.6 age range, 50-64 HRT, 45.8 (21-74)
years (8.3)
Hysterectomy Yes No Yes (84%) No (93%) Yes No N/A N/A N/A N/A
Oophorectomy 4049 (37.7%) 53 N/A N/A N/A N/A N/A N/A 872 (100%)
(BO) (0.3%)
Follow-up, years 16.2-20.7 0-11 0-8 d d 2.6-4.1 HRT, mean 6.2 (range 0.6-22); no HRT,
5.8 (0.1-18)
BC riska 0.78 1.28 1.17 1.60 1.06 1.26 1.30 2.00 0.73 1.31
overall (0.65-0.93) (1.13-1.45) (1.10-1.26) (1.52-1.69) (1.03-1.10) (1.24-1.29) (1.22-1.38) (1.91-2.09) (0.41-1.32) (0.66-2.57)
HR (95% CI) RR (95% CI) OR (95% CI) RR (95% CI) HR (95% CI)
BC risk by age/ 0.77 1.36 1.33 2.22 1.08 1.57 0.81 1.45 0.47 1.64
HRT duration (0.57-1.06) (1.09-1.69) (1.19-1.48) (1.96-2.52) (0.99-1.18) (1.48-1.66) (0.55-1.20) (1.19-1.78) (0.20-1.15) (0.68-3.98)
50-59 years 50-59 years 40-44 years 40-44 years 50-59 years 50-59 years <1 year use <1 year use BO <45 years BO <45 years
5 years use ‡5 years use
https://doi.org/10.1016/j.annonc.2024.10.824

0.79 1.22 1.39 2.14 1.17 1.83 1.25 1.74 0.59 (0.25-1.40)
(0.61-1.02) (1.02-1.48) (1.30-1.48) (2.03-2.26) (1.09-1.25) (1.75-1.91) (1.10-1.41) (1.60-1.89) BO <45 years; E alone or E + P 5
60-69 years 60-69 years 45-49 years 45-49 years 60-69 years 60-69 years 1-4 years use 1-4 years use years use
‡5 years use ‡5 years use
0.76 1.27 1.33 2.10 1.25 2.20 1.32 2.17 0.24 (0.06-0.98)
(0.52-1.12) (0.96-1.67) (1.25-1.42) (2.01-2.21) (1.11-1.39) (2.02-2.39) (1.20-1.46) (2.03-2.33) BO <45 years; E alone or E + P >5
70-79 years 70-79 years 50-54 years 50-54 years 70-79 y 70-79 years 5-9 years use 5-9 years use years use
‡5 years use ‡5 years use
0.75 1.26 1.97 1.14 1.70 1.37 2.31 3.38 (1.17-9.73)
(0.54-1.03) E (1.12-1.41) (1.81-2.15) (1.08-1.21) (1.64-1.76) (1.22-1.54) (2.08-2.56) BO <45 years; P alone or E + P £5

Annals of Oncology
alone/BO 55-59 years 55-59 years all ages all ages ‡10 years use ‡10 years use years use
All ages 5-9 years use 5-9 years use
0.31 1.08 1.75 1.17 2.05 1.78 (0.18-17.7)
(0.06-1.45) (0.90-1.31) (1.48-2.06) (1.08-1.27) (1.94-2.17) BO <45 years; P alone or E + P >5
E alone/BO 60-69 years 60-69 years all ages all ages years use
50-59 years ‡10 years use ‡10 years use
Continued
139
Annals of Oncology J. Kim & P. N. Munster

IMPACT OF ENDOGENOUS ESTROGENS AND

BC, breast cancer; BO, bilateral oophorectomy; CEE, conjugated equine estrogens; CGHFBC, Collaborative Group on Hormonal Factors in Breast Cancer; CI, confidence interval; CPRD, Clinical Practice Research Datalink; DDG, dydrogesterone;
E2, estradiol; E, estrogen; EE, ethinylestradiol; HR, hazard ratio; LNG, levonorgestrel; MP, medroxyprogesterone; MPA, medroxyprogesterone acetate; N/A, information not available; NET, norethisterone; NETA, norethisterone acetate; NGT,
PROGESTERONE ON HRT-ASSOCIATED BREAST CANCER
RISK
E+P Bilateral oophorectomy (BO) has been shown to decrease
N/A breast cancer risk.127,128 Surgical or chemical deprivation of

JAMA Oncol. 2018137

ovarian hormones has been associated with a decrease in
breast cancer risk, recurrence, and death.129-133 Also, risk-
BRCA1 carriers

reducing oophorectomy in BRCA1/2 carriers leads to a

significant reduction (by 40%-50%) of breast cancer risk and
E alone

death in most studies.134 These findings suggest a causal

N/A

role of endogenous ovarian hormones in breast cancer risk.

In the WHI trial of postmenopausal women with hyster-
‡5 years use
<5 years use

ectomy, estrogen-alone HRT showed no increase in breast

(1.27-1.53)

(1.52-1.76)

cancer risk (HR 0.84, 95% CI 0.54-1.33) compared with

placebo in women with BO after 18 years of follow-up.135 In
1.39b

1.64b
E+P

(1.00-1.48)

Lancet. 2003,59 201961

the Nurses’ Health Study, women with both oophorectomy

1.22

and hysterectomy showed a decreased risk of breast cancer

Million Women

(HR 0.75, 95% CI 0.68-0.84) compared with women with

‡5 years use
<5 years use
(1.01-1.32)

(1.24-1.47)

hysterectomy alone.128 In this study, estrogen-alone HRT

E alone

was more prevalently used in women with oophorectomy

1.15b

1.35b

(78.3%) than in women without oophorectomy (36.0%).128

The Nurses’ Health Study also reported that estrogen-
alone HRT was not associated with increased breast can-
cer risk in women with BO.136 Together, these findings
Estrogen-alone HRT is highlighted in light pink; estrogen-plus-progestin HRT in light blue. Statistically significant risk is represented in boldface.

norgestrel; OR, odds ratio; P, progestin; RCT, randomized clinical trial; RR, relative risk; SD, standard deviation; WHI, Women’s Health Initiative.

suggest that estrogen-alone HRT is not likely to increase

E+P
N/A

breast cancer risk in the absence of ovarian hormones.

Deprivation of ovarian hormones appears to eliminate or
QResearch/CPRD

neutralize any potential breast cancer risk from estrogen-

BMJ. 202060

alone HRT. BRCA1 carriers who underwent BO before age

E alone

45 years and received estrogen-alone HRT showed a

N/A

nonsignificant yet numerical reduction of breast cancer risk

(HR 0.47, 95% CI 0.20-1.15, P ¼ 0.1), vis-à-vis their coun-
terparts not taking HRT137 (Table 2). In contrast, estrogen-
plus-progestin or progestin-alone HRT following oophorec-
tomy was associated with a significant increase in breast
E+P
N/A

cancer risk in BRCA1 carriers (HR 3.38, 95% CI 1.17-9.73,

P ¼ 0.02).137
Depletion of ovarian hormones also offers insights into
Lancet. 201940
Meta-analysis

the role of endogenous estrogens and progesterone in

CGHFBC

breast cancer risk associated with HRT. In postmenopausal

E alone
N/A

women, oophorectomy further reduces estrogen levels (by

BC risk estimated using incidence or cases of invasive breast cancer.

40% for E1; by 37% for E2) similar to concentrations in

BC mortality calculated with 20-year follow-up after recruitment.

premenopausal women following oophorectomy.15 The

observations that estrogen-alone HRT has little to no impact
(0.94-1.95)

on breast cancer risk after depletion of ovarian hormones

E+P

suggest that endogenous estrogens alone are not likely to

Ann Intern Med. 2019135
1.35

elevate breast cancer risk. The increased risk of breast

cancer by estrogen-plus-progestin HRT after depleting
JAMA. 202044

ovarian hormones points to endogenous progesterone as

(0.37-0.97)

an oncogenic hormonal driver for breast cancer. As estrogen

E alone

is known to induce progesterone receptor (PgR) expression

WHI

0.60

in mammary epithelial cells,138-140 exogenous and endoge-

Table 2. Continued

nous estrogens may also contribute to breast cancer risk by

augmenting progesterone signaling.141 Endogenous testos-
BC mortality

References

terone, whose levels are significantly reduced post-oopho-

(95% CI)

rectomy,15 is unlikely to account for the progestin-mediated

increased breast cancer risk.
b
a

140 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025

J. Kim & P. N. Munster Annals of Oncology

NO INCREASED RISK OF BREAST CANCER BY ESCALATED Parous women are generally at a lower risk of breast
LEVELS OF ESTROGENS FROM OVARIAN STIMULATION cancer than nulliparous women.155,156 This protection of
Despite a short duration, fertility treatments, such as IVF or pregnancy against breast cancer is largely attributable to an
assisted reproductive technology (ART), have raised a early age at first pregnancy.155,156 While pregnancy at
concern for a potential increase in breast cancer risk, younger ages (20-30 years) shows a protective effect against
because such treatments markedly increase the endoge- breast cancer risk, this protection may be lost in later-age
nous production of estrogens.142,143 IVF or ART commonly pregnancies.155,156 First full-term pregnancy at an age
involves ovarian stimulation by the administration of go- older than 30-35 years is associated with an increased risk
nadotropins to render the maximum number of eggs har- of breast cancer.155,156
vested in a single IVF cycle.144 During an IVF cycle, The mechanism underlying this pregnancy-associated
gonadotropins spur the growth and maturation of multiple breast cancer risk reduction appears to be complex.157,158
follicles, simultaneously, into preovulatory follicles, thereby Observational data suggest that the timing of pregnancy
releasing supraphysiological levels of particularly E2 (500- (i.e. early age at first pregnancy), rather than parity, is the
4000 pg/ml) in the follicular phase.145-147 After the final most important determinant of the breast cancer risk
maturation of the oocytes in the preovulatory follicles by an reduction linked to pregnancy.155,156 Thus, the pregnancy-
injection of human chorionic gonadotropin, the oocytes are associated protective effect might be hormone indepen-
recovered via follicle aspiration.146 The luteal phase of an dent. Considering the treatment effects of high-dose es-
IVF cycle, however, is defective due to inadequate corpus trogen and progestin therapies in advanced breast
luteum function leading to insufficient progesterone pro- cancer,86,92 it may also be possible that high physiological
duction.148 Typically, the luteal-phase defect requires the levels of pregnancy estrogens and progesterone might act
administration of exogenous progesterone to prepare the as anti-carcinogenic in breast tissue. Other putative mech-
endometrium for the implantation of transplanted embryos anisms include pregnancy-driven alterations in breast cells,
and to improve pregnancy rates.148 Thus, women under- spurring a switch from an undifferentiated to a more
going an IVF or ART procedure are exposed to transiently differentiated state resistant to carcinogenesis.157,158
yet acutely elevated concentrations of endogenous estro- Most studies have indicated that pregnancy does not
gens, as high as 10 times the levels in a normal menstrual affect the risk of recurrence or death among breast cancer
cycle.145,146 survivors.159,160 Breast cancer survivors with pregnancy had
Recent meta-analyses, which examined the impact of significantly better overall survival than those without
ovarian stimulation and hormone fertility treatment on pregnancy (HR 0.46, 95% CI 0.27-0.77, P < 0.05).160 Thus,
breast cancer risk, found no significantly increased risk of pregnancy appears to be not only safe for breast cancer
breast cancer (odds ratio 0.97, 95% CI 0.90-1.04).142,143 A survivors, but also may potentially be protective against
large cohort study, assessing 255 786 women in the UK breast cancer recurrence. These data suggest that
treated with ART, indicated that the absence of breast pregnancy-associated increases in steroid hormone syn-
cancer risk increase in women with IVF/ART was not thesis may not have adverse effect on breast cancer
attributed to pregnancy/live births.149 Additionally, in a recurrence.
Dutch population-based study, breast cancer risk was An early onset of menarche and a late onset of meno-
significantly reduced with 7 or more cycles of IVF or fertility pause are associated with an increased risk of breast can-
treatments compared with 1-2 cycles (HR 0.55, 95% CI 0.39- cer,161 while lactation or breastfeeding is associated with a
0.77).150 Moreover, ovarian stimulation was associated with decreased risk of breast cancer.162 Early-age menarche and
significantly reduced risks of breast cancer recurrence (RR late-age menopause would increase exposure to menstrual
0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38- hormones. As lactation inhibits the menstrual cycle and
0.76) in young women diagnosed with breast cancer who ovulation, it would reduce menstrual hormone exposure.162
sought oocyte/embryo cryopreservation, and a reduced risk Collectively, these findings support an oncogenic role of
of recurrence (RR 0.34, 95% CI 0.17-0.70) in breast cancer menstrual hormones in breast cancer.
survivors receiving ART.151 While the mechanism is unclear
for these seemingly counterintuitive breast cancer risk re- ONCOGENIC ROLE OF PROGESTERONE IN BREAST CANCER
ductions and survival benefits, collective evidence suggests Estrogen is the major mitogenic hormone in pubertal murine
that high levels of estrogens induced by ovarian stimulation mammary glands.77,163 In adult mice, however, estrogen has
appear to have no adverse effect on breast cancer risk or little impact on mammary epithelial proliferation while
recurrence. eliciting a notable induction of PgR expression in mammary
epithelial cells.138-140 In contrast, progesterone, particularly
REPRODUCTIVE FACTORS AND BREAST CANCER RISK when treated with E2, robustly stimulates adult mammary
The oncogenic roles of endogenous hormones are indicated epithelial proliferation in ovariectomized mice and pri-
by the association of reproductive factorsdsuch as preg- mates.77-79,140,164 Normal breast epithelial cells significantly
nancy, lactation, menarche, and menopausedwith breast increase proliferation by 62%-103% in the luteal phase
cancer risk.152-154 compared with the follicular phase.165 Additionally,

Volume 36 - Issue 2 - 2025 https://doi.org/10.1016/j.annonc.2024.10.824 141

Annals of Oncology J. Kim & P. N. Munster

progesterone levels are significantly and positively corre- endocrine therapy was more effective in reducing recur-
lated with breast epithelial cell proliferation.165 Collectively, rence and mortality for breast tumors expressing both
animal and human studies indicate that progesterone is the ER and PgR (ER positive/PgR positive) than ER-positive/PgR-
principal hormonal factor driving adult mammary/breast negative breast tumors.177-179 Fittingly, tamoxifen resistance
epithelial proliferation.76,141 was associated with a loss of PgR expression in ER-positive/
The potent mitogenic role of progesterone in the PgR-positive breast tumors.180
mammary epithelium is consistent with the oncogenic Together, these findings suggest that the risk-reducing
impact of progestins in elevating breast cancer risk in and therapeutic effects of antiestrogens may be mediated
clinical studies of HRT and hormonal contracep- by the ability of antiestrogens to suppress progesterone
tives.40,44,59-61,105,107 In particular, the Nurses’ Health signaling.
Study showed a significantly elevated risk of breast can-
cer among postmenopausal women using progestin-alone HORMONAL FACTORS FOR BREAST CANCER RECURRENCE
HRT (RR 2.24, 95% CI 1.26-3.98) compared with never- AND PROGRESSION
users.166 Employing a sensitive progesterone assay, a
recent study reported an increased risk of breast cancer The therapeutic effects of antiestrogens, such as tamoxifen
in postmenopausal women with higher blood levels of and aromatase inhibitors, on reducing breast cancer recur-
progesterone compared with lower progesterone levels rence and progression have naturally pointed to estrogen as
(HR 1.24, 95% CI 1.07-1.43, P ¼ 0.004).23 The effects of a main hormonal driver for the development, growth, and
antiprogestins to prevent mouse mammary tumors, as progression of ER-positive breast cancer.66,181 This concept
well as ovarian cancer in mice, lend further support to dates back to the discovery in the late 19th century linking
the oncogenic role of endogenous progesterone and oophorectomies to regression of metastatic breast cancer in
progestins in breast cancer.167,168 premenopausal patients.30,182 This observation led to a
It is worth noting that bioidentical progesterone may seeming logical conclusion that the therapeutic effect of
confer a lower risk of breast cancer than progestins.169 oophorectomy for patients with metastatic breast cancer
Micronized progesterone, used along with estrogen HRT, was derived from the deprivation of ovarian estrogens
was not significantly associated with an increased risk of while presuming an absence of benefit for ER-negative
breast cancer when used up to 5 years (HR 1.13, 95% CI breast tumors.183-185
0.99-1.29).170 Breast cancer risk, however, was significantly At odds with this notion, further data showed thera-
elevated with long-time use of estrogen plus micronized peutic effects of oophorectomy in both ER-positive
progesterone (>5 years) (HR 1.31, 95% CI 1.15-1.48), albeit (response rate, 71%) and ER-negative (21%) metastatic
less than with estrogeneprogestin HRT (HR 2.02, 95% CI breast cancers.186 Similarly, oophorectomy was associated
1.81-2.26).170,171 Accordingly, the progestin MPA exhibits with significant reductions (55%-62%) in breast cancer
higher proliferative activity in mammary epithelial cells than mortality among BRCA1/2 carriers with nonmetastatic ER-
does progesterone.78 positive or ER-negative breast cancer.131,187 Notably, the
protective effect of oophorectomy against breast cancer
death was even more pronounced in ER-negative breast
MECHANISM UNDERLYING THE PREVENTIVE AND cancer (HR 0.07, 95% CI 0.01-0.51, P ¼ 0.009) than in ER-
THERAPEUTIC EFFECTS OF ANTIESTROGENS positive breast cancer (HR 0.48, 95% CI 0.25-0.86, P ¼
In large randomized preventive trials of tamoxifen and the 0.01).131,187 Collectively, these findings suggest that oo-
aromatase inhibitor anastrozole, these endocrine therapies phorectomy (i.e. deprivation of ovarian hormones) reduces
have reduced the risk of ER-positive breast cancer by 30%- the recurrence of ER-positive as well as ER-negative breast
50%, particularly in women with an increased risk of breast cancers.
cancer.69-74 However, tamoxifen did not reduce breast Plausible alternative explanations may be the culpable
cancer risk in women who never used estrogen-alone HRT effects of ovarian progesterone. Its deprivation com-
(RR 1.00, 95% CI 0.67-1.50).71 Counterintuitively, the plemented by the loss of ovarian estrogens may be the
tamoxifen-mediated risk reduction of breast cancer was primary reason for the recurrence suppression and the
pronounced among women who also used estrogen-alone reduced breast cancer mortality post-oophorectomy in
HRT (RR 0.43, 95% CI 0.2-0.95).71 BRCA1/2 carriers with ER-positive or ER-negative non-
Tamoxifen has dual properties as antiestrogenic and es- metastatic breast cancer. Similarly, depletion of both
trogenic in breast tissue and breast cancer, depending upon ovarian progesterone and estrogens would likely be
its concentrations and biological context.164,172,173 Absent responsible for the tumor regression observed in ER-
estrogen, tamoxifen exhibits partial estrogenic activity,164 positive and ER-negative metastatic breast cancers after
whereas in the presence of estrogen, tamoxifen acts as an therapeutic oophorectomy.186 Also, the reason for tumor
antiestrogen that decreases estrogen-induced PgR expres- regression in only 20%-50% of patients with metastatic
sion.174-176 Accordingly, tamoxifen exhibited higher sensi- breast cancer following oophorectomy183,186,188 may be
tivity to ER-positive/PgR-positive breast tumors than attributable to non-hormonal causes of tumor progression
ER-positive/PgR-negative breast tumors.177 Similarly, rather than the rest being ER-negative tumors.

142 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025

J. Kim & P. N. Munster Annals of Oncology

HRT FOR BREAST CANCER SURVIVORS It has been well recognized that HRT provides an array of
Further corroborating evidence on the oncogenic role of health benefitsdincluding alleviation of menopausal
progestogens in breast cancer may be gleaned from two symptoms, mood improvement, weight control, and pre-
independent RCTs that assessed the breast cancer risk of vention of bone fractures.4,5,199,200 There are, however, risks
HRT among breast cancer survivors in Sweden: the HABITS that need to be weighed for HRT use. Estrogen-alone HRT
and the Stockholm trials.189,190 The participants of these may increase endometrial cancer risk in postmenopausal
trials were postmenopausal women without evidence of women with an intact uterus, while estrogen-plus-progestin
recurrence after the diagnosis and treatment of non- therapy could increase breast cancer risk in these women.
metastatic breast cancer. After HRT versus no treatment of Therefore, the risks and benefits of HRT should be carefully
2-5 years and median follow-ups of 2-10 years, the HABITS assessed for individual women.201 If a woman with an
trial showed a significant increase of recurrence (HR 2.4, average risk for breast cancer and an intact uterus, for
95% CI 1.3-4.2),189,191 whereas the Stockholm trial reported instance, experiences significant menopausal symptoms,
no significant impact of HRT on breast cancer recurrence she may opt for estrogen, combined with minimal use of
(relative hazard 0.82, 95% CI 0.35-1.9).190,192 No mortality micronized progesterone or progestineIUD to counter po-
difference was observed in both trials. tential endometrial hyperplasia. If she is more concerned
There were two major differences between these trials: about breast cancer risk than endometrial cancer risk, she
progestin exposure and tamoxifen use. In the HABITS trial, may choose estrogen alone at a lower dose and regularly
nearly half (46%) of the participants were treated with monitor endometrial growth. In postmenopausal women
continuous estrogeneprogestin HRT with 47% for estrogen seeking HRT after a hysterectomy alone or in combination
alone or combined with low exposure of a progestin.189 In with an oophorectomy, estrogen alone would relieve
contrast, as the Stockholm trial was specifically designed to menopausal symptoms with minimal cancer risks.
minimize progestin exposure from HRT, 95% of the partic- Overall, current scientific evidence suggests that estrogen
ipants were treated with estrogen alone or combined with therapy, coupled with minimal use of a progestogen, is
low exposure of a progestin.190 Thus, investigators of these likely to offer net health benefits in women in need of HRT.
trials attributed the increased risk of recurrence in the
ACKNOWLEDGEMENTS
HABITS trial to higher exposure of progestins.192 Also, more
women were treated with tamoxifen as an adjuvant ther- We thank Dr JoAnn Manson at Harvard Medical School; Dr
apy in the Stockholm trial (52%) than in the HABITS trial Susan Domchek at University of Pennsylvania Perelman
(21%). The risk-reducing effect of breast cancer by tamox- School of Medicine; Dr Kathy Miller, Dr Lisa Landrum, Dr
ifen was promoted by estrogen-alone HRT,71 which would Lawrence Quilliam, Dr Emanuele Pelosi, Dr Quyen Hoang, Dr
induce PgR and thus potentiate the anti-breast-cancer ef- John Turchi, and Andro Botros at Indiana University School
fect of tamoxifen via suppression of progesterone of Medicine; Dr Michele Coté and Rana German at the
signaling.174-176 Thus, higher use of tamoxifen, combined Komen Tissue Bank at Indiana University Melvin and Simon
with progestin-limited estrogen HRT, may have also miti- Comprehensive Cancer Center; Dr Facundo Fernández at
gated the risk of breast cancer recurrence in the Stockholm Georgia Institute of Technology; Dr Seung-Oe Lim at Purdue
trial. University; Dr Mindy Goldman at University of California,
A recent combined analysis of RCTs, prospective, and San Francisco; Dr Hyung Seok Park at Yonsei University
retrospective studies showed no increase in breast cancer College of Medicine and Dr Chi-Heum Cho at Keimyung
recurrence (RR 0.85, 95% CI 0.54-1.33) and mortality (RR University School of Medicine, South Korea; and Dr Bhaskar
0.91, 95% CI 0.38-2.19),193 albeit with disagreements Ponugoti for the reading of the manuscript and their
among studies.194-197 While HRT is generally contra- comments.
indicated for breast cancer survivors,198 collective evidence
cautiously suggests that estrogen therapy, combined with FUNDING
minimal use of a progestogen, might be a safe option for This work was supported by the U.S. Department of De-
these women in need of HRT. fense [grant number W81XWH2210390 to JK] and Indiana
University HealtheIndiana University School of Medicine
CONCLUSIONS Strategic Research Initiative (no grant number) (to JK).
There is a long-held notion that estrogen exposure will in-
DISCLOSURE
crease the risk for breast cancer. Conversely, a body of
emerging clinical and basic research evidence suggests that JK is listed as the inventor on a patent application filed by
progestogens (synthetic or endogenous progesterone) are Indiana University that describes a method of targeting
most likely the primary hormonal factor underlying seem- progesterone signaling for ovarian and breast cancer pre-
ingly estrogen-associated breast cancer risk. Progestogens vention. PNM has declared no conflicts of interest.
appear to be the principal hormone driving the develop-
ment and recurrence of breast cancer, while estrogens may REFERENCES
contribute to breast cancer risk by amplifying progesterone 1. Teal S, Edelman A. Contraception selection, effectiveness, and
signaling. adverse effects: a review. JAMA. 2021;326(24):2507-2518.

Volume 36 - Issue 2 - 2025 https://doi.org/10.1016/j.annonc.2024.10.824 143

Annals of Oncology J. Kim & P. N. Munster

2. Grady D. Clinical practice. Management of menopausal symptoms. 24. Lobo RA. Menopause and aging. In: Strauss JFIII, Barbieri RL, editors.
N Engl J Med. 2006;355(22):2338-2347. Yen & Jaffe’s Reproductive Endocrinology. 8th ed. Philadelphia, PA:
3. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of Elsevier; 2019. p. 322-356.
estrogen plus progestin in healthy postmenopausal women: principal 25. Asch RH, Greenblatt RB. Steroidogenesis in the postmenopausal
results from the Women’s Health Initiative randomized controlled ovary. Clin Obstet Gynaecol. 1977;4(1):85-106.
trial. JAMA. 2002;288(3):321-333. 26. Cleary MP, Grossmann ME. Minireview: obesity and breast
4. Flores VA, Pal L, Manson JE. Hormone therapy in menopause: con- cancer: the estrogen connection. Endocrinology. 2009;150(6):
cepts, controversies, and approach to treatment. Endocr Rev. 2537-2542.
2021;42(6):720-752. 27. Dowsett M, Folkerd E. Reduced progesterone levels explain the
5. Manson JE, Crandall CJ, Rossouw JE, et al. The Women’s Health reduced risk of breast cancer in obese premenopausal women: a new
Initiative randomized trials and clinical practice: a review. JAMA. hypothesis. Breast Cancer Res Treat. 2015;149(1):1-4.
2024;331(20):1748-1760. 28. Maroulis GB, Abraham GE. Ovarian and adrenal contributions to
6. Collaborative Group on Epidemiological Studies of Ovarian peripheral steroid levels in postmenopausal women. Obstet Gynecol.
CancerBeral V, Doll R, Hermon C, et al. Ovarian cancer and oral 1976;48(2):150-154.
contraceptives: collaborative reanalysis of data from 45 epidemio- 29. Vermeulen A. The hormonal activity of the postmenopausal ovary.
logical studies including 23,257 women with ovarian cancer and 87, J Clin Endocrinol Metab. 1976;42(2):247-253.
303 controls. Lancet. 2008;371(9609):303-314. 30. Beatson GT. On the treatment of inoperable cases of carcinoma of
7. Iversen L, Sivasubramaniam S, Lee AJ, Fielding S, Hannaford PC. the mamma: suggestions for a new method of treatment, with
Lifetime cancer risk and combined oral contraceptives: the Royal illustrative cases. Lancet. 1896;148(3802):104-107.
College of General Practitioners’ Oral Contraception Study. Am J 31. Lupulescu A. Estrogen use and cancer incidence: a review. Cancer
Obstet Gynecol. 2017;216(6):580.e581-580.e589. Invest. 1995;13(3):287-295.
8. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. 32. Santen RJ, Simpson E. History of estrogen: its purification, structure,
N Engl J Med. 2006;354(3):270-282. synthesis, biologic actions, and clinical implications. Endocrinology.
9. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J 2019;160(3):605-625.
Med. 2001;344(4):276-285. 33. Kohn GE, Rodriguez KM, Hotaling J, Pastuszak AW. The history of
10. Sahin NH, Bal MD, Boga NM, Gökdemirel S, Taşpınar A. Women’s estrogen therapy. Sex Med Rev. 2019;7(3):416-421.
perception of the menopause and hormone treatment: barriers 34. Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev
against hormone therapy. Climacteric. 2011;14(1):152-156. Endocrinol. 2017;13(4):220-231.
11. Trémollieres FA, André G, Letombe B, et al. Persistent gap in meno- 35. Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of
pause care 20 years after the WHI: a population-based study of exogenous estrogen and endometrial carcinoma. N Engl J Med.
menopause-related symptoms and their management. Maturitas. 1975;293(23):1164-1167.
2022;166:58-64. 36. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among
12. Abraham GE, Odell WD, Swerdloff RS, Hopper K. Simultaneous users of conjugated estrogens. N Engl J Med. 1975;293(23):1167-
radioimmunoassay of plasma FSH, LH, progesterone, 17-hydrox- 1170.
yprogesterone, and estradiol-17 beta during the menstrual cycle. 37. Hemminki E, Kennedy DL, Baum C, McKinlay SM. Prescribing of
J Clin Endocrinol Metab. 1972;34(2):312-318. noncontraceptive estrogens and progestins in the United States,
13. Carmina E, Stanczyk FZ, Lobo RA. Evaluation of hormonal status. In: 1974-86. Am J Public Health. 1988;78(11):1479-1481.
Strauss III JF, Barbieri RL, Gargiulo AR, editors. Yen & Jaffe’s Repro- 38. Brinton LA, Felix AS. Menopausal hormone therapy and risk of
ductive Endocrinology. 8th ed. Philadelphia, PA: Elsevier; 2019887- endometrial cancer. J Steroid Biochem Mol Biol. 2014;142:83-89.
915.e884. 39. Jewett PI, Gangnon RE, Trentham-Dietz A, Sprague BL. Trends of
14. Rothman MS, Carlson NE, Xu M, et al. Reexamination of testosterone, postmenopausal estrogen plus progestin prevalence in the United
dihydrotestosterone, estradiol and estrone levels across the menstrual States between 1970 and 2010. Obstet Gynecol. 2014;124(4):727-
cycle and in postmenopausal women measured by liquid chroma- 733.
tography-tandem mass spectrometry. Steroids. 2011;76(1-2):177-182. 40. Collaborative Group on Hormonal Factors in Breast Cancer. Type and
15. Stanczyk FZ, Chaikittisilpa S, Sriprasert I, et al. Circulating androgen timing of menopausal hormone therapy and breast cancer risk: in-
levels before and after oophorectomy in premenopausal and post- dividual participant meta-analysis of the worldwide epidemiological
menopausal women. Climacteric. 2019;22(2):169-174. evidence. Lancet. 2019;394(10204):1159-1168.
16. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Case records of the 41. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal
Massachusetts General Hospital. Weekly clinicopathological exercises. hormone therapy: annual trends and response to recent evidence.
Laboratory reference values. N Engl J Med. 2004;351(15):1548-1563. JAMA. 2004;291(1):47-53.
17. Longcope C. Estriol production and metabolism in normal women. 42. Ameye L, Antoine C, Paesmans M, de Azambuja E, Rozenberg S.
J Steroid Biochem. 1984;20(4B):959-962. Menopausal hormone therapy use in 17 European countries during
18. Albrecht ED, Pepe GJ. Placental steroid hormone biosynthesis in the last decade. Maturitas. 2014;79(3):287-291.
primate pregnancy. Endocr Rev. 1990;11(1):124-150. 43. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated
19. Kallen CB. Steroid hormone synthesis in pregnancy. Obstet Gynecol equine estrogen in postmenopausal women with hysterectomy: the
Clin North Am. 2004;31(4):795-816, x. Women’s Health Initiative randomized controlled trial. JAMA.
20. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and 2004;291(14):1701-1712.
laboratory studies: a reference table for clinicians. Obstet Gynecol. 44. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of
2009;114(6):1326-1331. menopausal hormone therapy with breast cancer incidence and
21. Schock H, Zeleniuch-Jacquotte A, Lundin E, et al. Hormone concen- mortality during long-term follow-up of the Women’s Health Initiative
trations throughout uncomplicated pregnancies: a longitudinal study. randomized clinical trials. JAMA. 2020;324(4):369-380.
BMC Pregnancy Childbirth. 2016;16(1):146. 45. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone
22. Tulchinsky D, Hobel CJ, Yeager E, Marshall JR. Plasma estrone, therapy and long-term all-cause and cause-specific mortality: the
estradiol, estriol, progesterone, and 17-hydroxyprogesterone in hu- Women’s Health Initiative randomized trials. JAMA. 2017;318(10):
man pregnancy. I. Normal pregnancy. Am J Obstet Gynecol. 927-938.
1972;112(8):1095-1100. 46. Dhont M. History of oral contraception. Eur J Contracept Reprod
23. Trabert B, Bauer DC, Buist DSM, et al. Association of circulating Health Care. 2010;15(suppl 2):S12-S18.
progesterone with breast cancer risk among postmenopausal women. 47. Kiley J, Hammond C. Combined oral contraceptives: a comprehensive
JAMA Netw Open. 2020;3(4):e203645. review. Clin Obstet Gynecol. 2007;50(4):868-877.

144 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025

J. Kim & P. N. Munster Annals of Oncology

48. Burkman R, Bell C, Serfaty D. The evolution of combined oral 74. Cuzick J, Chu K, Keevil B, et al. Effect of baseline oestradiol serum
contraception: improving the risk-to-benefit ratio. Contraception. concentration on the efficacy of anastrozole for preventing breast
2011;84(1):19-34. cancer in postmenopausal women at high risk: a case-control study of
49. Tyrer L. Introduction of the pill and its impact. Contraception. the IBIS-II prevention trial. Lancet Oncol. 2024;25(1):108-116.
1999;59(suppl 1):11s-16s. 75. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous
50. Golobof A, Kiley J. The current status of oral contraceptives: progress estrogen, androgen, and progesterone concentrations and breast
and recent innovations. Semin Reprod Med. 2016;34(3):145-151. cancer risk among postmenopausal women. J Natl Cancer Inst.
51. Christin-Maitre S. History of oral contraceptive drugs and their use 2004;96(24):1856-1865.
worldwide. Best Pract Res Clin Endocrinol Metab. 2013;27(1):3-12. 76. Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ.
52. Grimes DA, Lopez LM, O’Brien PA, Raymond EG. Progestin-only pills Hormone replacement therapy with estrogen or estrogen plus
for contraception. Cochrane Database Syst Rev. 2013;(11):CD007541. medroxyprogesterone acetate is associated with increased epithelial
53. Persson I, Weiderpass E, Bergkvist L, Bergström R, Schairer C. Risks of proliferation in the normal postmenopausal breast. J Clin Endocrinol
breast and endometrial cancer after estrogen and estrogen-progestin Metab. 1999;84(12):4559-4565.
replacement. Cancer Causes Control. 1999;10(4):253-260. 77. Haslam SZ. Progesterone effects on deoxyribonucleic acid synthesis in
54. Beral V, Bull D, Reeves G. Million Women Study Collaborators. normal mouse mammary glands. Endocrinology. 1988;122(2):464-
Endometrial cancer and hormone-replacement therapy in the Million 470.
Women Study. Lancet. 2005;365(9470):1543-1551. 78. Wang S, Counterman LJ, Haslam SZ. Progesterone action in normal
55. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives mouse mammary gland. Endocrinology. 1990;127(5):2183-2189.
and the risk of breast cancer. N Engl J Med. 2002;346(26):2025-2032. 79. Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B. Ef-
56. Karlsson T, Johansson T, Höglund J, Ek WE, Johansson Å. Time- fects of hormone replacement therapy on the mammary gland of
dependent effects of oral contraceptive use on breast, ovarian, and surgically postmenopausal cynomolgus macaques. Am J Obstet
endometrial cancers. Cancer Res. 2021;81(4):1153-1162. Gynecol. 1996;174(1 Pt 1):93-100.
57. Hunter DJ, Colditz GA, Hankinson SE, et al. Oral contraceptive use and 80. Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B. Ef-
breast cancer: a prospective study of young women. Cancer Epi- fects of conjugated estrogens, medroxyprogesterone acetate, and
demiol Biomarkers Prev. 2010;19(10):2496-2502. tamoxifen on the mammary glands of macaques. Breast Cancer Res
58. Stadel BV, Schlesselman JJ, Murray PA, et al. Oral contraceptives and Treat. 1998;48(3):221-229.
breast cancer. Lancet. 1989;1(8649):1257-1259. 81. Carroll JS, Hickey TE, Tarulli GA, Williams M, Tilley WD. Deciphering
59. Beral V, Million Women Study Collaborators. Breast cancer and hor- the divergent roles of progestogens in breast cancer. Nat Rev Cancer.
mone-replacement therapy in the Million Women Study. Lancet. 2017;17(1):54-64.
2003;362(9382):419-427. 82. Munster PN, Carpenter JT. Estradiol in breast cancer treatment:
60. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone reviving the past. JAMA. 2009;302(7):797-798.
replacement therapy and risk of breast cancer: nested case-control 83. Carter AC, Sedransk N, Kelley RM, et al. Diethylstilbestrol: recom-
studies using the QResearch and CPRD databases. BMJ. 2020;371: mended dosages for different categories of breast cancer patients.
m3873. Report of the Cooperative Breast Cancer Group. JAMA. 1977;237(19):
61. Beral V, Peto R, Pirie K, Reeves G. Menopausal hormone therapy and 2079. 2078.
20-year breast cancer mortality. Lancet. 2019;394(10204):1139. 84. Ingle JN, Ahmann DL, Green SJ, et al. Randomized clinical trial of
62. Narod SA. Hormone replacement therapy and the risk of breast diethylstilbestrol versus tamoxifen in postmenopausal women with
cancer. Nat Rev Clin Oncol. 2011;8(11):669-676. advanced breast cancer. N Engl J Med. 1981;304(1):16-21.
63. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J 85. Ellis MJ, Gao F, Dehdashti F, et al. Lower-dose vs high-dose oral
Med. 1998;339(22):1609-1618. estradiol therapy of hormone receptor-positive, aromatase inhibitor-
64. Osborne CK, Wakeling A, Nicholson RI. Fulvestrant: an oestrogen resistant advanced breast cancer: a phase 2 randomized study. JAMA.
receptor antagonist with a novel mechanism of action. Br J Cancer. 2009;302(7):774-780.
2004;90(suppl 1 suppl 1):S2-S6. 86. Shete N, Calabrese J, Tonetti DA. Revisiting estrogen for the treat-
65. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J ment of endocrine-resistant breast cancer: novel therapeutic ap-
Med. 2003;348(24):2431-2442. proaches. Cancers (Basel). 2023;15(14):3647.
66. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aroma- 87. Jordan VC. Tamoxifen: a personal retrospective. Lancet Oncol.
tase inhibitors versus tamoxifen in premenopausal women with 2000;1(1):43-49.
oestrogen receptor-positive early-stage breast cancer treated with 88. Song RX, Mor G, Naftolin F, et al. Effect of long-term estrogen
ovarian suppression: a patient-level meta-analysis of 7030 women deprivation on apoptotic responses of breast cancer cells to 17beta-
from four randomised trials. Lancet Oncol. 2022;23(3):382-392. estradiol. J Natl Cancer Inst. 2001;93(22):1714-1723.
67. Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast 89. Ingle JN, Ahmann DL, Green SJ, et al. Randomized clinical trial of
cancer. Lancet. 2021;397(10286):1750-1769. megestrol acetate versus tamoxifen in paramenopausal or castrated
68. Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis women with advanced breast cancer. Am J Clin Oncol. 1982;5(2):155-
Primers. 2019;5(1):66. 160.
69. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of 90. Muss HB, Wells HB, Paschold EH, et al. Megestrol acetate versus
breast cancer: extended long-term follow-up of the IBIS-I breast tamoxifen in advanced breast cancer: 5-year analysis–a phase III trial
cancer prevention trial. Lancet Oncol. 2015;16(1):67-75. of the Piedmont Oncology Association. J Clin Oncol. 1988;6(7):1098-
70. Cuzick J, Sestak I, Forbes JF, et al. Use of anastrozole for breast cancer 1106.
prevention (IBIS-II): long-term results of a randomised controlled 91. Bines J, Dienstmann R, Obadia RM, et al. Activity of megestrol acetate
trial. Lancet. 2020;395(10218):117-122. in postmenopausal women with advanced breast cancer after
71. Veronesi U, Maisonneuve P, Rotmensz N, et al. Tamoxifen for the nonsteroidal aromatase inhibitor failure: a phase II trial. Ann Oncol.
prevention of breast cancer: late results of the Italian Randomized 2014;25(4):831-836.
Tamoxifen Prevention Trial among women with hysterectomy. J Natl 92. Mattsson W. Current status of high dose progestin treatment in
Cancer Inst. 2007;99(9):727-737. advanced breast cancer. Breast Cancer Res Treat. 1983;3(2):231-235.
72. Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-year follow- 93. Attardi BJ, Zeleznik A, Simhan H, et al. Comparison of progesterone
up of the Royal Marsden randomized, double-blinded tamoxifen and glucocorticoid receptor binding and stimulation of gene
breast cancer prevention trial. J Natl Cancer Inst. 2007;99(4):283-290. expression by progesterone, 17-alpha hydroxyprogesterone cap-
73. Chlebowski RT. IBIS-I tamoxifen update: maturity brings questions. roate, and related progestins. Am J Obstet Gynecol. 2007;197(6):
Lancet Oncol. 2015;16(1):7-9. 599.e1-599.e7.

Volume 36 - Issue 2 - 2025 https://doi.org/10.1016/j.annonc.2024.10.824 145

Annals of Oncology J. Kim & P. N. Munster

94. Lei K, Chen L, Georgiou EX, et al. Progesterone acts via the nuclear 114. Nilsson CG, Lähteenmäki PL, Luukkainen T. Ovarian function in
glucocorticoid receptor to suppress IL-1b-induced COX-2 expression amenorrheic and menstruating users of a levonorgestrel-releasing
in human term myometrial cells. PLoS One. 2012;7(11):e50167. intrauterine device. Fertil Steril. 1984;41(1):52-55.
95. Poulin R, Baker D, Poirier D, Labrie F. Androgen and glucocorticoid 115. Barbosa I, Olsson SE, Odlind V, Goncalves T, Coutinho E. Ovarian
receptor-mediated inhibition of cell proliferation by medrox- function after seven years’ use of a levonorgestrel IUD. Adv Contra-
yprogesterone acetate in ZR-75-1 human breast cancer cells. Breast cept. 1995;11(2):85-95.
Cancer Res Treat. 1989;13(2):161-172. 116. Mørch LS, Meaidi A, Corn G, et al. Breast Cancer in Users of Levo-
96. Ruan X, Mueck AO. The WHO claims estrogens are ‘carcinogenic’: is norgestrel-Releasing Intrauterine Systems. JAMA. 2024;332(18):1578-
this true? Climacteric. 2023;26(3):263-270. 1580.
97. Brantley KD, Ziegler RG, Craft NE, Hankinson SE, Eliassen AH. Circu- 117. Tsilidis KK, Allen NE, Key TJ, et al. Oral contraceptive use and repro-
lating estrogen metabolites and risk of breast cancer among post- ductive factors and risk of ovarian cancer in the European Prospective
menopausal women in the Nurses’ Health Study. Cancer Epidemiol Investigation into Cancer and Nutrition. Br J Cancer. 2011;105(9):
Biomarkers Prev. 2024. https://doi.org/10.1158/1055-9965.EPI-24- 1436-1442.
0577. 118. Iversen L, Fielding S, Lidegaard O, Mørch LS, Skovlund CW,
98. Yager JD. Endogenous estrogens as carcinogens through metabolic Hannaford PC. Association between contemporary hormonal
activation. J Natl Cancer Inst Monogr. 2000;(27):67-73. contraception and ovarian cancer in women of reproductive age in
99. Yager JD. Mechanisms of estrogen carcinogenesis: the role of E2/E1- Denmark: prospective, nationwide cohort study. Br Med J. 2018;362:
quinone metabolites suggests new approaches to preventive inter- k3609.
ventionea review. Steroids. 2015;99(Pt A):56-60. 119. Mueck AO, Seeger H, Rabe T. Hormonal contraception and risk of
100. Sampson JN, Falk RT, Schairer C, et al. Association of estrogen endometrial cancer: a systematic review. Endoc Relat Cancer.
metabolism with breast cancer risk in different cohorts of post- 2010;17(4):R263-R271.
menopausal women. Cancer Res. 2017;77(4):918-925. 120. Collaborative Group on Epidemiological Studies on Endometrial
101. Ziegler RG, Fuhrman BJ, Moore SC, Matthews CE. Epidemiologic Cancer. Endometrial cancer and oral contraceptives: an individual
studies of estrogen metabolism and breast cancer. Steroids. participant meta-analysis of 27 276 women with endometrial cancer
2015;99(Pt A):67-75. from 36 epidemiological studies. Lancet Oncol. 2015;16(9):1061-
102. Collaborative Group on Hormonal Factors in Breast Cancer. Breast 1070.
cancer and hormonal contraceptives: collaborative reanalysis of in- 121. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI.
dividual data on 53 297 women with breast cancer and 100 239 A clinical trial of estrogen-replacement therapy after ischemic stroke.
women without breast cancer from 54 epidemiological studies. N Engl J Med. 2001;345(17):1243-1249.
Lancet. 1996;347(9017):1713-1727. 122. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone
103. Collaborative Group on Hormonal Factors in Breast Cancer. Breast replacement therapy on cardiovascular events in recently
cancer and hormonal contraceptives: further results. Contraception. postmenopausal women: randomised trial. BMJ. 2012;345:
1996;54(suppl 3):1s-106s. e6409.
104. Huber D, Seitz S, Kast K, Emons G, Ortmann O. Use of oral contra- 123. Cherry N, McNamee R, Heagerty A, Kitchener H, Hannaford P. Long-
ceptives in BRCA mutation carriers and risk for ovarian and breast term safety of unopposed estrogen used by women surviving
cancer: a systematic review. Arch Gynecol Obstet. 2020;301(4):875-884. myocardial infarction: 14-year follow-up of the ESPRIT randomised
105. Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, controlled trial. Br J Obstet Gynaecol. 2014;121(6):700-705; discus-
Lidegaard Ø. Contemporary hormonal contraception and the risk of sion 705.
breast cancer. N Engl J Med. 2017;377(23):2228-2239. 124. Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of
106. Giaquinto AN, Sung H, Miller KD, et al. Breast Cancer Statistics, 2022. estrogen plus progestin and estrogen alone: analyses of data from 2
CA Cancer J Clin. 2022;72(6):524-541. Women’s Health Initiative randomized clinical trials. JAMA Oncol.
107. Fitzpatrick D, Pirie K, Reeves G, Green J, Beral V. Combined and 2015;1(3):296-305.
progestagen-only hormonal contraceptives and breast cancer risk: a 125. McKee M, Britton A, Black N, McPherson K, Sanderson C, Bain C.
UK nested case-control study and meta-analysis. PLoS Med. Methods in health services research. Interpreting the evidence:
2023;20(3):e1004188. choosing between randomised and non-randomised studies. BMJ.
108. Niemeyer Hultstrand J, Gemzell-Danielsson K, Kallner HK, Lindman H, 1999;319(7205):312-315.
Wikman P, Sundström-Poromaa I. Hormonal contraception and risk of 126. Kunz R, Oxman AD. The unpredictability paradox: review of empirical
breast cancer and breast cancer in situ among Swedish women 15-34 comparisons of randomised and non-randomised clinical trials. BMJ.
years of age: a nationwide register-based study. Lancet Reg Health 1998;317(7167):1185-1190.
Eur. 2022;21:100470. 127. Robinson WR, Nichols HB, Tse CK, Olshan AF, Troester MA. Associa-
109. Heting M, Wenping L, Yanan W, Dongni Z, Xiaoqing W, Zhli Z. Levo- tions of premenopausal hysterectomy and oophorectomy with breast
norgestrel intrauterine system and breast cancer risk: an updated cancer among black and white women: the Carolina Breast Cancer
systematic review and meta-analysis of observational studies. Heli- study, 1993-2001. Am J Epidemiol. 2016;184(5):388-399.
yon. 2023;9(4):e14733. 128. Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the
110. Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal time of hysterectomy and long-term health outcomes in the nurses’
contraceptives and intrauterine contraceptive devices. Am J Obstet health study. Obstet Gynecol. 2009;113(5):1027-1037.
Gynecol. 1999;181(5 Pt 1):1263-1269. 129. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment
111. Committee on Practice Bulletins-Gynecology, Long-Acting Reversible of early breast cancer by hormonal, cytotoxic, or immune therapy.
Contraception Work Group. Practice Bulletin No. 186: long-acting 133 Randomised trials involving 31,000 recurrences and 24,000
reversible contraception: implants and intrauterine devices. Obstet deaths among 75,000 women. Early Breast Cancer Trialists’ Collabo-
Gynecol. 2017;130(5):e251-e269. rative Group. Lancet. 1992;339(8785):71-85.
112. Schreiber CA, Barnhar K. Contraception. In: Strauss JFIII, Barbieri RL, 130. Cuzick J, Ambroisine L, Davidson N, et al. Use of luteinising-hormone-
editors. Yen & Jaffe’s Reproductive Endocrinology. 8th ed. Philadel- releasing hormone agonists as adjuvant treatment in premenopausal
phia, PA: Elsevier; 2019. p. 962-978. patients with hormone-receptor-positive breast cancer: a meta-
113. Landgren BM, Balogh A, Shin MW, Lindberg M, Diczfalusy E. Hor- analysis of individual patient data from randomised adjuvant trials.
monal effects of the 300 microgram norethisterone (NET) minipill. 2. Lancet. 2007;369(9574):1711-1723.
Daily gonadotrophin levels in 43 subjects during a pretreatment cycle 131. Metcalfe K, Lynch HT, Foulkes WD, et al. Effect of oophorectomy on
and during the second month of NET administration. Contraception. survival after breast cancer in BRCA1 and BRCA2 mutation carriers.
1979;20(6):585-605. JAMA Oncol. 2015;1(3):306-313.

146 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025

J. Kim & P. N. Munster Annals of Oncology

132. Parker WH, Feskanich D, Broder MS, et al. Long-term mortality 154. Kelsey JL, Gammon MD, John EM. Reproductive factors and breast
associated with oophorectomy compared with ovarian conservation cancer. Epidemiol Rev. 1993;15(1):36-47.
in the nurses’ health study. Obstet Gynecol. 2013;121(4):709-716. 155. MacMahon B, Cole P, Lin TM, et al. Age at first birth and breast cancer
133. Parker WH, Jacoby V, Shoupe D, Rocca W. Effect of bilateral oopho- risk. Bull World Health Organ. 1970;43(2):209-221.
rectomy on women’s long-term health. Womens Health (Lond). 156. Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years
2009;5(5):565-576. according to risk factor status: data from the Nurses’ Health Study.
134. Eleje GU, Eke AC, Ezebialu IU, et al. Risk-reducing bilateral salpingo- Am J Epidemiol. 2000;152(10):950-964.
oophorectomy in women with BRCA1 or BRCA2 mutations. Cochrane 157. Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role
Database Syst Rev. 2018;8:CD012464. of pregnancy in breast cancer. Breast Cancer Res. 2005;7(3):131-142.
135. Manson JE, Aragaki AK, Bassuk SS, et al. Menopausal estrogen-alone 158. Fu S, Ke H, Yuan H, Xu H, Chen W, Zhao L. Dual role of pregnancy in
therapy and health outcomes in women with and without bilateral breast cancer risk. Gen Comp Endocrinol. 2024;352:114501.
oophorectomy: a randomized trial. Ann Intern Med. 2019;171:406- 159. Azizi M, Ebrahimi E, Moghadam ZB, Shahhosseini Z, Modarres M.
414. Pregnancy rate, maternal and neonatal outcomes among breast
136. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen cancer survivors: a systematic review. Nurs Open. 2023;10(10):6690-
therapy and the risk of invasive breast cancer. Arch Intern Med. 6707.
2006;166(9):1027-1032. 160. Arecco L, Blondeaux E, Bruzzone M, et al. Safety of pregnancy after
137. Kotsopoulos J, Gronwald J, Karlan BY, et al. Hormone replacement breast cancer in young women with hormone receptor-positive dis-
therapy after oophorectomy and breast cancer risk among BRCA1 ease: a systematic review and meta-analysis. ESMO Open. 2023;8(6):
mutation carriers. JAMA Oncol. 2018;4(8):1059-1065. 102031.
138. Shyamala G, Chou YC, Louie SG, Guzman RC, Smith GH, Nandi S. 161. Collaborative Group on Hormonal Factors in Breast Cancer.
Cellular expression of estrogen and progesterone receptors in mam- Menarche, menopause, and breast cancer risk: individual participant
mary glands: regulation by hormones, development and aging. meta-analysis, including 118 964 women with breast cancer from 117
J Steroid Biochem Mol Biol. 2002;80(2):137-148. epidemiological studies. Lancet Oncol. 2012;13(11):1141-1151.
139. Haslam SZ, Shyamala G. Effect of oestradiol on progesterone re- 162. Abraham M, Lak MA, Gurz D, Nolasco FOM, Kondraju PK, Iqbal J.
ceptors in normal mammary glands and its relationship with lacta- A narrative review of breastfeeding and its correlation with breast
tion. Biochem J. 1979;182(1):127-131. cancer: current understanding and outcomes. Cureus. 2023;15(8):
140. Beleut M, Rajaram RD, Caikovski M, et al. Two distinct mechanisms e44081.
underlie progesterone-induced proliferation in the mammary gland. 163. Daniel CW, Silberstein GB, Strickland P. Direct action of 17 beta-
Proc Natl Acad Sci U S A. 2010;107(7):2989-2994. estradiol on mouse mammary ducts analyzed by sustained release
141. Brisken C. Progesterone signalling in breast cancer: a neglected hor- implants and steroid autoradiography. Cancer Res. 1987;47(22):6052-
mone coming into the limelight. Nat Rev Cancer. 2013;13(6):385-396. 6057.
142. Beebeejaun Y, Athithan A, Copeland TP, Kamath MS, Sarris I, 164. Isaksson E, Wang H, Sahlin L, von Schoultz B, Cline JM, von Schoultz E.
Sunkara SK. Risk of breast cancer in women treated with ovarian Effects of long-term HRT and tamoxifen on the expression of pro-
stimulation drugs for infertility: a systematic review and meta-anal- gesterone receptors A and B in breast tissue from surgically post-
ysis. Fertil Steril. 2021;116(1):198-207. menopausal cynomolgus macaques. Breast Cancer Res. Treat.
143. Cullinane C, Gillan H, Geraghty J, et al. Fertility treatment and breast- 2003;79(2):233-239.
cancer incidence: meta-analysis. BJS Open. 2022;6(1):zrab149. 165. Söderqvist G, Isaksson E, von Schoultz B, Carlström K, Tani E, Skoog L.
144. Alper MM, Fauser BC. Ovarian stimulation protocols for IVF: is more Proliferation of breast epithelial cells in healthy women during the
better than less? Reprod Biomed Online. 2017;34(4):345-353. menstrual cycle. Am J Obstet Gynecol. 1997;176(1 Pt 1):123-128.
145. Joo BS, Park SH, An BM, Kim KS, Moon SE, Moon HS. Serum estradiol 166. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and
levels during controlled ovarian hyperstimulation influence the progestins and the risk of breast cancer in postmenopausal women.
pregnancy outcome of in vitro fertilization in a concentration- N Engl J Med. 1995;332(24):1589-1593.
dependent manner. Fertil Steril. 2010;93(2):442-446. 167. Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY. Prevention of Brca1-
146. Wei CX, Zhang L, Pang CH, Qi YH, Zhang JW. Effect of the ratios of mediated mammary tumorigenesis in mice by a progesterone
estradiol increase on the outcome of in vitro fertilization-embryo antagonist. Science. 2006;314(5804):1467-1470.
transfer with antagonist regimens: a single center retrospective 168. Kim O, Park EY, Kwon SY, et al. Targeting progesterone signaling
cohort study. BMC Pregnancy Childbirth. 2023;23(1):134. prevents metastatic ovarian cancer. Proc Natl Acad Sci U S A.
147. Drakopoulos P, Racca A, Errázuriz J, et al. The role of progesterone 2020;117(50):31993-32004.
elevation in IVF. Reprod Biol. 2019;19(1):1-5. 169. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast
148. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. cancer risk in relation to different types of hormone replacement
Luteal phase support for assisted reproduction cycles. Cochrane therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448-454.
Database Syst Rev. 2015;2015(7):CD009154. 170. Fournier A, Mesrine S, Dossus L, Boutron-Ruault MC, Clavel-
149. Williams CL, Jones ME, Swerdlow AJ, et al. Risks of ovarian, breast, Chapelon F, Chabbert-Buffet N. Risk of breast cancer after stopping
and corpus uteri cancer in women treated with assisted reproductive menopausal hormone therapy in the E3N cohort. Breast Cancer Res
technology in Great Britain, 1991-2010: data linkage study including Treat. 2014;145(2):535-543.
2.2 million person years of observation. BMJ. 2018;362:k2644. 171. Stute P, Wildt L, Neulen J. The impact of micronized progesterone on
150. van den Belt-Dusebout AW, Spaan M, Lambalk CB, et al. Ovarian breast cancer risk: a systematic review. Climacteric. 2018;21(2):111-
stimulation for in vitro fertilization and long-term risk of breast can- 122.
cer. JAMA. 2016;316(3):300-312. 172. Horwitz KB, Koseki Y, McGuire WL. Estrogen control of progesterone
151. Arecco L, Blondeaux E, Bruzzone M, et al. Safety of fertility preser- receptor in human breast cancer: role of estradiol and antiestrogen.
vation techniques before and after anticancer treatments in young Endocrinology. 1978;103(5):1742-1751.
women with breast cancer: a systematic review and meta-analysis. 173. Noguchi S, Miyauchi K, Nishizawa Y, Koyama H. Induction of proges-
Hum Reprod. 2022;37(5):954-968. terone receptor with tamoxifen in human breast cancer with special
152. Kapil U, Bhadoria AS, Sareen N, Singh P, Dwivedi SN. Reproductive reference to its behavior over time. Cancer. 1988;61(7):1345-1349.
factors and risk of breast cancer: a review. Indian J Cancer. 174. Castellano-Díaz E, González-Quijano MI, Limiñana JM, Díaz-Chico BN.
2014;51(4):571-576. Tamoxifen decreases the estradiol induced progesterone receptors by
153. Bernstein L. Epidemiology of endocrine-related risk factors for breast interfering with nuclear estrogen receptor accumulation. J Steroid
cancer. J Mammary Gland Biol Neoplasia. 2002;7(1):3-15. Biochem. 1989;33(1):133-139.

Volume 36 - Issue 2 - 2025 https://doi.org/10.1016/j.annonc.2024.10.824 147

Annals of Oncology J. Kim & P. N. Munster

175. Karck U, Kommoss F. Does tamoxifen change oestrogen and proges- cancereis it safe?), a randomised comparison: trial stopped. Lancet.
terone receptor expression in the endometrium and breast? Eur J 2004;363(9407):453-455.
Cancer. 2000;36(suppl 4):S45-S46. 190. von Schoultz E, Rutqvist LE, Stockholm Breast Cancer Study Group.
176. Biçaku E, Marchion DC, Schmitt ML, Münster PN. Selective inhibition Menopausal hormone therapy after breast cancer: the Stockholm
of histone deacetylase 2 silences progesterone receptor-mediated randomized trial. J Natl Cancer Inst. 2005;97(7):533-535.
signaling. Cancer Res. 2008;68(5):1513-1519. 191. Holmberg L, Iversen OE, Rudenstam CM, et al. Increased risk of
177. Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progester- recurrence after hormone replacement therapy in breast cancer
one receptor status significantly improves outcome prediction over survivors. J Natl Cancer Inst. 2008;100(7):475-482.
estrogen receptor status alone for adjuvant endocrine therapy in two 192. Fahlén M, Fornander T, Johansson H, et al. Hormone replacement
large breast cancer databases. J Clin Oncol. 2003;21(10):1973-1979. therapy after breast cancer: 10 year follow up of the Stockholm
178. Arpino G, Weiss H, Lee AV, et al. Estrogen receptor-positive, pro- randomised trial. Eur J Cancer. 2013;49(1):52-59.
gesterone receptor-negative breast cancer: association with growth 193. Coronado PJ, Gómez A, Iglesias E, et al. Eligibility criteria for using
factor receptor expression and tamoxifen resistance. J Natl Cancer menopausal hormone therapy in breast cancer survivors: a safety
Inst. 2005;97(17):1254-1261. report based on a systematic review and meta-analysis. Menopause.
179. Li Y, Yang D, Yin X, et al. Clinicopathological characteristics and breast 2024;31(3):234-242.
cancer-specific survival of patients with single hormone receptor- 194. O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS.
positive breast cancer. JAMA Netw Open. 2020;3(1):e1918160. Hormone replacement therapy after a diagnosis of breast cancer in
180. Gross GE, Clark GM, Chamness GC, McGuire WL. Multiple proges- relation to recurrence and mortality. J Natl Cancer Inst. 2001;93(10):
terone receptor assays in human breast cancer. Cancer Res. 754-762.
1984;44(2):836-840. 195. Mudhune GH, Armour M, McBride KA. Safety of menopausal hor-
181. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. mone therapy in breast cancer survivors older than fifty at diagnosis:
2019;321(3):288-300. a systematic review and meta-analysis. Breast. 2019;47:43-55.
182. Love RR, Philips J. Oophorectomy for breast cancer: history revisited. 196. Poggio F, Del Mastro L, Bruzzone M, et al. Safety of systemic hor-
J Natl Cancer Inst. 2002;94(19):1433-1434. mone replacement therapy in breast cancer survivors: a systematic
183. Buchanan RB, Blamey RW, Durrant KR, et al. A randomized comparison review and meta-analysis. Breast Cancer Res Treat. 2022;191(2):
of tamoxifen with surgical oophorectomy in premenopausal patients 269-275.
with advanced breast cancer. J Clin Oncol. 1986;4(9):1326-1330. 197. Col NF, Kim JA, Chlebowski RT. Menopausal hormone therapy after
184. Nourmoussavi M, Pansegrau G, Popesku J, Hammond GL, Kwon JS, breast cancer: a meta-analysis and critical appraisal of the evidence.
Carey MS. Ovarian ablation for premenopausal breast cancer: a re- Breast Cancer Res. 2005;7(4):R535-R540.
view of treatment considerations and the impact of premature 198. Jacobson M, Mills K, Graves G, Wolfman W, Fortier M. Guideline No.
menopause. Cancer Treat Rev. 2017;55:26-35. 422f: menopause and breast cancer. J Obstet Gynaecol Can.
185. Connolly RM, Miller KD. Back to the beginning: the role of ovarian 2021;43(12):1450-1456.e1.
suppression in management of hormone sensitive breast cancer in 199. Papadakis GE, Hans D, Gonzalez Rodriguez E, et al. Menopausal
premenopausal women. J Clin Oncol. 2023;41(7):1339-1341. hormone therapy is associated with reduced total and visceral
186. Conte CC, Nemoto T, Rosner D, Dao TL. Therapeutic oophorectomy in adiposity: the OsteoLaus cohort. J Clin Endocrinol Metab.
metastatic breast cancer. Cancer. 1989;64(1):150-153. 2018;103(5):1948-1957.
187. Evans DG, Phillips KA, Milne RL, et al. Survival from breast cancer in 200. Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone
women with a BRCA2 mutation by treatment. Br J Cancer. therapy on cognition and mood in recently postmenopausal women:
2021;124(9):1524-1532. findings from the randomized, controlled KEEPS-Cognitive and
188. Ingle JN, Krook JE, Green SJ, et al. Randomized trial of bilateral oo- Affective Study. PLoS Med. 2015;12(6):e1001833; discussion
phorectomy versus tamoxifen in premenopausal women with meta- e1001833.
static breast cancer. J Clin Oncol. 1986;4(2):178-185. 201. The North American Menopause Society. The 2022 hormone therapy
189. Holmberg L, Anderson H. HABITS steering and data monitoring position statement of The North American Menopause Society.
committees. HABITS (hormonal replacement therapy after breast Menopause. 2022;29(7):767-794.

148 https://doi.org/10.1016/j.annonc.2024.10.824 Volume 36 - Issue 2 - 2025