Download Fertility Drugs and Young-Onset Breast cancer

Published by Oxford University Press 2012.
DOI:10.1093/jnci/djs255
Advance Access publication on July 6, 2012.
Article
Fertility Drugs and Young-Onset Breast Cancer: Results From the
Two Sister Study
Chunyuan Fei, Lisa A. DeRoo, Dale P. Sandler, Clarice R. Weinberg
Manuscript received November 30, 2011; revised April 24, 2012; accepted April 30, 2012.
Correspondence to: Clarice R. Weinberg, PhD, Biostatistics Branch, National Institute of Environmental Health Sciences, P.O. Box 12233, Mail Drop A3-03,
Research Triangle Park, NC 27709 (e-mail: [email protected]).
Background
Fertility drugs stimulate hyperovulation, which may have implications for breast cancer. We examined the association between use of fertility drugs (clomiphene citrate [CC] and follicle-stimulating hormone [FSH]) and subsequent risk of young-onset (<50 years at diagnosis) breast cancer.
Methods We conducted the Two Sister Study, a sister-matched case–control study, by enrolling 1422 women between
September 2008 and December 2010, who were younger than age 50 years at diagnosis with breast cancer and
were enrolled within 4 years of diagnosis, and 1669 breast cancer–free control sisters from the Sister Study.
Participants reported their use of fertility drugs (CC and FSH) and ever-users reported whether a pregnancy had
resulted that lasted 10 or more (10+) weeks. Conditional logistic regression was used to estimate confounderadjusted odds ratios (ORs) and 95% confidence intervals (CIs) for fertility drug use with or without conception of
a 10+ week pregnancy.
Results A total of 288 participants reported having used ovulation-stimulating drugs (193 CC only, 29 FSH only, and
66 both). Overall, women who had used fertility drugs showed a non-statistically significantly decreased
risk of breast cancer, compared with nonusers (OR = 0.82, 95% CI = 0.63 to 1.08). Women who had used fertility drugs but had not conceived a 10+ week pregnancy under treatment showed a statistically significantly
decreased risk of breast cancer compared with nonusers (OR = 0.62, 95% CI = 0.43 to 0.89). Women who had used
fertility drugs and conceived a 10+ week pregnancy under treatment showed a statistically significantly increased
risk of breast cancer compared with unsuccessfully treated women (OR = 1.82, 95% CI = 1.10 to 3.00), although
their risk was not increased compared with women who had not used fertility drugs (OR = 1.13, 95% CI = 0.78
to 1.64).
Conclusions
In the absence of a 10+ week pregnancy under treatment, exposure to ovulation-stimulating fertility drugs was
associated with reduced risk of young-onset breast cancer. This apparent association was absent in women who
conceived a 10+ week pregnancy under treatment, for whom risk was higher than that of unsuccessfully treated
women, but similar to that of untreated women.
J Natl Cancer Inst 2012;104:1021–1027
Hormones play an important role in breast cancer. Well-documented
risk factors, such as early menarche, late age at first birth, late menopause, and long-term hormone therapy, are related to the duration of
lifetime exposure to estrogen and progesterone (1,2).
Treatment with ovulation-stimulating fertility drugs causes
recruitment and maturation of multiple ovarian follicles, temporarily elevating estrogen; in women treated with clomiphene citrate (CC), the peak serum levels of estrogen are two- to threefold
higher than normal (average: 200 pg/mL at peak) (3,4), and peak
levels are even higher in women who undergo in vitro fertilization (IVF) treatment, which typically involves the use of folliclestimulating hormone (FSH)-containing drugs (5,6). If pregnancy
results, the supernumerary ovarian corpora lutea produce both
estrogen and progesterone and raise the levels far above normal in
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the first 9 weeks (7,8). It is estimated that 6% of babies born in the
United States in 2005 were conceived with ovulation-stimulating
drugs (9).
The widespread use of ovulation-stimulating fertility drugs
has raised concern about possible implications for breast cancer.
Some, but not all, studies report increased risk following infertility
treatment (10–31). A recent meta-analysis was inconclusive, citing
methodological limitations of previous studies, which included
infrequent use of fertility drugs, unspecified treatments, incomplete
control for confounding, and small numbers of case subjects (32).
Breast cancers in women younger than age 50 years are
rare but can be aggressive and carry a worse prognosis compared with those in older women (33), and distinct risk factors
are associated with such young-onset disease. We conducted a
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sister-controlled study and examined whether use of ovulationstimulating fertility drugs is associated with risk of breast cancer
in women younger than age 50 years. To examine the possible
consequences of the high hormonal exposures experienced in
early pregnancy by women who conceive with ovarian hyperstimulation, we separated fertility-drug exposures according
to whether or not that treatment had resulted in a pregnancy
lasting at least 10 weeks.
Methods
Study Design
The Two Sister Study is a family-based retrospective study of
environmental and genetic factors related to young-onset breast
cancer, which was developed from the Sister Study (http://www.
sisterstudy.org/2Sisters_English/2Sisters.htm). The Sister Study is
an ongoing prospective cohort study of more than 50 000 women
aged 35–74 years, enrolled between 2004 and 2009, who had a
sister diagnosed with breast cancer but had not been diagnosed
themselves at the time of enrollment (http://www.sisterstudy.org).
This study was undertaken to study environmental and genetic risk
factors for breast cancer, using a cohort of women known to be at
increased risk. We identified Sister Study participants whose sister had been diagnosed within 4 years and had been younger than
age 50 years at diagnosis (case sisters), and asked them to forward
to their affected sister our invitation to enroll in the Two Sister
Study. Enrollment was accomplished between September 2008 and
December 2010.
To allow for treatment time, case sisters were not contacted until
at least a year after diagnosis. Each enrolled case sister completed
the same two-part computer-assisted telephone interview (CATI)
on demographics, lifestyle, reproductive factors, health conditions,
and medications as their control sister(s) had when they enrolled
in the Sister Study. In addition, case sisters completed a CATI
on breast cancer diagnosis, tumor characteristics, and treatment,
providing contact information for their medical providers, and
authorizing release of cancer-related medical records.
Of the 3283 families identified as potentially eligible (ie, the
Sister Study participant had reported she had a sister diagnosed
with breast cancer at age younger than 50 years and had been diagnosed within 4 years), 403 Sister Study participants did not respond.
Of the remaining 2880 participants, 91 case sisters were deceased,
and 77 were determined to be ineligible (mostly because the control sister had misreported the case sister’s age at diagnosis or the
4-year limit had been exceeded by the time we made contact). Of
the remaining 2712 families, 2492 Sister Study participants agreed
to send their sister our letter of invitation between 2008 and 2010.
Of those, 411 young-onset case sisters did not respond, 63 declined
to participate, and the remaining 2018 expressed interest. However,
264 of those were then found to be ineligible (mostly because the
time since diagnosis was >4 years). Of the remainder, 1422 of 1754
(81.1%) case sisters who completed all telephone interviews were
included along with their 1669 control sisters, after excluding
20 control sisters who had been more than 7 years younger than
their case sister’s age at diagnosis when they completed their interviews, and for whom there was at least one alternate control sister
available.
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Medical records of cancer diagnosis and treatment were obtained
for 1245 of 1422 (88%) case sisters. Agreement between CATI
self-report and medical records was excellent. The positive predictive value of self-report was 99.5% for invasive cancer, 98.8% for
estrogen receptor–positive (ER+) cancer, 98.9% for progesterone
receptor–positive (PR+) cancer, and 98.8% for ductal carcinoma.
Therefore, for subset analyses restricted to families with specific
tumor characteristics, self-report was substituted when medical
records were unavailable.
Both the Sister Study and the Two Sister Study were approved
by the institutional review boards of the National Institute of
Environmental Health Sciences, National Institutes of Health, and
the Copernicus Group. Written informed consent was provided by
all but 119 case sisters who completed just the telephone interview
and provided verbal consent.
Exposure Assessment
Before the interview, participants were mailed memory aids
including visual cue cards, lists of relevant medications, and
a chronological life calendar to record landmark events, such
as births or major surgeries. Women were asked in the CATI
whether they had ever sought medical help to become pregnant. Women who reported ever taking fertility medications
provided the medication names, when they first took them,
the number of menstrual cycles of use, and whether any
treatment had resulted in a pregnancy lasting 10 or more
(10+) weeks.
Medications were coded using the Slone Drug Dictionary (34),
with linking to active ingredients and American Hospital Formulary
Service (AHFS) drug classes using Pharmacologic–Therapeutic
Classification codes from AHFS. We considered two major types
of ovulation-inducing fertility drugs: CC and gonadotropins
(eg, FSH), identified by class codes 68:16:12:00 and 68:18:02:00,
respectively (Supplementary Table 1, available online). A multicomponent fertility drug, Pergonal, which lacks a class code and
is often used in IVF treatment protocols, was included as “FSH”
because it contains FSH.
Statistical Analysis
In this sister-matched case–control study, case sisters were younger
than age 50 years at diagnosis, whereas the matched control sisters may have been older when they enrolled in the Sister Study.
To ensure comparable opportunity for exposure in within-sibship
comparisons, we assessed time-varying variables with reference
to an “index age,” which was defined for each set of sisters as the
smallest of the numbers reported for the age of the case sister at
diagnosis and the age(s) of her control sister(s) at their completion of the CATIs. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression to
account for sibling matching.
Fertility-drug use was categorized as nonuser, CC only, FSH
only, or both CC and FSH. Because biological consequences
of exposure may differ for users of ovulation-stimulating drugs
who do vs who do not conceive a 10+ week pregnancy with
treatment, we conceptualized seven exposure categories (nonuser,
CC only [conceived vs did not conceive with treatment], FSH only
[conceived vs did not conceive with treatment], and both CC and
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FSH [conceived vs did not conceive with treatment]) based on full
cross-classification. We compared the model that included all seven
unordered categories (using six dummy variables) with a reduced
model that included the four categories for ovulation-stimulating
drugs together with a dummy variable for occurrence of a resulting
stimulated pregnancy (three dummy variables for drugs and one
for stimulated pregnancy). The latter model fit as well and was
adopted as a joint exposure model (Model I). We further collapsed
the four drug-exposure categories to aggregate into just two (users
vs nonusers) and this aggregation caused very little loss of fit. The
final parsimonious model thus included just users vs nonusers of
ovulation-stimulating drugs (Model II).
The exposure parsed in this way has some unusual features: a
stimulated pregnancy by definition can only happen in women with
exposure to ovulation-stimulating drugs; consequently, the relative risk for women with a stimulated pregnancy compared with
women without fertility-drug exposure is estimated as the exponentiated sum of the coefficient for drug use plus the coefficient
for stimulated pregnancy (ie, as the product of the two odds ratios,
one for her drug exposure and one for her pregnancy, given drug
exposure). In addition, the exponentiated coefficient for stimulated
pregnancy is interpretable as estimating the odds ratio for the
pregnancy exposure relative to women with exposure to fertility
drugs who did not conceive.
In further exploratory analyses, subcategories were considered
based on age at first use (<35 vs ≥35 years), and whether the first
treatment came before vs after the first birth. Stimulated pregnancies were also classified according to whether a stimulated pregnancy was their first birth.
We used directed acyclic graphs (35) to identify potential confounders. The following were considered: relative birth order
among participating sisters, education, household income per person, age at menarche (<12, 12–13, ≥14 years), age at first birth (<25,
25–29, 30–34, ≥35 years, or nulliparous), parity (0, 1, 2, ≥3 children),
infertility (had ever been at risk of pregnancy for 12 months without conceiving or had ever sought help to become pregnant), menopausal status (premenopause, postmenopause, and premenopausal
hysterectomy with retained ovarian tissue) at index age, duration of
breast-feeding (treated as a continuous variable), body mass index
(BMI) at ages 30–39 years (<18.5, 18.5–24.9, 25.0–29.9, ≥30.0 kg/
m2), hormonal birth control history (nonuser, user for <10 years,
user for ≥10 years, and user with unknown duration), smoking
(nonsmoker, <1, 1–9.9, ≥10 pack-years) and average alcohol consumption during the previous 10 years (nondrinker, <13, 13–<48,
48–<180, ≥180 drinks/year). Age at first birth (<25, 25–<30, 30–<35,
≥35 years), parity (0, 1, 2, ≥3 children), and duration of breastfeeding were cumulated to the exact index age (in days). Other timevarying variables were cumulated up through index age minus one
(in years). Age at first birth and menopausal status at index age were
included in all models. We adjusted for relative birth order among
participating sisters to account for design-induced differences
between case sisters and control sisters. Other potential confounders (including age at menarche, self-reported BMI at ages 30–39
years, and infertility) had negligible impact on the estimates and
were not included in the final models. Subset analyses were also
performed according to tumor characteristics (invasive, ER+, and
ductal carcinoma; there were more cancers with missing PR status
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than missing ER status [67 vs 26], and the negative predictive value
for self-reported PR status was lower than that for ER, so PR status
was not used in the analyses).
All statistical analyses were carried out using the SAS software,
PHREG procedure, version 9.2 (SAS Institute Inc, Cary, NC).
Maximum likelihood methods were used to estimate the odds
ratios and P values are based on likelihood ratio tests. All statistical
tests were two-sided and P values less than .05 were considered
statistically significant.
Results
The mean age of control sisters was 47.7 years (standard deviation
[SD] = 6.2 years) at enrollment, and the mean age of case sisters
was 44.7 years (SD = 4.0 years) at diagnosis. The youngest age at
diagnosis was 28 years. Of the 1422 case sisters, 621 (43.7%) were
diagnosed before age 45 years, and 203 (14.3%) were diagnosed
before age 40 years. A total of 1185 (84.0%) case sisters had invasive
tumors (n = 12 missing data), 1095 (78.4%) had ER+ tumors (n = 26
missing data), 962 (71.0%) had PR+ tumors (n = 67 missing data),
and 1229 (87.8%) had ductal tumors (n = 23 missing data).
Most (90%) of the families were non-Hispanic white and most
participants (90%) had completed some college (Table 1). Compared
with control sisters, case sisters reported a statistically significantly
(P < .05) younger age at menarche, older age at first birth, were
more likely to report having taken hormonal birth control pills for
Table 1. Characteristics of participant sisters at index age in the
Two Sister Study*
Control sisters
(n = 1669)
Case sisters
(n = 1422)
Non-Hispanic white
Black
Hispanic
Other
Relative birth order among
participating sisters, No. (%)†
1487 (89.1)
75 (4.5)
63 (3.8)
44 (2.6)
1253 (88.1)
71 (5.0)
57 (4.0)
41 (2.9)
First (oldest)
Second
Third or younger
Education, No. (%)
915 (54.8)
610 (36.5)
144 (8.6)
530 (37.3)
792 (55.7)
100 (7.0)
High school or less
Some college but no degree
Associate or technical degree
Bachelor degree
Master or doctoral degree
Household income per person
in US dollars‡, mean (SD)
Age at menarche‡, No. (%)
217 (13.0)
280 (16.8)
253 (15.2)
525 (31.5)
394 (23.6)
$40 179
(25 998)
177 (12.4)
210 (14.8)
200 (14.1)
480 (33.8)
355 (25.0)
$38 780
(24 883)
<12 y
12–<14 y
≥14 y
Parity, No. (%)
276 (16.5)
956 (57.3)
436 (26.1)
268 (18.8)
833 (58.6)
321 (22.6)
358 (21.5)
259 (15.5)
618 (37.1)
433 (26.0)
304 (21.4)
227 (16.0)
554 (39.0)
337 (23.7)
Characteristic
Race, No. (%)
0 child
1 child
2 children
≥3 children
(Table Continued)
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Table 1 (Continued).
Characteristic
Control sisters
(n = 1669)
Case sisters
(n = 1422)
Table 2. Associations of young-onset breast cancer with fertility
drugs and stimulated pregnancies*
Age at first birth among parous
women§, No. (%)
<25 y
25–<30 y
30–<35 y
≥35 y
Total duration of breastfeeding
in weeks, mean (SD)
Body mass index at ages 30–39 y‡,
No. (%)
501(30.0)
465 (27.9)
242 (14.5)
102 (6.1)
46.3 (70.8)
346 (24.3)
423 (29.7)
255 (17.9)
94 (6.6)
44.5 (64.4)
<18.5 kg/m2
18.5–24.9 kg/m2
25.0–29.9 kg/m2
≥30.0 kg/m2
Use of hormonal birth control‡,
No. (%)
53 (3.2)
1157 (69.5)
312 (18.7)
143 (8.6)
Nonuser
<10 y
≥10 y
Unknown duration
Cigarette smoking‡, No. (%)
163 (9.8)
889 (53.4)
590 (35.4)
24 (1.4)
135 (9.5)
700 (49.3)
568 (40.0)
17 (1.2)
Never-smoker
<1 pack-year
1–<10 pack-years
≥10 pack-years
Alcohol drinking in the 10 years
preceding index age‡, No. (%)
1044 (62.6)
148 (8.9)
235 (14.1)
240 (14.4)
859 (60.4)
157 (11.0)
217 (15.3)
189 (13.3)
Nondrinker
<13 drinks/y
13–<48 drinks/y
48–<180 drinks/y
≥180 drinks/y
Menopausal status‡, No. (%)†
143 (8.7)
388 (23.7)
306 (18.7)
425 (25.9)
378 (23.0)
151 (10.7)
313 (22.1)
260 (18.4)
373 (26.4)
318 (22.5)
Premenopausal
Postmenopausal
Premenopausal hysterectomy,
with retained ovarian tissue
1396 (83.7)
147 (8.8)
124 (7.4)
1269 (89.2)
76 (5.3)
77 (5.4)
33 (2.3)
1002 (70.8)
283 (20.0)
98 (6.9)
* Index age was defined as the smallest of the numbers reported for the age
at diagnosis for the case sister and the age(s) at interview of her control
sister(s), to ensure equal opportunity for exposures. All time-varying variables
(parity, age at first birth among parous women, total duration of breastfeeding,
use of hormonal birth control, cigarette smoking, alcohol drinking, and
menopausal status) were defined with reference to the index age, except
household income, which was assessed at the interview.
† P < .01; calculated using two-sided likelihood ratio tests based on conditional
logistic regression.
‡ Missing data: household income per person (46 control sisters and 35 case
sisters), age at menarche (one control sister), parity (one control sister),
duration of breastfeeding (three control sisters), body mass index at age 30
(four control sisters and six case sisters), hormonal birth control (three control
sisters and two case sisters), smoking (two control sisters), alcohol drinking
(29 control sisters and seven case sisters), and menopausal status (two
control sisters).
§ P < .05; calculated using two-sided likelihood ratio tests based on conditional
logistic regression.
more than 10 years, were less likely to have had low BMI at age
30–39 years, and less likely to have experienced menopause before
the index age. There were no substantial differences in education,
parity, breastfeeding, smoking, or alcohol drinking.
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Control
sisters
(n = 1669)
Case sisters
(n = 1422)
No. (%)
No. (%)
Adjusted
OR (95%
CI)†
Adjusted
OR (95%
CI)‡
1511 (90.5) 1292 (90.9)
1.00 (referent)
—
107 (6.4)
86 (6.0)
FSH only
12 (0.7)
17 (1.2)
CC and FSH
39 (2.3)
27 (1.9)
Stimulated
pregnancy
Model II
Nonusers of
fertility drugs
Use of fertility
drug(s)
Stimulated
pregnancy
69 (4.1)
72 (5.1)
0.80 (0.58 to
1.09)
1.40 (0.63 to
3.12)
0.73 (0.43 to
1.24)
—
Variable
Model I
Nonusers of
fertility drugs
CC only
0.61 (0.41
to 0.90)
1.03 (0.44
to 2.40)
0.53 (0.29
to 0.96)
1.82 (1.10
to 3.02)
1511 (90.5) 1292 (90.9)
1.00 (referent)
—
158 (9.5)
130 (9.1)
69 (4.1)
72 (5.1)
0.82 (0.63 to 0.62 (0.43
1.08)
to 0.89)
—
1.82 (1.10
to 3.00)
* ”Young-onset” refers to case sisters diagnosed with breast cancer at age
less than 50 years. Model II is like Model I, except that the drug categories
(use of CC only, use of FSH only, and use of both CC and FSH) have been
aggregated. Model II fits as well based on a non-statistically significant loss
of goodness of fit (P > .30). OR = odds ratio; CI = confidence interval; CC =
clomiphene citrate; FSH = follicle-stimulating hormone; — = not applicable.
† Adjusted for relative birth order among included sisters, age at first birth (with
nulliparous status treated as a separate category), and menopausal status at
index age.
‡ Adjusted for relative birth order among included sisters, age at first birth
(with nulliparous status treated as a separate category), and menopausal
status at index age; stimulated pregnancy was simultaneously included in
the model. Note that we do not show a referent here because the nonusers
are the referent category for effects of drug use with no resulting 10+
week pregnancy, whereas the referent for effects of a 10+ week stimulated
pregnancy is users of ovulation-stimulating drugs who did not have a 10+
week pregnancy.
Women who reported use of CC alone (n = 193 women) or
both CC and FSH (n = 66 women) showed a non-statistically
significantly reduced odds of young-onset breast cancer compared
with nonusers of these drugs (Table 2). However, after adjusting
for exposure to a 10+ week stimulated pregnancy, compared
with nonusers, women who had taken CC only or both CC and
FSH, but without success (ie, without a pregnancy that lasted ≥10
weeks), were less likely to be diagnosed with young-onset breast
cancer (CC only, OR = 0.61, 95% CI = 0.41 to 0.90; CC and FSH,
OR = 0.53; 95% CI = 0.29 to 0.96; Table 2). Use of FSH only (n =
29 women: 17 case sisters and 12 control sisters) without success
was not associated with risk (OR = 1.03, 95% CI = 0.44 to 2.40),
but the number of exclusive users of FSH was small. When the fit
of the model (Model I) that treated the fertility-drug-use histories
as four categories (nonusers, users of CC only, FSH only, or both
CC and FSH) was compared with that of a simpler model where
the ovulation-stimulating drugs were aggregated to form just two
categories (exposed or not), as in Model II (Table 2), the loss of
goodness of fit was not statistically significant (P > .30), indicating
that the effects of CC and FSH were not distinguishable in our
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data. Women with a history of use of fertility drugs (aggregated)
showed a non-statistically significantly decreased risk compared
with women who were nonusers (OR = 0.82, 95% CI = 0.63 to
1.08). However, as shown in Table 2, when the occurrence of
pregnancy was included in the model, women who used fertility
drugs, but had not conceived a 10+ week pregnancy under
treatment, showed a statistically significantly decreased risk of
breast cancer compared with nonusers (OR = 0.62, 95% CI =
0.43 to 0.89). Women who used fertility drugs and had conceived
a 10+ week pregnancy under treatment showed a statistically
significantly increased risk of breast cancer compared with other
users (unsuccessfully treated; OR = 1.82, 95% CI = 1.10 to 3.00;
Table 2). Note that in this model, the comparison for those
treated but without a consequent 10+ week pregnancy is with
women without a history of use of ovulation-stimulating drugs,
whereas the comparison for treated women with a stimulated
10+ week pregnancy is with other (unsuccessfully treated) women
who also used ovulation-stimulating drugs. Overall, women
who received treatment and conceived under treatment did not
Table 3. Associations of invasive estrogen receptor–positive
young-onset breast cancer with fertility drugs and stimulated
pregnancies*
Variable
Control
sisters
(n = 1067)
Case
sisters
(n = 907)
No. (%)
No. (%)
Model I
No fertility-drug 968 (90.7)
use
CC only
67 (6.3)
Adjusted
Adjusted
OR (95%
OR (95% CI)†
CI)‡
816 (90.0)
1.00 (referent)
—
58 (6.4)
0.61 (0.37
to 1.01)
1.20 (0.40
to 3.62)
0.65 (0.32
to 1.32)
2.23 (1.19,
to 4.16)
FSH only
7 (0.7)
11 (1.2)
CC and FSH
25 (2.3)
22 (2.4)
Stimulated
pregnancy
Model II
No fertility-drug
use
Use of fertility
drug
Stimulated
pregnancy
39 (3.7)
51 (5.6)
0.88 (0.60 to
1.31)
1.71 (0.60 to
4.89)
0.99 (0.54 to
1.81)
—
968 (90.7)
816 (90.0)
1.00 (referent)
—
99 (9.3)
91 (10.0)
39 (3.7)
51 (5.6)
0.96 (0.68 to
1.34)
—
0.66 (0.42
to 1.04)
2.23 (1.20
to 4.14)
* “Young-onset” refers to case sisters diagnosed with breast cancer at age
less than 50 years. Model II is like Model I, except that the drug categories
(use of CC only, use of FSH only, and use of both CC and FSH) have been
aggregated. Model II fits as well based on a non-statistically significant loss
of goodness of fit (P > .30). OR = odds ratio; CI = confidence interval; CC =
clomiphene citrate; FSH = follicle-stimulating hormone; — = not applicable.
† Adjusted for relative birth order among included sisters, age at first birth (with
nulliparous status treated as a separate category), and menopausal status at
index age.
‡ Adjusted for relative birth order among included sisters, age at first birth
(with nulliparous status treated as a separate category), and menopausal
status at index age; stimulated pregnancy was simultaneously included in the
model. Note that we do not show a referent here because the unexposed
group is the referent category for effects of drug use with no resulting 10+
week pregnancy, whereas the referent for effects of a 10+ week stimulated
pregnancy is the group with exposure to ovulation-stimulating drugs who did
not have a 10+ week pregnancy.
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have a statistically significantly increased risk of breast cancer
compared with untreated women (OR = 0.62 × 1.82 = 1.13, 95%
CI = 0.78 to 1.64).
We conducted further analyses to explore the factors (menopausal
status at index age, whether or not the first use preceded the first
birth, whether or not their first pregnancy was a stimulated pregnancy, age at first use, ER status of the cancer, and whether or not it
was invasive) that might modify the associations of fertility-drug use
and stimulated pregnancy with risk of breast cancer, and to explore
evidence for a dose–response relationship with the number of treated
cycles or the number of stimulated 10+ week pregnancies. There
were no statistically significant findings (data not shown), but there
was a suggestion of a stronger association with stimulated pregnancy
if it had been their first birth (OR = 2.04, 95% CI = 1.16 to 3.58),
especially if the cancer was invasive and ER+ (OR = 2.69, 95%
CI = 1.32 to 5.49). The class of fertility drug did not appear to modify the association between stimulated pregnancy and risk (P = .86).
In exploratory dose–response analyses, the number of stimulated
pregnancies was not statistically significantly related to risk (P = .13),
nor was the number of treated menstrual cycles (P = .88).
When analyses were restricted to ER+ invasive breast cancer
(n = 907 case sisters), the results were similar (Table 3). Stratification
by combined ER and PR status or restriction to ductal carcinoma did
not substantially modify the associations between fertility drugs and
stimulated pregnancies with risk of breast cancer (data not shown).
Age at first use showed no statistically significant modification
of the associations across categories of fertility drugs. Although
there was some evidence for elevated risk in women who had used
both CC and FSH, with first use after age 35 years (Supplementary
Table 2, available online), the numbers in this category were too
small for reliable inference. The patterns of association were similar for women whose first use of these drugs preceded their first
birth compared with those whose first use came later (data not
shown; Pinteraction = .49).
Discussion
In this sister-matched case–control study, the Two Sister Study, we
analytically differentiated between users of ovulation-stimulating
drugs who conceived vs those who did not conceive under treatment, to account for the fact that there are known hormonal effects
of ovarian stimulation in the first trimester of pregnancy. We
found statistically significantly reduced risk of young-onset breast
cancer in women with a history of unsuccessful use of ovulationstimulating fertility drugs compared with nonusers. Women who
had used fertility drugs and had conceived a 10+ week pregnancy
under treatment were at statistically significantly increased risk of
young-onset breast cancer compared with unsuccessfully treated
women, but had risk similar to that of nonusers.
The most widely used fertility drug, CC, is classified as a selective estrogen-receptor modulator (SERM) and acts as an estrogen
antagonist in the hypothalamus by binding to the ERs and blocking the effects of estrogen (36). Given its mode of action and its
short duration of use, we doubt that unsuccessful cycles of CC use
(usually fewer than six) would plausibly pharmacologically protect
against breast cancer. However, a history of CC use could serve as
a marker for historically lower average endogenous estrogen levels
JNCI | Articles 1025
in women with categories of infertility for which CC is prescribed.
CC is often the preferred first treatment for patients with polycystic ovarian syndrome or suspected ovulatory dysfunction.
Others have reported apparent protection (ie, association with
reduced risk) in women who took CC. In the Nurse’s Health Study
II, women who had undergone CC treatment for ovulatory infertility had reduced risk of breast cancer (15). Some studies have found
increased risk in specified subgroups, such as CC-treated infertile
women with nonovulatory disorders (19) and CC users more than
20 years after treatment (31).
We were unable to distinguish the associations of CC with risk
of breast cancer from those of FSH, which is the primary ovulation
stimulator used in IVF protocols, but we had a few participants
who had only been exposed to FSH and not CC. However, the
point estimate for unsuccessful use of FSH alone was 1.03, suggesting that conception under treatment with FSH could confer
increased risk compared with untreated women (OR = 1.03 × 1.82
= 1.87). Consistent with our data, several studies have reported
increased risk of breast cancer in FSH users (26,30). IVF (using
FSH) is attempted for a diverse array of diagnoses, including
tubal occlusion and male factor infertility. However, for women
with either ovulatory dysfunction or infertility of uncertain cause
but with patent oviducts, FSH is probably prescribed only after
CC has failed. Thus, the small category of women with history
of FSH use but no CC use would likely comprise women with
fertility problems for which CC was not tried because it could
not succeed, such as tubal occlusion, and specific indications for
nonuse of CC might explain a lack of protective association in
these women.
No previous study simultaneously accounted for stimulated
pregnancy and use of fertility drugs, instead effectively aggregating
two very different exposure histories. Our data suggest that exposure to a stimulated pregnancy is enough to undo the reduction in
risk associated with a history of exposure to ovulation-stimulating
drugs. In young women, increased breast cell differentiation during pregnancy can lead to a long-term protective effect. Ovulationstimulating treatment causes abnormally high exposure to ovarian
hormones during the first 9 weeks of pregnancy (7,8) and could
potentially raise risk by modifying breast tissue remodeling (37).
Fourteen of 23 earlier studies followed up infertile women
or women who sought infertility treatment in clinics (13,14,16–
22,25,26,28,29,31), of which one study (comparing women with
IVF-based deliveries to other women delivering during the
same interval in Sweden) found a statistically significant reduced
risk (25) and others found no association or increased risk. Two
studies (11,23) recruited participants who had given birth. The
Jerusalem Perinatal Study reported a borderline statistically significantly increased risk of breast cancer among CC users compared with women who conceived spontaneously (11). A study of
Swedish women with live births found no statistically significant
association with IVF, but the follow-up period was short (23). In
both designs, treated women with stimulated pregnancy would be
overrepresented.
Our sister-based design provided several advantages and
opportunities. Sisters tend to be well matched for social factors,
health care–seeking behaviors, and other unmeasured potential
confounders. We were able to identify and enroll a large sample
1026 Articles | JNCI
of young-onset case sisters by approaching their already-enrolled
unaffected sister. This strategy produced a large sample of highly
motivated participants.
This study has a few limitations. We relied on self-reported
fertility-drug use, and recall bias may be present. We enhanced
recall by providing lists of medication names in the interview
materials. In addition, infertility treatment is a major life event,
and likely to be remembered. A second limitation is that we do
not have data on the specific diagnosis for infertility. However,
reliable information on diagnosis is hard to obtain, because infertility workups are complex, time-consuming, often inconclusive,
and frequently cut short by conception. Patients may be managed empirically (without a definitive diagnosis) with CC, which
is widely regarded as inexpensive, safe, noninvasive, and effective.
Another limitation of our design is that case sisters were on average younger than control sisters. By considering exposures up to
the same index age for both case sisters and control sisters, we
ensured that sisters being compared had similar opportunities
for exposure. Nevertheless, by adopting this strategy, we had to
neglect exposures that may have occurred between the index age
and the age at diagnosis (for case sisters) or the age at interview
(for control sisters). However, only one control sister (and no case
sister) was first exposed to fertility drugs during that interval.
Finally, we delayed contact for at least a year after diagnosis to
allow for treatment and recovery, and some case sisters with more
aggressive cancers may have died before we could contact them.
Although only 91 case sisters were excluded because the control
sister reported they had died, some of the other nonresponders
may have been deceased or too sick, and consequently some of
our findings may not apply to particularly aggressive cancers. The
use of sister controls, however, confers internal validity through
case–control comparisons.
In conclusion, in this sister-based case–control study, a history
of unsuccessful use of ovulation-stimulating fertility drugs was
associated with a statistically significantly reduced risk of youngonset breast cancer, but the occurrence of a stimulated 10+ week
pregnancy appeared to offset the protective association. Use of
fertility drugs, particularly CC, may have pharmacological effects
(38) and could (more plausibly) serve as a marker for a different
hormonal milieu in women with categories of infertility for which
CC is used. For those who achieve conception through treatment,
the elevated production of ovarian hormones early in a stimulated
pregnancy might increase the risk of breast cancer by modifying
pregnancy-related remodeling of breast tissue (37).
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Funding
Intramural Research Program of the National Institutes of Health; National
Institute of Environmental Health Sciences (Z01-ES044005 [CRW] and
Z01-ES102245 [DPS]). Additional funding: Susan G. Komen for the Cure
(FAS0703856 to CRW).
Notes
We thank Dr Donna Baird and Dr Allen Wilcox of the National Institute of
Environmental Health Sciences for helpful comments on the paper.
Aside from receiving yearly progress reports and their original decision to
approve the project, Susan G. Komen for the Cure had no role, and the authors
are responsible for the design and conduct of this study; collection, analysis, and
interpretation of the data; and preparation of this article.
Affiliations of authors: Biostatistics Branch (CF, CRW) and Epidemiology
Branch (LAD, DPS), National Institute of Environmental Health Sciences,
Research Triangle Park, NC.
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