ARTICLE IN PRESS
THE BREAST
The Breast 16 (2007) S175S181
www.elsevier.com/locate/breast
Original Article
Fertility and adjuvant treatment in young women with breast cancer
Ann H. Partridge, Kathryn J. Ruddy
Dana-Farber Cancer Institute, Brigham and Womens Hospital, Harvard Medical School, 44 Binney Street, D1210 Boston, MA 02115, USA
Abstract
Women of childbearing age with breast cancer are often concerned about whether they will become infertile after treatment, and for
those who wish to bear children, whether a subsequent pregnancy will alter their risk of disease recurrence. The risk of chemotherapyrelated amenorrhea (CRA), menopause, and infertility appear to be related to patient age and type of treatment received, though data
regarding actual fertility following treatment are limited. There are options available for fertility preservation for young women who wish
to have a biologic child after breast cancer and are at risk for infertility. Options include cryopreservation of embryos, oocytes, ovarian
tissue prior to treatment, and ovarian suppression through chemotherapy. However, most of these are considered experimental, and
there are limited data regarding the safety of such strategies. There has been concern that pregnancy after breast cancer may worsen
prognosis in light of the endocrine manipulations used to treat breast cancer, particularly for women with hormone sensitive disease.
Several studies addressing the potential risk of pregnancy after breast cancer have not revealed any negative effect on prognosis.
However, these studies have signicant limitations, and concerns about a negative impact for some remain. Ongoing and future
prospective studies evaluating fertility and pregnancy issues for young breast cancer survivors are warranted for this vulnerable
population facing this difcult issue.
r 2007 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer; Young women; Fertility; Amenorrhea; Pregnancy
Introduction
Young women with breast cancer face a variety of
unique medical and psychosocial concerns as a result of
their diagnosis and subsequent treatment. In addition to
being at higher risk of dying from breast cancer than older
women, young women with breast cancer have an
increased risk of psychosocial distress at diagnosis and in
follow-up.1,2 Fertility and family planning, in particular,
are extraordinarily important issues for the younger patient
population.1,3,4 These concerns may contribute to the
greater psychosocial distress that younger women experience with the diagnosis and treatment of breast cancer.5,6
Breast cancer treatments have long been known to affect
menstrual status and fertility among premenopausal
women diagnosed with breast cancer. Premenopausal
women may become amenorrheic due to systemic breast
cancer treatment, resulting in potential loss of fertility,
onset of menopausal symptoms, problems with sexual
Corresponding author. Tel.: +1 617 632 3800; fax: +1 617 632 1930.
0960-9776/$ - see front matter r 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.breast.2007.07.029
functioning, and exposure to the long-term health risks of
early menopause. Because the vast majority of women with
breast cancer are diagnosed after childbearing age, and in
light of the only recent widespread attention to this
important cancer survivorship issue, there are only limited
data available regarding actual fertility for young women
with breast cancer.
Risk of chemotherapy-related amenorrhea (CRA)
and menopause
The risk of CRA, menopause, and infertility appear to
be related to patient age and type of treatment received.
The human ovary has a xed number of primordial
follicles, which is maximal at 5 months gestation and
declines with age. The rate of decline rises when a woman
reaches age 37 years; on average, this precedes menopause
by approximately 1214 years. There are multiple mechanisms by which chemotherapy may cause ovarian damage.
Dividing cells are vulnerable to the actions of most
cytotoxic agents. Drugs may also interrupt follicular
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A.H. Partridge, K.J. Ruddy / The Breast 16 (2007) S175S181
S176
maturation. In general, alkylating agents, including cyclophosphamide, present the greatest potential for impaired
fertility.7 Alkylating agents are not cell-cycle specic, so
they may affect cells that are not actively dividing including
oocytes and pregranulosa cells of primordial follicles. The
degree of damage will determine whether amenorrhea is
temporary or permanent. If fewer oocytes remain after
chemotherapy, periods may be irregular and menopausal
symptoms may occur. If no oocytes remain viable, periods
may cease altogether and menopause will ensue.
CRA may be reversible in that some women will resume
menstrual function months or occasionally years after
treatment. However, the vast majority of women who
remain amenorrheic 1 year following treatment will not
regain ovarian function. While standard endocrine therapies such as tamoxifen or ovarian suppression do not
generally cause ovarian toxicity, they involve years of
treatment during which time a womans fertility will be
declining naturally with age.8 Despite the importance of
menstrual functioning and fertility for many young women
with breast cancer, the available data regarding CRA are
limited by heterogeneity across studies regarding the
denitions of amenorrhea and menopause, use of amenorrhea as a surrogate for fertility, and lack of long-term
follow-up. Nevertheless, some conclusions can be drawn.
Table 1 presents approximate risks of CRA with common
breast cancer regimens by age group from published
studies. The risk of amenorrhea varies substantially with
age and regimen. For example, risk of CRA is less than
15% in women treated with doxorubicin and cyclophosphamide (AC) under age 40, but nearly 60% for women
treated in the older premenopausal years. The cyclophosphamide-methotrexate-5-uorouracil (CMF) regimen
appears to be more gonadotoxic, with rates of amenorrhea
at 12 months after chemotherapy in the 3040% range for
women under 40 and 7590% for women over 40.
Cyclophosphamide-epirubicin-5-uorouracil (CEF) or cyclophosphamide-doxorubicin-5-uorouracil (CAF/FAC)
or may be even more gonadotoxic than CMF, with rates
of CRA at 1 year 4050% in the under 40 age group and
90100% in those 40 and older.9 A recent prospective
cohort survey study evaluated 595 women ages 2540 years
old treated for early breast cancer with different chemotherapy regimens. AC, ACT (doxorubicin-cyclophosphamide-paclitaxel), and TAC/ACD (doxorubicinTable 1
Risk of chemotherapy-related amenorrhea in follow-up with common
standard chemotherapy regimens811,14,56
Treatment
Age o30
Age 3040
Age 440
None
AC 4
CMF 6
CAF/CEF 6
TAC 6
AC 4, T 4
0
19
o5
13
3138
2025
5763
7696
8089
2347
62
38 (15% age o40)
cyclophosphamide-docetaxel) use less total cyclophosphamide than FAC/CAF and CMF do. This study revealed
that menstrual cycles were more likely to persist among
women treated with regimens that contained less total
cyclophosphamide.10 While women who were on CMF
were more likely than those on AC, ACT, or TAC to bleed
during the 1 month following chemotherapy (approximately 50% vs. 20%, odds ratio 2.9, 95% CI 1.75), 1 year
later the likelihood of menses was lower in the CMF group
(OR 0.37, 95% CI 0.370.67).
The impact of treatment duration and dose density, as
well as of newer drugs, remains uncertain. In the cohort
study by Petrek et al., there was a suggestion that the
addition of docetaxel to AC regimens may increase the risk
of CRA with short-term follow-up.10 In a randomized
comparison of TAC vs. FAC for women with nodepositive early breast cancer, amenorrhea occurred among
62% of premenopausal women in the group receiving TAC
compared to 52% of premenopausal women randomized
to FAC (p 0.007). 11 Several studies have evaluated the
impact of the addition of paclitaxel.10,1215 These limited
data suggest that when controlling for age, the effect of
adding paclitaxel to AC-type chemotherapy has little if any
effect on the subsequent risk of CRA. One preliminary
study evaluating the risks of newer treatments and
schedules including the addition of paclitaxel to AC, dose
density (i.e., giving chemotherapy every 2 weeks rather
than every 3 weeks) and the addition of trastuzumab
revealed no substantial effect of these newer regimens on
the risk of CRA.15 Future research evaluating more
modern adjuvant therapy regimens would be of great
value, and prospective evaluation of the risk of CRA in the
context of future clinical trials should be considered in
studies that include premenopausal women.
While many young women with breast cancer will
remain premenopausal after adjuvant treatment, the
duration of the premenopausal status, and associated
fertility, may be shortened. In a retrospective analysis of
long-term follow-up data from International Breast Cancer
Study Group (IBCSG) Trials V and VI, Partridge et al.16
recently evaluated the time to menopause among premenopausal women with early breast cancer. In evaluating
women who had reported that they were menstruating
in months 1224 after diagnosis (N 767), this analysis
found that women who had received 6 or 7 cycles of
CMF chemotherapy had a median age of menopause that
was younger than women who received little or no
chemotherapy. For example, women diagnosed and
treated under age 40 had a median age of menopause of
41, whereas young women who received 0 or 1 cycle of
CMF had a median age of menopause of 44. While it is
not clear that these data apply to women treated with
more modern regimens, the potential for delayed but
nevertheless premature menopause should be considered when assisting young women with their treatment
and family planning decisions both at diagnosis and in
follow-up.
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Another important limitation to available studies is the
use of surrogate measures of fertility such as presence or
absence of menstrual periods. Interruptions in menstrual
bleeding are not particularly sensitive or specic for
ovarian reserve, and continued menstruation is a poor
surrogate for continued fertility, especially as women
age.17,18 In the general population, there are low rates of
conception in women over 45 despite the fact that many
menstruate into their 50s. Women may be infertile for 510
years before menses cease. Women with decreased ovarian
reserve often have shorter, more regular, cycles due to
accelerated follicle development. Measurement of hormonal levels (e.g., follicle-stimulating hormone FSH, luteinizing hormone LH, estradiol, inhibin B, anti-mullerian
hormone AMH), and evaluation of antral follicle count
and ovarian volume by transvaginal ultrasound may be
better predictors of ovarian function. However, hormonal
treatments for breast cancer interfere with many of these
indicators. And, even when women are not receiving
hormonal therapy, no particular laboratory test or imaging
modality is a perfect reection of a womans ability to
become pregnant in the future. Accurate assessment of
ovarian function has implications not only for family
planning, but also for issues related to contraception and
optimal breast cancer treatment, especially in the era of
aromatase inhibitor therapy for post-menopausal women
with hormone receptor-positive disease. Further research
in this area is warranted particularly with regard to the
effects of newer regimens on ovarian function and to
determine better predictors and more reliable measures of
ovarian function among breast cancer survivors.
Strategies to preserve fertility for women with breast cancer
Recognizing the importance of future biologic children
among many young patients with cancer, the American
Society of Clinical Oncology (ASCO) recently convened an
expert panel to develop guidelines for fertility preservation.7 For women with breast cancer, the issue of fertility
preservation is more complex than in other cancers because
of concerns that fertility preservation strategies, and/or
subsequent pregnancy, may increase risk of cancer
recurrence particularly among women with hormone
receptor-positive disease. Nevertheless, young women with
breast cancer who are interested in future fertility should
consider carefully the actual anticipated benets of
adjuvant systemic therapy against the risk of infertility,
and importance of future fertility to her. Forgoing
treatment in low risk, low benet situations may be a
reasonable option for some women. For those women who
do need to undergo adjuvant chemotherapy, suppression of
ovarian function through hormonal manipulation of the
pituitarygonadal axis during cytotoxic treatment has been
considered as a strategy to preserve ovarian function in
young women with cancer. Oral contraceptives have been
evaluated in limited studies of patients with cancers with no
clear protective effect found.19,20 In light of concerns that
S177
exogenous hormones may increase the risk of recurrence or
promote the development of a second primary even in
women with a history of hormone receptor-negative
disease, there is little enthusiasm for evaluating this
strategy among women with breast cancer. Multiple small
studies have evaluated the utility of LHRH-agonists to
preserve ovarian function during cytotoxic therapy, including among women with breast cancer. This research
has suggested that receipt of LHRH-agonists throughout
treatment may increase a womans likelihood of remaining
premenopausal after chemotherapy.2124 However, available studies are limited by small sample size, lack of a
randomized control group, and lack of denitive information regarding actual fertility outcomes. Some have also
failed to show any difference in rates of amenorrhea.25,26
Randomized controlled trials are currently underway
internationally to evaluate this strategy in women with
cancer. The Southwestern Oncology Group is running an
ongoing randomized evaluation among women with
hormone receptor-negative Stage I-IIIA breast cancer to
receive or not receive goserelin through treatment
(www.cancer.gov/clinicaltrials/SWOG-S0230). In the UK,
the OPTION trial is similar, but is also including women
with hormone receptor-positive disease (www.isdscotland.
org/isd/1663.html). The prognostic effect of continued
menstrual cycling, particularly for women with hormone
receptor-positive breast cancer, is an important consideration if this strategy for fertility preservation is successful.
There is evidence that amenorrhea is associated with
improved prognosis compared to continue menstruation
through chemotherapy.9,27 However, it is not clear whether
this will be the situation for women who receive tamoxifen.
The potential benet of ovarian suppression in addition to
tamoxifen for women with hormone receptor-positive
breast cancer is currently under active investigation in the
SOFT trial (www.ibcsg.org). Other promising agents under
evaluation for fertility preservation include GNRH antagonists and anti-apoptotic agents such as sphingosine1-phosphate. However, if ovarian suppression through
chemotherapy ultimately does preserve fertility, a woman
who is interested in fertility preservation might have to
weigh the potential risks of this strategy against the
likelihood that it would improve her chance of having a
biologic child in the future.
Embryo cryopreservation is a standard, widely available
treatment for infertility that may be used for fertility
preservation in women with breast cancer. Although
success rates are slightly lower than with transfer of fresh
embryos, women who have a partner or want to use donor
sperm can undergo ovarian stimulation and oocyte
harvesting, followed by in vitro fertilization (IVF) and
freezing of embryos in order to plan pregnancy after breast
cancer treatment is completed. This strategy may be
expensive and may not be covered by insurance for some
women. Further, ovarian stimulation and oocyte harvesting may necessitate a delay of 26 weeks prior to beginning
adjuvant treatment.7 There has been concern that the high
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hormonal levels resulting from conventional ovarian
stimulation protocols for IVF may increase the risk of
recurrence for a woman with hormone receptor-positive
breast cancer. Estradiol levels during traditional stimulated
IVF cycles are 2000 pg/ml, while levels are only 200 pg/ml
in the normal menstrual cycle. However, the embryo yield
with natural cycle IVF (e.g., without exogenous hormonal stimulation) is extremely low.28 Therefore, ovarian
stimulation protocols designed to mitigate potential risk
have been evaluated including the use of tamoxifen or
aromatase inhibitors for ovarian stimulation prior to
oocyte harvesting and IVF. In a study of 36 young women
with breast cancer desiring future fertility, Oktay et al.28
compared novel ovarian stimulation regimens: tamoxifen
alone, tamoxifen plus FSH, and letrozole plus FSH.
Tamoxifen plus FSH produced higher estradiol levels than
the other two regimens, although any potential negative
effect of this might be offset by the estrogen receptor
blockade by tamoxifen. Letrozole plus FSH resulted in the
lowest levels of peak estradiol, and both tamoxifen- and
letrozole-based stimulation strategies produced a reasonable number of embryos. Patients undergoing these
procedures had similar outcomes in limited follow-up
compared with a historical control group. However,
further research is warranted to understand more fully
the risks and benets of this strategy. Further, embryo
cryopreservation does carry the potential ethical dilemma
of what to do with the resultant embryos if a patient dies
prior to their use.
For patients who do not have a partner and do not wish
to create embryos using donated sperm, oocyte cryopreservation is an option available at a limited number of
centers. To date, oocyte freezing has had limited success
due to technical difculties including crystal formation
within the oocyte causing cytoplasmic damage, sensitivity
to temperature changes, dopolymerization of the meiotic
spindle by cryoprotectants leading to aneuploidy, and
hardening of the zona pellucida with resulting difculty
with fertilization. Success rates are only 20% even at the
most experienced centers, 34 times lower than with
embryo cryopreservation.29,30 Similar to embryo cryopreservation, oocyte cryopresevation may be expensive and
necessitate a delay in beginning treatment, and this strategy
also requires ovarian stimulation in a patient at risk for
micrometastases and disease recurrence.31 Ethical issues
are less problematic with oocyte cryopreservation than
when embryos are stored. In light of the limited success
rate of this strategy to date and associated concerns, oocyte
cryopreservation should be considered experimental and
only conducted at specialized centers under IRB-approved
protocols.
Ovarian tissue cryopreservation for future orthotopic or
heterotopic reimplantation and stimulation is another
method under study for fertility preservation prior to
cancer treatment.32 Case reports of its use and success in
producing offspring have been published, though the
worldwide experience is extremely limited.3336 It appears
that approximately 70% of transplanted ovarian follicles
survive in younger patients, with fewer surviving in older
patients. However, there is a risk of ischemia-reperfusion
injury on reimplantation despite improving techniques, and
in some young women, removal of ovarian tissue for this
highly experimental technique may result in more compromised natural fertility in the future than may have been the
case had ovarian tissue not been removed. There is also a
theoretical risk that reimplanted ovarian tissue may harbor
breast cancer micrometastases that would increase the risk
of recurrence in a woman after successful adjuvant
treatment for breast cancer. Given this concern, technical
difculties, and the limited worldwide experience with this
technique, this option should also only be conducted under
IRB-approved protocols at the present time.
For some patients, a combination of fertility preservation strategies may be the best choice. However, given the
complicated psychosocial and medical issues facing young
breast cancer survivors, the potential risks and technical
difculties associated with available fertility preservation
options, further research to understand the actual number
of babies resulting from these strategies that otherwise
would not have been born is warranted.37
Safety and outcomes of pregnancy after breast cancer
There has been concern that pregnancy after breast
cancer may worsen prognosis, especially among women
with hormone receptor-positive disease. To date the effect
of subsequent pregnancy after a diagnosis of breast cancer
on prognosis including relapse and survival has not been
reported prospectively. Evidence from several retrospective
studies on pregnancy following breast cancer has not
shown a decrement in survival or an increase in risk of
recurrence, however these studies are all limited by
signicant biases and concerns remain for some women.3850 Table 2 presents recent studies evaluating
survival among breast cancer survivors who had a
subsequent pregnancy compared to survivors who did
not have a pregnancy after breast cancer. Although not all
Table 2
Recent studies evaluating safety of pregnancy after breast cancer
Study
Sankila et al.39
von Schoultz
et al.40
Kroman et al.38
Velentgas et al.43
Gelber et al.46
Mueller et al.48
Blakely et al.39
Ives et al.49
Number of
breast cancer
survivors with
subsequent
pregnancy
Number
of
controls
Relative risk
(95% CI) of
recurrence or
death
91
50
471
2119
0.20 (0.100.50)
0.48 (0.181.29)
173
53
94
438
47
123
5514
265
188
2775
323
2416
0.55
0.80
0.44
0.54
0.70
0.59
(0.281.06)
(0.302.30)
(0.210.46)
(0.410.71)
(0.251.95)
(0.370.95)
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studies reach statistical signicance, they all suggest that
women who have a pregnancy after breast cancer may fare
better with regard to disease outcomes than women who do
not. In a recently published study by Ives et al., 2539
women under 45 years old in Western Australia diagnosed
with breast cancer between 1982 and 2000 were evaluated
for subsequent pregnancy and disease outcomes.50 In this
study, 123 out of the 2539 women (5%) became pregnant
after breast cancer, and only 50 (41%) of these women had
received chemotherapy. Similar to previous studies, Ives
and colleagues found that women who had a pregnancy
after breast cancer were more likely to be alive in followup. This effect was stronger if a woman waited at least 2
years after diagnosis to have a pregnancy (HR for death
0.48, 95% CI 0.270.83), but was also present at trend level
if the delay was between 6 and 24 months (HR 0.45, 95%
CI 0.161.28). While these data are reassuring, all studies
are confounded potentially by the healthy mother effect,
that women who are able to have a pregnancy after breast
cancer are healthier and less likely to develop a recurrence
than those who do not, independent of the pregnancy.39
However, it is possible that there is a benecial biologic
effect from the high hormonal levels of pregnancy.
Conventionally, high dose estrogen and progestins have
been used as a treatment modality for breast cancer. And
there has been an anti-tumor effect seen in in vitro and
animal models, possibly due to signaling via the insulin
growth factor pathway.51 Conducting a randomized
controlled trial of pregnancy after breast cancer to answer
this question more denitively would be obviously unethical. Ongoing prospective studies may help to elucidate
further the potential risks and benets of pregnancy after
breast cancer. A common recommendation is that women
wait at least 2 years after treatment is completed before
attempting conception, primarily because this is the time
of highest risk of aggressive breast cancer recurrence.
However, the available data have not revealed any
detriment in disease outcomes from becoming pregnant
sooner. Given that many women with breast cancer are at
risk of recurrence long beyond the rst few years after
diagnosis, and that fertility wanes with age, some women
may elect not to wait a substantial period of time to
become pregnant after diagnosis. For women with
hormone receptor-positive disease, a 5-year delay is usually
recommended in order for women to receive standard
duration hormonal therapy. However, this approach is
problematic for many women given the concerns about
declining fertility, and some may elect to forgo some of the
benet of hormonal therapy, and come off treatment early
to try to become pregnant in follow-up.
Whether a breast cancer survivor who is interested in
future fertility ultimately becomes pregnant is complicated
by a range of medical and psychosocial issues. There are
sparse data on actual fertility and pregnancy outcomes
among women with a history of breast cancer. Findings
from select populations of young women with breast
cancer suggest that approximately 515% of young breast
S179
cancer survivors will become pregnant at least once after
their diagnosis.22,52
Although an increased rate of birth defects might be
expected among offspring conceived using eggs exposed to
potentially mutagenic drugs, none has been found, though
data are limited in adult cancer populations. It is reassuring
that three large studies including nearly 4000 total
offspring of childhood cancer survivors, excluding clearly
hereditary cancers like retinoblastoma, revealed no statistically signicant increase in cancers or malformations.53
There are also concerns that women who have been treated
with cytotoxic agents in the past may be at increased risk of
peripartum complications (e.g., risk of cardiomyopathy of
pregnancy in a woman previously treated with an anthracycline and trastuzumab) although there are no available
data, and future research in this area is warranted. Given
these concerns, it is prudent for women with a history of
breast cancer treatment to receive high risk obstetrics
care during a pregnancy.
Addressing patient concerns
Young women facing a diagnosis of breast cancer are
often alarmed by the potential impact of treatment on their
future fertility. Their complex medical issues are tied to
complex emotional consequences, with desire for future
pregnancies potentially impacting their treatment decisions.4 In a recent survey by Thewes et al. of 228 women
under age 40 at diagnosis, 71% of breast cancer survivors
recalled discussing fertility issues with a health professional
at the time of diagnosis.54 Duffy et al. surveyed 166 breast
cancer patients diagnosed at age 50 or younger and found
that only 34% recalled a discussion with a physician about
fertility, though 68% recalled a discussion about menopause.55 In a survey of 657 women who were diagnosed
with breast cancer at age 40 or younger, Partridge et al.
found that 57% described fertility as a major concern, but
only 51% said that fertility issues had been adequately
addressed by their healthcare providers.4 Thewes et al. also
found that women want to discuss fertility issues both at
the time of treatment decision-making and in follow-up.54
Clearly it is important for health care providers to address
the possibility of infertility with every premenopausal
woman with breast cancer, and refer to a fertility specialist
as needed. Options for preserving fertility should be
explored early, so as to minimize delays in beginning
treatment that may be required for fertility preservation
strategies. Because a short delay before chemotherapy is
unlikely to worsen outcomes among women with early
breast cancer (unlike in more acute disease situations such
as leukemia), avenues for fertility preservation are particularly relevant in this disease.
Conclusions
Fertility after the diagnosis and treatment of breast
cancer is one of the most difcult issues facing young breast
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cancer survivors and their clinicians. The difculty is
compounded by the relative lack of denitive information
regarding several important outcomes. Given the continued uncertainty, patient preferences regarding their future
fertility, and the desire to have a biologic child should be a
critical factor for women as they make their breast cancer
treatment decisions both at diagnosis and in follow-up.
Clinicians caring for young women should be aware of
these concerns and address fertility issues early on in their
care, and risk of infertility should be considered in the riskbenet analysis for treatment.
Conict of interest statement
16.
17.
18.
19.
20.
None declared.
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