THEMED ARTICLE y Breast Cancer Review

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Motherhood after breast

cancer: searching for
la dolce vita
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Expert Rev. Anticancer Ther. 11(2), 287–298 (2011)

Hatem A Azim Jr†1, Advances in the field of adjuvant therapy in breast cancer have led to significant improvements
Fedro A Peccatori2, in breast cancer survival. This has resulted in a progressive decline in breast cancer-related
Evandro de Azambuja1 mortality, such that in 2010 there were estimated to be 400,000 breast cancer survivors under
the age of 40 in the USA. Hence, enquiry into the feasibility of fertility preservation, subsequent
and Martine J Piccart1
pregnancy and breastfeeding is increasingly encountered. Fertility counseling remains suboptimal
1
Department of Medical Oncology,
in breast cancer clinics, and there is a wide perception that pregnancy could worsen the
Jules Bordet Institute, Boulevard de
Waterloo, 121, 1000 Brussels, Belgium prognosis of young breast cancer survivors, despite the lack of evidence supporting this notion.
2
Department of Medicine, Division of In addition, fertility preservation by means of embryo or oocyte cryopreservation requires
Hematology Oncology, European ovarian stimulation, which is associated with a significant rise in estradiol levels and might delay
Institute of Oncology, Milan, Italy
†
Author for correspondence:
initiation of therapy. All these factors, and others, have influenced the quality of fertility
Tel.: +32 2541 3099 counseling offered to young breast cancer patients. In this article, we will critically analyze the
Fax: +32 2541 3477 available clinical and biological evidence on the safety and feasibility of pregnancy and
For personal use only.

hatem.azim@bordet.be
breastfeeding following breast cancer. In addition, we will discuss the different fertility-
preservation techniques available for these patients.

Keywords : breastfeeding after breast cancer • fertility counseling • fertility preservation • pregnancy after
breast cancer

Breast cancer in young women tends to be more
aggressive compared with their older counter-
parts [1–4] . Young breast cancer patients are more
often diagnosed with node-positive and triple-
negative disease, and consequently adjuvant
chemotherapy is more frequently considered
in these patients [1,2] . However, advances in the
field of adjuvant therapies have improved breast
cancer survival and significantly reduced the risk
of recurrence, such that there were an estimated
400,000 breast cancer survivors below the age
of 40 years in the USA in 2010 [5] .
Given the rising trend of delaying pregnancy
to later in life [6] , more women are diagnosed
with breast cancer before completing their fami-
lies. Therefore, patient enquiry into fertility-pres-
ervation techniques, chances of future concep-
tion, pregnancy and breastfeeding is increasingly
encountered nowadays in breast cancer clinics.
An internet-based survey has pointed out that
more than 50% of young women have fertility
concerns upon being diagnosed with breast can-
cer [7] . However, unfortunately, fertility counsel-
ing for these women remains unsatisfactory and
lacks a standardized approach [8,9] . The lack of
strong evidence on one hand, and conceptual
fears that subsequent pregnancy and breastfeed-
ing could worsen breast cancer outcome on the
other, interfere with the wishes of many breast
cancer survivors to start or complete their fami-
lies [10] . Hence, there is indeed an urgent need to
provide more robust recommendations on how
to properly counsel these women [8] . In this arti-
cle, we will critically discuss in detail the safety
and feasibility of pregnancy and breastfeeding
following completion of breast cancer therapy.
We will also touch on advances in the field of
fertility preservation.
Risk of amenorrhea following adjuvant
systemic therapies
Normally, there is a progressive loss of oocytes
from fetal life through menopause [11] . At the
age of 37 years, there is accelerated atresia of the
oocytes, resulting in an average age of meno-
pause of around 51 years in Western nations
[11,12] . The situation is quite different in breast
cancer patients, because adjuvant systemic
anticancer therapy, particularly chemotherapy,
significantly increases the risk of developing

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 Review Azim Jr, Peccatori, de Azambuja & Piccart
early menopause [13] . Earlier work by Partridge and colleagues
involving 767 breast cancer patients under the age of 40 years
has shown that those who received one or six cycles of cyclo-
phosphamide, methotrexate and 5-flourouracil, and resumed
their menses afterwards developed menopause at 44 and 41 years
of age, respectively (p < 0.0001) [14] . The same group went on
to show that those women whose menses resumed had reduced
ovarian reserve when compared with population age-matched
controls [15] .
Chemotherapy induces temporary amenorrhea in the major-
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ity of patients. Menses are resumed in some, with resumption
occurring within 6 months following chemotherapy cessation
for approximately 60% of those patients, and within 12 months
for 90% [16] . Thus, amenorrhea for more than 1 year follow-
ing chemotherapy cessation could be regarded as permanent,
chemotherapy-induced menopause. The main determinant of
developing permanent menopause following chemotherapy is
age [13] . It is estimated that approximately 50–90% of women
above the age of 40 years will develop permanent menopause
secondary to chemotherapy, which will vary according to the
number of chemotherapy cycles and the drugs used, particularly
the cumulative dose of cyclophosphamide. The risk is significantly
lower in younger women (i.e., <40 years of age), ranging from
15 to 45% [17–19] . Newer regimens utilizing taxanes, dose-dense
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administrations and trastuzumab did not appear to increase the
risk of amenorrhea observed with older regimens [16,20] . Table 1
summarizes the risk of amenorrhea associated with different
­chemotherapy regimens.
Pregnancy & its relationship with breast cancer
There is a strong body of evidence linking pregnancy to the risk
of developing breast cancer [21] . This started centuries ago, when
it was noted that nuns had an elevated breast cancer risk [22] .
This observation led to the hypothesis that pregnancy is protec-
tive against breast cancer, which was subsequently supported by
numerous epidemiological studies [23–25] . One outcome of these
studies was the finding that the protective effect is not immedi-
ate and that there is a transient increase in breast cancer risk for
a few years following pregnancy. This was clearly demonstrated
in a large population-based study from Norway involving more
Table 1. Risk of chemotherapy-induced amenorrhea
according to age.
Chemotherapy Age <30 years Age 30–40 Age >40 years
regimen (%) years (%) (%)
AC × 4 13 57–63
CMF × 6 19 31–38 76–96
CAF/CEF × 6 23–47 23–47 80–90
FEC 100 × 6 †
76.3 76.3
FEC 100 × 3 – D × 3 †
63.5 63.5
†
Values provided are for premenopausal patients and are not age specific.
AC: Doxorubicin, cyclophosphamide; CAF: Cyclophosphamide, doxorubicin, 5-fluorouracil;
CEF: Cyclophosphamide, epirubicin, 5-fluorouracil; CMF: Cyclophosphamide, methotrexate,
5-fluorouracil; D: Docetaxel; FEC: 5-fluorouracil, epirubicin, cyclophosphamide.
288
than 800,000 parous women [26] . At a mean period of 16 years,
there was a short-term increase in the risk of breast cancer in
the 3 years after a full-term pregnancy, which was followed by
a long-lasting decrease in risk. Similar results were obtained in
smaller studies, with an increased breast cancer risk ranging from
3 to 5 years following pregnancy [27–29] . The duration of this
risk depends on several factors, including parity and age at first
delivery, with younger first-time mothers showing the shortest
duration of increased risk. Hence, pregnancy seems to exert a
bidirectional time-dependent effect on breast cancer: it is pro-
tective in the long term, but in the short term tumor incidence
is increased.
Several hypotheses have been described that try to explain the
time-dependent effect of pregnancy on the risk of breast cancer.
It has been suggested that the short-term increase in breast cancer
risk following pregnancy could be secondary to the process of
postnatal breast involution, which is a tissue-remodeling pro-
cess analogous to wound healing in which angiogenesis, inflam-
mation and extracellular matrix alterations are activated  [30,31] .
Asztalos and colleagues showed that TGFb3, which is important
for extracellular matrix stability, is downregulated in women
without breast cancer who have been pregnant within the pre-
ceding 2 years, which was not the case in those who had been
pregnant 5–10  years ago or in nulliparous women [32] . The
effect of pregnancy on the mammary stem cells has also been
proposed as a potential hypothesis behind the associated short-
term risk. In this study, an Australian group recently found in
animal models a transient 11-fold increase in mammary stem
cell (MaSC) numbers following pregnancy [33] . It is suggested
that pregnancy could stimulate MaSCs to grow via the effect
of growth hormone (GH) of pregnancy on the MaSCs, which
express GH receptors [34–36] .
By contrast, pregnancy-related hormonal changes seem to be
more related to the long-term protective effect than the short-
term transient increase in risk. In a study conducted in nullipa-
rous women and two groups of parous women (2 and 10 years
following pregnancy), there was reduced expression of estrogen
receptor (ER)a (p = 0.006) and increased expression of ERb
(p = 0.003) in both parous groups compared with nulliparous
women [32] .
Pregnancy following breast cancer:
understanding the risks
Several case–control and population-based studies
Ref.
have been conducted to try to address the safety of
pregnancy following breast cancer diagnosis (Table 2)
[15,17]
[37–52] . None of these studies have shown a detrimen-
[12,13] tal effect of pregnancy on breast cancer outcome.
[16,17] Moreover, a recent study demonstrated that the mean
[19]
10‑year cumulative mortality of breast cancer patients
with subsequent pregnancy was within the range of
[19]
the 10‑year mortality predicted by ‘Adjuvant!Online’
for women with T1 N0 tumors in perfect health [52] .
Nevertheless, available evidence suggests that breast
cancer survivors are frequently counseled against
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Table 2. Studies comparing survival in women who got pregnant following breast cancer diagnosis with breast cancer controls.
Study (year) Patients who Patients who did Age at Study design Overall survival Matching criteria for Ref.
got pregnant not get pregnant diagnosis relative risk (95% CI) choosing controls
after BC (n) after BC (n) (years)
Cooper et al. (1970) 28 56 ≤40 Matched CC 0.64 (0.31–1.31) Age, stage, nodal status [37]

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Mignot et al. (1986) 68 136 ≤45 Matched CC 0.86 (0.34–2.18) Age, year of tumor treatment, [38]
stage, histology
Ariel et al. (1989) 46 900 22–45 Population based 0.85 (0.55–1.33) NA [39]

Sankila et al. (1994) 91 471 <40 Matched CC 0.21 (0.10–0.45) Age, year of diagnosis, stage [40]

Malamos et al. (1996) 21 222 <35 Hospital based 0.55 (0.39–0.77) NA [41]

Lethaby et al. (1996) 14 334 <45 Population based 0.78 (0.58–1.05) NA [42]

Velentgas et al. (1999) 53 265 <45 Matched CC 0.80 (0.30–2.30) Stage [43]

Birgisson et al. (2000) 14 33 <50 Matched CC 0.54 (0.25–1.13) Year of diagnosis, tumor size, [44]
nodal status
Gelber et al. (2001) 94 188 <53 Matched CC 0.44 (0.21–0.96) Sage, year of diagnosis, nodal [45]
status, tumor size
Mueller et al. (2003) 328 2002 <45 Matched CC 0.54 (0.41–0.71) Age, race/ethnicity, year of [46]
diagnosis, stage
Blakely et al. (2004) 47 323 <35 Hospital based 0.47 (0.27–0.82) NA [47]

Ives et al. (2007) 123 2416 <45 Population based 0.59 (0.37–0.95) NA [48]

Kroman et al. (2008) 199 10037 <45 Population based 0.73 (0.54–0.99) NA [49]

Largillier et al. (2009) 118 762 <35 Hospital based 0.23 (0.10–0.52) NA [50]
† [51]
Kranick et al. (2010) 107 344 <45 Matched CC 1.2 (0.8–2.0) Age, year of diagnosis, stage
Verkooijen et al. (2010) 492 8529 <40 Population based Not provided‡ NA [52]
†
Hazard ratio.
‡
Provided mortality rates that were lower in the pregnancy group compared with the non-pregnancy group 16.8 (95% CI: 13.3–20.9).
BC: Breast cancer; CC: Case–control; NA: Not applicable; NR: Not reported.
Motherhood after breast cancer: searching for la dolce vita
Review

289
 Review Azim Jr, Peccatori, de Azambuja & Piccart
future conception. In a study by Gelber and colleagues, 23 out
of 33 induced abortions (69%) were recorded as having been
recommended by the treating physician [45] . Similar observations
were encountered in other studies as well [10] . This highlights
a wide perception within the medical community that preg-
nancy worsens the prognosis of these women. It is postulated
that the hormonal milieu of pregnancy could stimulate breast
cancer recurrence.
In an attempt to refine our understanding in this area, we
recently conducted a meta-ana­lysis addressing the safety of preg-
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nancy following breast cancer diagnosis and its effect on overall
survival [53] . In this study, we analyzed 14 case–control, popu-
lation-based and hospital-based studies published between 1970
and 2009. The primary objective was to examine the effect of
pregnancy on overall survival in the whole population. We then
performed sensitivity analyses using published and individual
patient data from three studies to better characterize the effect of
pregnancy on different subgroups. The ana­lysis included nearly
20,000 patients, of whom 1417 patients got pregnant following
breast cancer diagnosis and were compared with breast cancer
patients who did not get pregnant. Seven studies had matched
controls and matching criteria were mainly age, stage and year of
diagnosis. The primary ana­lysis showed that patients who became
pregnant had a 41% reduced risk of death compared with breast
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cancer controls (hazard ratio: 0.59; 95% CI: 0.50–0.70). This
apparent protective effect was seen mainly in patients under the
age of 35 years with lymph node-negative disease.
The major drawback of this ana­lysis remains in the selection
of controls. It was previously suggested that patients who became
pregnant following breast cancer diagnosis are possibly healthier,
what was described as the ‘healthy mother effect’ [40] . Recently,
a group from the University of California (CA, USA) evalu-
ated the association between mental and physical health scores,
and childbearing after breast cancer [54] . This study compared
27 women having children after breast cancer and 54 age and
stage-matched breast cancer controls. The assessments were car-
ried out before the pregnancy events took place. Interestingly,
they demonstrated that mental but not physical health scores
were marginally different between cases and controls (p = 0.08).
Thus, according to this study, the perception that breast can-
cer patients who subsequently became pregnant were physically
healthier does not seem to be entirely true. However, in most of
the previous studies, selection of controls did not account for the
time to relapse, as relapsing patients would not consider getting
pregnant, and thus the observed protective effect of pregnancy
could reflect selection bias.
In the meta-ana­lysis, a sensitivity ana­lysis involving four stud-
ies was carried out, in which patients who got pregnant follow-
ing breast cancer diagnosis were compared with controls who
were known to be free of relapse at a time interval equivalent
to that elapsing between breast cancer diagnosis and pregnancy
in the investigational group [38,43,45,49] . The ana­lysis included
414 patients who became pregnant following breast cancer diag-
nosis and were compared with 10,626 breast cancer controls. The
results showed that subsequent pregnancy is associated with a
290
15% nonsignificant reduction in the risk of death (hazard ratio:
0.85; 95% CI: 0.53–1.35). This result further suggests that preg-
nancy does not confer a detrimental effect on breast cancer sur-
vival. It also points out that pregnancy might exert a protective
effect that could be restricted to a certain breast cancer subtype
(e.g., hormone receptor positive). Unfortunately, all of these stud-
ies included patients treated a long time ago, and thus none of
them provided information regarding hormone receptor status.
To address this point, we are currently conducting a multicentric
case–control study to address the effect of pregnancy on different
breast cancer subtypes. It is important to note that promoting
the possible protective effect of pregnancy in these patients is
not of high clinical relevance, as pregnancy is not meant to be a
therapeutic intervention against breast cancer. However, we need
to ensure that pregnancy does not adversely affect breast cancer
outcome, and thus improve the counseling of women wishing
to conceive.
The timing of pregnancy following breast cancer diagnosis is
another point that deserves emphasis. To address this, we per-
formed a sensitivity ana­lysis by separately analyzing patients who
got pregnant within 6–24 months following breast cancer diag-
nosis and those who got pregnant at a later time. We found that
pregnancy 2 years following breast cancer diagnosis conferred a
significant reduction in overall mortality, with no evidence of het-
erogeneity (pooled relative risk: 0.55; 95% CI: 0.36–0.84; p-value
for heterogeneity = 0.16). The same findings were observed in
women becoming pregnant within 6–24 months of diagnosis,
yet with significant heterogeneity (I 2 : 71.5%; p  =  0.007). In
this context, it is important to point out the bidirectional, time-
dependent effect of pregnancy on breast cancer observed in the
epidemiological studies of the general population [26–28] . As noted
earlier, biological evidence suggests that pregnancy might serve as
a fertile soil for incipient lesions in the breast in the short term [31] .
In addition, a recent population-based study from Singapore has
shown that the risk of death decreases significantly with increas-
ing interval between diagnosis and subsequent childbirth [52] .
Hence, owing to the reassuring results of patients who got preg-
nant more than 2 years following breast cancer diagnosis, and
the possible adverse effect of pregnancy and high incidence of
tumor recurrence during the first 2 years [55] , a minimum period
of 2 years following diagnosis should be allowed before attempting
to get pregnant. This would also allow patients to recover from
chemotherapy-induced ovarian toxicity.
For patients with a history of ER-positive breast cancer, 5 years
of adjuvant hormonal therapy remains the current standard of
care [56] , and women should complete their treatment before con-
sidering pregnancy. A conflict will always remain for those women
with ER-positive disease who are willing to interrupt hormonal
therapy to become pregnant. These women should be counseled
that the interruption of hormonal therapy could be detrimen-
tal for their breast cancer outcome, and this should therefore
be discouraged. Nevertheless, an interesting research question
remains open in whether or not women interrupting their adju-
vant endocrine therapy and becoming pregnant would benefit
from ­restarting hormonal treatment after childbirth.
Expert Rev. Anticancer Ther. 11(2), (2011)
 Motherhood after breast cancer: searching for la dolce vita
It is frequently quoted that pregnancy in women with a his-
tory of breast cancer is associated with a higher risk of abor-
tion compared with the general population [57] . Caution should
be taken when interpreting this data. In most of the studies
reported, no clear distinction was made between spontaneous
and induced abortion, the latter being frequently advocated by
treating physicians as mentioned earlier [8] . However, on review-
ing the results of studies that provided detailed information on
abortion, the risk of spontaneous abortion does not appear to
be significantly higher in breast cancer survivors compared with
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the general population. In the second largest population-based
study reported by the Danish group, which involved 371 women
with a history of breast cancer, only 15 women (4%) experienced
spontaneous abortion [49] . This compares very favorably to the
risk in the general population, which is in the range of 15% [58] .
In the same study, 157 patients (42%) were subjected to induced
abortion. The results of this study clearly reflect the potential
bias we might face on interpreting the data on reported abor-
tions without specifying the reason (i.e., spontaneous or induced),
which results in overestimating the risk of spontaneous abortion
in breast cancer survivors. The same was observed in a large
Australian population-based study involving 175 pregnancies
in women with previous history of breast cancer [48] . In this
study 12% experienced spontaneous abortion, while 34% had
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elective termination.
Two large studies have assessed the fetal outcome in women
with a history of breast cancer [59,60] . In a large Danish study,
216  women who became pregnant following breast cancer
diagnosis were compared with a large cohort of 10,453 women
without breast cancer [59] . The mean gestational age at deliv-
ery was 39 weeks in both groups, with similar risks of preterm
delivery, low birth weight and congenital anomalies (6.5, 1.5
and 3.4%, respectively). By contrast, a larger Swedish popula-
tion-based study has suggested that pregnancy in women with
a history of breast cancer should be regarded as ‘high risk’ [60] .
In this study, 331 women who first gave birth at a mean time
of 3 years following breast cancer diagnosis were identified out
of a total number of 2,870,932 births registered in the Swedish
database between 1973 and 2002. The large majority (~91%)
of births from women previously treated for breast cancer had
no adverse events. However, this group was associated with an
increased risk of delivery complications (odds ratio [OR]: 1.5;
95% CI: 1.2–1.9), cesarean section (OR: 1.3; 95% CI: 1.0–1.7),
very preterm birth (<32  weeks; OR: 3.2; 95%  CI: 1.7–6.0)
and low birth weight (<1500 g; OR: 2.9; 95% CI: 1.4–5.8).
Despite this, it is important to point out that the large majority
of infants were born at full term, with Apgar scores at 5 min
of seven or more. A slight increase in the incidence of congeni-
tal malformations were encountered in the breast cancer group
compared with the general population (7 vs 4%, respectively).
The reason for this difference, which was not observed in other
studies, is not very clear. This study included patients who got
pregnant as early as 7 months following breast cancer surgery,
with a mean period of approximately 3 years. It is possible that
those women who got pregnant shortly after chemotherapy or
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Review
hormonal therapy were prone to the in utero toxic effects of these
agents. Unfortunately, the Swedish trial did not provide detailed
­information in this regard.
On the other hand, only four neonatal deaths were reported,
with no differences observed between the two groups. The higher
incidence of women above the age of 35 years in the breast can-
cer group (53 vs 11%) could partly explain the increased risk of
complications; however, this was also observed in the Danish
study (49 vs 9%) [59] , with no differences observed in the rate
of pregnancy complications. Another explanation could be the
fact that more breast cancer survivors in the Swedish study had
a history of infertility for more than 1 year compared with the
control arm (OR: 2.53; 95% CI: 1.6–3.9).
Breastfeeding & breast cancer risk
Breastfeeding is known to have immediate and long-lasting
advantages for both infant and mother. Breast-fed newborns
suffer lower rates of neonatal infection, autoimmune disease and
subsequent obesity, and benefit from better neuropsychological
and cognitive development [61–63] . For mothers, lactation facili-
tates maternal weight loss following delivery, controls postpartum
bleeding and reduces blood glucose levels in women experienc-
ing gestational diabetes mellitus [63,64] . Importantly, it provides
a unique opportunity for the mother to naturally bond with her
newborn, which could have a considerably positive psychological
effect, particularly for a woman with a history of breast cancer [65] .
In 2002, the Collaborative Group on Hormonal Factors and
Breastfeeding conducted the largest ana­lysis evaluating the effect
of breastfeeding on breast cancer incidence in healthy women [66] .
They analyzed 47 case–control and cohort studies from 30 dif-
ferent countries, which included at least 100 women with subse-
quent breast cancer. The relative risk reduction of breast cancer
incidence was 4.3% (95% CI: 2.9–5.8; p < 0.0001) for each year
of breastfeeding. Subgroup analyses found no differences related
to age, ethnicity, parity, age at first delivery, or BMI. The mag-
nitude of benefit appears to be even higher in BRCA1 carriers.
Jernstrom and colleagues have shown that women with BRCA1
mutation who breastfed their babies for more than 1 year had a
45% reduction in the risk of developing breast cancer compared
with women who never breast fed (OR: 0.55; 95% CI: 0.38–0.80;
p = 0.001) [67] .
Several hypotheses have been postulated to explain the protec-
tive effect of breastfeeding on breast cancer incidence. Some stud-
ies have linked the reduced risk of developing breast cancer with
the duration of lactation amenorrhea [68] . Others have pointed
to the role of prolactin, which is a key hormone involved in both
mammary development and lactation. The effect of prolactin on
breast cancer development has been the object of considerable con-
troversy, although evidence currently favors the view that elevated
prolactin levels could be protective against breast cancer [69] . Early
anecdotal evidence suggested breast cancer regression following
pituitary stalk section [70] . Later studies in the adjuvant setting
have shown that high postoperative serum prolactin levels and
the presence of activated Stat5, which is a prolactin ­transcription
factor, are associated with better prognosis [71–73] .
291
 Review Azim Jr, Peccatori, de Azambuja & Piccart
Breastfeeding: safety & feasibility following breast
cancer diagnosis
There are no epidemiological data regarding breastfeeding fol-
lowing breast cancer. To our knowledge, only two reports have
addressed the effect of breastfeeding on breast cancer outcome.
The first was conducted on 94 patients who got pregnant follow-
ing breast cancer diagnosis and were previously enrolled in an
International Breast Cancer Study Group case–control study [45] .
Data on breastfeeding were reported by the referring oncolo-
gist and lacked details about duration, exclusiveness and site of
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lactation in cases of breast-conserving surgery. Nonetheless, 27
of the 94 women were reported as having breastfed their babies,
25 were reported as having bottle-fed, while 42 had unknown
nursing status. Breastfeeding was not considered in the original
survival ana­lysis, but subsequent review suggested that breast-
feeding was not detrimental, but was rather associated with bet-
ter survival [74] . At a median follow-up of 10 years from breast
cancer diagnosis, only one patient died out of 27 women who
breastfed their babies (3%), compared with six patients out of
25 women who did not breastfeed (24%). Those with unknown
nursing status had a survival somewhere in between (four out
of 42 women; 9%). While this ana­lysis is very small and lacks
much vital information regarding lactation habits and duration,
it emphasizes that breastfeeding does not seem to worsen breast
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cancer outcome.
We recently published a study addressing the pattern of breast-
feeding in a series of 20 patients who got pregnant following
the completion of adjuvant systemic therapy for breast cancer.
We also investigated the effect of breastfeeding on breast cancer
outcome [75] . In this study, ten women (50%) initiated breast-
feeding, four (20%) stopped within 1 month and six (30%) had
long-term success with a median period of 11 months (range:
7–17 months). At a median follow-up of 48 months following
delivery, all 20 women were alive with two relapses occurring,
one in each group (i.e., lactating and nonlactating). Although
we acknowledge the small size of the study, it confirms the previ-
ous observation regarding the lack of the apparent detrimental
effects of breastfeeding on breast cancer outcome. This is further
endorsed by the Society of Obstetricians and Gynecologists of
Canada, which clearly states that “women previously treated for
breast cancer who do not show any evidence of residual tumor
should be encouraged to breastfeed their children” [76] .
However, it is evident that breast cancer survivors are faced with
considerable challenges when they attempt breastfeeding. Several
studies have reported that milk production is significantly reduced
in the breast that was previously subjected to a conservative sur-
gery and radiotherapy [77–79] . This is in addition to nipple pain
and discomfort during latching [75] . An early study has shown
that only four out of ten patients were able to lactate from the
treated breast, while no similar problems were encountered in
the contralateral breast [77] . Later on, Moran and colleagues ret-
rospectively analyzed over 3000 patients treated in their hospital
from 1965 to 2003, and were able to identify 29 pregnancies in
21 patients (one patient had bilateral breast cancer) [78] . Four
women elected pharmacological suppression of lactation and out
292
of the remaining 18 women, lactation occurred in ten (56%), did
not occur in seven (39%) and was unknown in one (5%). Breast
volume was reported to be significantly diminished in 80% of
treated breasts. This observation is consistent with that of our
group and is probably related to radiotherapy-induced fibrosis.
The proximity of the incision to the areola and nipple, the loca-
tion of the tumor, and the dose and type of radiotherapy are all
factors contributing to lactation success from the treated breast
[80] . However, it is important to point out that none of the previ-
ously reported studies described compromised milk production
from the contralateral breast.
In a recent exploratory ana­lysis on the experience of breast-
feeding in breast cancer survivors, Gorman and colleagues dem-
onstrated that a number of themes emerged from their inter-
views  [65] . These included uncertainty regarding the possibility
of breastfeeding, worries about nursing from one side only and
the challenge of not having sufficient milk production. Patients
and physicians should be informed that the milk produced by one
breast is sufficient for the nutritional needs of a newborn [81] . The
experience of mothers who chose to use exclusively one breast for
breastfeeding validates this notion [82] , together with the historical
habit of wet nursing more than one child [83] .
Counseling remains a crucial point that could have a signifi-
cant impact on the success of breastfeeding in women who have
had breast cancer. We observed in our survey that the main rea-
sons for not initiating breastfeeding were uncertainty regarding
maternal safety and a priori unfeasibility expressed either by the
­obstetrician or by the oncologist [75] .
By contrast, we have also observed that proper lactation coun-
seling had a positive effect on the success of breastfeeding and in
facing the different challenges highlighted earlier. In our study,
five out of 20 women were offered qualified lactation counseling
[75] . All five women – including a woman who breastfed twice –
enjoyed successful prolonged breastfeeding with a median dura-
tion of 12 months (range: 7–17 months). These results underscore
the need for and importance of proper counseling.
Fertility preservation
In the previous sections, we critically analyzed available evidence
on the feasibility and safety of pregnancy and breastfeeding in
breast cancer survivors. Despite the limitations of the available
data, it appears that these women can safely get pregnant and con-
sider breastfeeding. However, as mentioned earlier, a significant
proportion of breast cancer patients develop permanent amenor-
rhea secondary to adjuvant chemotherapy and are thus denied
this opportunity. In addition, the ovarian reserve of those who
experienced temporary amenorrhea is compromised [15] . Hence,
it is vital to try to preserve the ovarian function of women who
are considering pregnancy following the completion of breast
cancer therapies. Several methods have been proposed to preserve
their fertility. These include ovarian function suppression, in vitro
fertilization with embryo cryopreservation, ovarian tissue freez-
ing and oocyte cryopreservation [84] . For the sake of this article,
we will focus only on the former two techniques, as the latter
­methods remain highly investigational for the time being.
Expert Rev. Anticancer Ther. 11(2), (2011)
 Motherhood after breast cancer: searching for la dolce vita Review

Table 3. Phase II studies of luteinizing hormone-releasing hormone agonists to preserve fertility in

breast cancer.
Author (year) Patients Median age in LHRH agonist Chemotherapy used Resuming Pregnancies Ref.
(n) years (range) menses (n) (%) (n)
Fox et al. (2003) 24 35 (23–42) Leuprolide AC, AC-T, CAF, AC-CMF 23 (96%) 6 [85]

Del Mastro et al. 30 38 (29–47) Goserelin CEF × 6 21 (72%) NR [86]

(2006)
Recchia et al. 100 43 (27–50) Goserelin CMF/FEC ± T, E-CMF ± T, 67 (67%) 3 [87]
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Washington University Library on 12/28/14

(2006) E-HDCT-CMF
Urruticoechea 51 34† (20–34) Goserelin AC/FEC ± T 45 (90%) 8 [88]
et al. (2008)
†
Mean age.
AC: Doxorubicin, cyclophosphamide; CAF: Cyclophosphamide, doxorubicin, 5-fluorouracil; CMF: Cyclophosphamide, methotrexate, 5-fluorouracil; E: Epirubicin;
FEC: 5-fluorouracil, epirubicin, cyclophosphamide; HDCT: High-dose chemotherapy; LHRH: Luteinizing hormone-releasing hormone; NR: Not reported; T: Taxane.

Several Phase II studies have been published addressing the
role of luteinizing hormone-releasing hormone (LHRH) agonists
in preserving the fertility of young women undergoing adjuvant
systemic chemotherapy (Table 3) [85–88] . These studies were nonran-
domized, without a control group and involved a small number of
patients (range: 24–100 patients). Only one study used the ability
to conceive and live birth as end points. In this study, six pregnan-
cies occurred in 23 women [85] . It should be noted that this study
For personal use only.
women with breast cancer. The first randomized trial was pre-
sented at the Annual Meeting of the American Society of Clinical
Oncology (ASCO) 2008 and included only 49 patients (median
age: 39 years) who were randomized to chemotherapy with or
without triptorelin [89] . No difference was found between the two
treatment arms with respect to the risk of chemotherapy-related
amenorrhea at 18 months of follow-up. The median time to return
of menses was 6.1 months in the triptorelin arm, compared with

was first presented in 2003 and was not published until now. The
remaining studies had as their main end point the percentage
of patients who resumed menstruation following chemotherapy,
which ranged from 67 to 100%. This is a major limitation because
resuming menstruation is not a good surrogate for ovarian reserve
and ability to conceive, as highlighted earlier [15] .
Recently, three randomized trials were conducted to address
the potential role of LHRH in preserving the fertility of young
4.7 months in the control arm (p = 0.79).
The second study was recently published by an Egyptian group
in which 78 patients were randomized to six cycles of standard
chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide)
with or without goserelin [90] . In this study, the goserelin group
had a significantly lower incidence of premature ovarian failure
(11 vs 66%; p < 0.001), a higher incidence of ovulation (69 vs
25%; p < 0.001) and higher E2 levels (279 vs 75; p < 0.001).

Table 4. Ongoing randomized studies investigating the role of luteinizing hormone-releasing hormone in
fertility preservation of patients with invasive breast cancer.
Sponsor Target Design Primary objective Secondary objective
accrual (n)
Southwest Oncology 416 Phase III; adjuvant (neo) Rate of premature Ovarian reserve rate
Group cyclophosphamide-based regimen ovarian failure Pregnancy rate
± goserelin in HR- Ovarian dysfunction rate
Anglo Celtic Cooperative 400 Phase III; adjuvant (neo) Resuming menses within Incidence of menopausal
Oncology Group cyclophosphamide and/or 1 year symptoms
anthracycline-based regimen QoL
± goserelin BMD loss
Hormone levels
Pregnancy rate
MD Anderson 148 Phase III; adjuvant (neo) Resuming menses within Pregnancy rate
Cancer Center chemotherapy ± goserelin in HR- 1 year QoL
DFS, OS
German Breast Group 62 Phase II; adjuvant (neo) Resuming menses within Treatment delay
anthracycline-based regimen 8 months Toxicity
± goserelin in HR- QoL
Pregnancy rate
BMD: Bone mineral density; DFS: Disease-free survival; HR-: Hormone receptor negative; OS: Overall survival; QoL: Quality of life.
Data taken from [202].

www.expert-reviews.com 293
 Review Azim Jr, Peccatori, de Azambuja & Piccart
While both trials are very small, the second study was larger
in size (78 vs 49 patients in the former) with a younger patient
population (median age: 29 vs 39 years in the former). These fac-
tors could partly explain the different results obtained. However,
the latter trial suffered some limitations that should be taken
into consideration [91,92] . Only 33% of the patients in the control
arm resumed their menses, which is very low compared with
approximately 70% in previous reports for patients of the same
age treated with similar regimens. Moreover, patients were fol-
lowed up for only 8 months, which does not allow for adequate
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Washington University Library on 12/28/14
ovarian function recovery of the control group, which could take
up to 12 months. Finally, the design of the study and its short
follow-up did not allow for investigation of the fertility rate in
both groups, which remains the main question. In the 2010
ASCO meeting, Del Mastro presented on behalf of the Gruppo
Italiano Mammella the results of the largest randomized Phase III
randomized clinical trial, which investigated the effect of adding
triptorelin to modern chemotherapy on preserving the ovarian
function [93] . This study included 281 patients with a median
age of 39 years (range: 18–45 years) who received a median of
six adjuvant chemotherapy cycles. The triptorelin arm was asso-
ciated with a 19% absolute reduction in the risk of amenorrhea
(p = 0.0002). Premenopausal estrogen levels were more frequently
observed in those who received triptorelin compared with those
For personal use only.
who received chemotherapy alone (77 vs 58%; p = 0.006). This
study is not yet published, and it is still too early to comment
on the fertility rates in both treatment groups. However, if these
observations led to an improvement in fertility rates, and con-
firmed by other ongoing trials this could certainly place LHRH
agonists as a favored intervention to preserve fertility of young
women with breast cancer. Currently, several randomized clinical
trials are investigating the role of LHRH in fertility preservation
to confirm these results (Table 4) .
On the other hand, embryo cryopreservation has been an estab-
lished and widely available method in treating infertility since the
early 1980s. In the USA, the delivery rate is approximately 30 and
16% per embryo thaw in patients younger than 35 years and older
than 40 years of age, respectively [201] . In vitro fertilization (IVF)
in cancer patients for embryo ‘banking’ for future use has been
reported by several groups [94–96] . As patients undergoing IVF
with embryo cryopreservation are generally not infertile, preg-
nancy rates might well be higher than those achieved by couples
who potentially have poor oocytes and sperm quality.
However, it is important to take into account several points when
considering IVF for breast cancer patients. The use of traditional
ovarian-stimulation regimens result in a significant increase in
estradiol levels (ten- to 20-times the levels in a regular menstrual
cycle) [97] . Despite this lasting for only a few days (~10 days),
oncologists fear that the estrogenic milieu could stimulate breast
cancer progression or relapse. To address this point, some patients
were offered IVF during unstimulated cycles (natural-cycle IVF);
however, this technique is associated with low embryo yield [96,98] .
In addition, the fact that ovarian stimulation takes place prior to
commencing adjuvant chemotherapy could result in a significant
delay in initiating therapy, which could have a detrimental effect on
294
breast cancer outcome. Ethical and social considerations also exist.
This procedure requires a partner, and the fate of the cryopreserved
embryo, if available, remains a problem in case the patient died
before implantation. These latter two disadvantages to embryo
preservation could therefore represent a potential ­advantage for
ovarian tissue freezing and oocyte cryopreservation.
Oktay and colleagues have conducted a series of studies to
address some of these concerns [96,99–102] . They first used high-
dose tamoxifen (60 mg) for ovarian stimulation, which resulted
in a 2.5-fold increase in embryo yield compared with natural-
cycle IVF, with no breast cancer recurrences observed in the short
term [96] . Later, they investigated the role of letrozole for ovarian
stimulation and compared it with tamoxifen [100] . In this study,
60 patients with primary breast cancer were enrolled in which
29 patients underwent ovarian stimulation using three different
regimens: tamoxifen; tamoxifen plus low-dose follicle-stimulating
hormone (FSH); and letrozole plus low-dose FSH. Embryo yield
was compared across the three regimens, and recurrence rates
were compared with the remaining 31 patients who elected not
to undergo IVF. In this study, the letrozole arm was associated
with the highest embryo yield (5.3 ± 0.8 embryos) compared with
tamoxifen–FSH (3.8 ± 0.8 embryos; p < 0.05) and tamoxifen alone
(1.3 ± 0.2  embryos; p < 0.001). Furthermore, the letrozole arm
was associated with the lowest estradiol peak (380 ± 57 pg/ml),
which was significantly lower than the other two arms (p < 0.05).
At a median follow-up of 18 months, there was no difference in the
rate of recurrence between the IVF and the control groups (three
out of 29 vs three out of 31 patients). Given the appealing results
observed with letrozole, Oktay’s group more recently conducted
a prospective study involving 215 patients to determine the effect
of controlled ovarian stimulation using letrozole plus FSH on
disease-free survival in women undergoing embryo or oocyte cryo-
preservation prior to starting adjuvant chemotherapy [102] . A total
of 215 women were prospectively evaluated, of whom 79 elected
to undergo controlled ovarian stimulation and the rest served as
controls. The results showed that the time to starting adjuvant
chemotherapy was longer for patients who underwent controlled
ovarian stimulation (45 vs 33.4 days; p < 0.01). However, at a
median time of almost 2 years, there were no differences observed
in terms of disease-free and overall survival (p = 0.36). When we
consider that it is impossible to have a randomized trial in this
setting, this study represents a real step forward in evaluating the
risk of ovarian stimulation on breast cancer outcome. However,
longer follow-up is needed to better define such risk.
Expert commentary
Based on the available evidence, women with a history of success-
fully treated breast cancer should not be denied the opportunity
to get pregnant or to breastfeed their children. While treatment
modalities used to treat breast cancer (surgery, radiotherapy and
chemotherapy) could reduce the chances of subsequent conception
and breastfeeding, once encountered, they do not adversely affect
breast cancer prognosis. Thus, physicians should take this informa-
tion into account when counseling women with a history of breast
cancer and enquiring into the safety of subsequent pregnancy and
Expert Rev. Anticancer Ther. 11(2), (2011)
 Motherhood after breast cancer: searching for la dolce vita Review

breastfeeding. In addition, and as stressed in the recent ASCO
guidelines, they should be considered for fertility preservation [103] .
To date, there is no established method to preserve the fertility of
young women undergoing chemotherapy. However, data about
LHRH agonists and embryo cryopreservation is promising.
Fertility counseling needs to be better addressed in breast can-
cer clinics. Denying breast cancer survivors the opportunity to
become pregnant and/or breastfeed remains unjustified in the
absence of supporting evidence. This would indeed improve the
quality of life of these women and help them restore normalcy
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Washington University Library on 12/28/14
The coming few years will reveal much about the role of
LHRH in fertility preservation. Several large randomized tri-
als have completed their accrual, and their results are eagerly
awaited. These studies will provide sufficient evidence on the effect
of LHRH on ovarian function, ovarian reserve and rate of preg-
nancy, despite being tested as secondary end points. In parallel,
one can expect progressive improvements in ovarian tissue freezing
and oocyte cryopreservation techniques, which would help over-
come the ethical and social considerations associated with embryo
­cryopreservation for breast cancer patients.

in their lives.
Five-year view
Several questions remain unanswered regarding the impact of
pregnancy on breast cancer outcome in women with a history of
breast cancer. For example, although it appears that pregnancy
following breast cancer is generally safe, too little is known about
the timing of pregnancy and its effect according to breast cancer
subtypes. In this regard, we are currently conducting a multi-
centric case–control study, which will be adequately powered to
address these points.
Financial & competing interests disclosure
Hatem A Azim Jr acknowledges a translational research fellowship from
the European Society for Medical Oncology (ESMO) and a PHD grant
from the Universite libre de Bruxelles (ULB). The authors have no other
relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the sub-
ject  matter or materials discussed in the manuscript apart from
those disclosed.
The authors would like to thank Carolyn Straehle for her editorial
­assistance during the preparation of the manuscript.

Key issues
For personal use only.

• All published studies mentioned in this article and a recently conducted meta-ana­lysis confirm that pregnancy does not worsen the
survival rates of women with a history of breast cancer.
• There is a lack of sufficient evidence on the timing of pregnancy and outcome according to the endocrine responsiveness of a tumor.
However, waiting for a minimum of 2 years following completion of breast cancer therapy in patients with estrogen receptor-negative
tumors is a reasonable option. For those with estrogen receptor-positive breast cancer, 5 years of hormonal therapy should be
completed before attempting to become pregnant.
• Data on the safety of breastfeeding is very scarce; however, available evidence does not show any detrimental effects. The challenges
and fears faced by the patient entails offering them proper lactation counseling.
• The success rate of breastfeeding from the ipsilateral breast in women previously subjected to breast-conserving surgery and
radiotherapy is low (~4%), which is secondary to distortion in the nipple/areola complex and radiotherapy-induced fibrosis.
• The coadministration of luteinizing hormone-releasing hormone with chemotherapy appears to reduce the risk of permanent
amenorrhea secondary to chemotherapy. Whether or not this would result in improving the ovarian reserve and increasing the
pregnancy rate remains to be determined.
• Significant progress has been made in ovarian stimulation and embryo cryopreservation in breast cancer patients who are willing to
become pregnant afterwards. This approach could be considered in centers with a high experience dealing with such cases.

HER2-positive breast cancer have a 6 Berkowitz GS, Skovron ML, Lapinski RH,
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