European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 222–227

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Full length article

Breast cancer in pregnant patients: A review of the literature

María Teresa Martínez* , Begoña Bermejo, Cristina Hernando, Valentina Gambardella,
Juan Miguel Cejalvo, Ana Lluch
Medical Oncology and Hematology Unit, Health Research Institute INCLIVA, University of Valencia, The Centre of Networked Biomedical Cancer Research
(CIBERONC), Spain

A R T I C L E I N F O A B S T R A C T

Article history:
Received 3 January 2018 Breast cancer diagnosed during pregnancy is a rare occurrence at present; however, in recent years a
Received in revised form 16 April 2018 trend towards delayed childbirth is generating an increase in its incidence. This situation requires a
Accepted 22 April 2018 multidisciplinary approach involving obstetricians, oncologists and surgeons.
In this review we analyse diagnostic methods, different possible treatments and long-term patient
Keywords: prognosis. We conducted a search for articles published in PubMed, or in abstract form from the San
Breast cancer Antonio Breast Cancer Symposium (SABCS), the European Society for Medical Oncology (ESMO), and the
Pregnancy American Society of Clinical Oncology (ASCO) annual meeting, using the search terms:
Diagnosis
“Breast cancer and pregnancy”.
Treatment
Breast cancer occurring during pregnancy requires extra effort to offer patients the best
Prognosis
multidisciplinary management. There is no difference in the pathology-based classification, but breast
cancer during pregnancy seems to be associated with different patterns of gene expression.
Chemotherapy and surgery are generally safe and well-tolerated by patients during the second and
third trimesters of pregnancy. The poorer prognosis could be attributed mainly to a delay in diagnosis and
because breast cancer in young patients is a more aggressive disease. Finally, balancing the health of
mother and child must be paramount.
© 2018 Elsevier B.V. All rights reserved.

Introduction Based on the European records on PABC, the average age of

Breast cancer is the most frequent malignant tumour in women
and the leading cause of cancer-related female mortality
worldwide [1]. Although the average age of onset of breast cancer
is 61 years, approximately 1 in 40 women diagnosed with breast
cancer is very young, and the disease constitutes 5–7% of all cancer
deaths in these young women [2].
Pregnancy is one of the situations in which breast cancer can
appear in a young woman. It is estimated that 1 in every 3000
pregnancies is complicated by the appearance of breast cancer, and
this incidence seems to be increasing. Only 10% of patients
diagnosed with breast cancer at under 40 years of age develop the
disease during pregnancy [3]. Pregnancy-associated breast cancer
(PABC) is defined as breast cancer diagnosed during pregnancy or
within one year of delivery [4].
* Corresponding author.
E-mail address: maitemartinez3@yahoo.es (M.T. Martínez).
onset is 33 years, and the average gestational age is 21 weeks [5]. In
addition, breast cancer in this population of young patients is
associated at a rate of 50% with a positive family history and a 30%
risk of mutation of the BRCA1/BRCA2 genes [6,7]. In recent years we
are evidencing an increase in PABC; many causes are postulated as
triggers of this upgrowth, including the progressive increase in age
of first pregnancy [8].
There are few published works about the treatment of PABC, but
all of them support the continuation of pregnancy during
treatment. Therefore, a greater understanding of the biological
mechanisms, anatomopathological characteristics and different
treatment options are essential.
PABC is described by some authors as being particularly
aggressive because of low hormone receptor positivity and high
rate of HER2 overexpression [9,10]. Its pathogenic pathway is
probably different from that of non-PABC.
We performed this review in order to improve understanding of
breast cancer diagnosed during pregnancy, trying to discern the
biological mechanisms underlying this type of breast cancer and

https://doi.org/10.1016/j.ejogrb.2018.04.029
0301-2115/© 2018 Elsevier B.V. All rights reserved.
 M.T. Martínez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 222–227
the treatments that are considered safe for both the mother and
the fetus.
Material and methods
PubMed database, the European Society for Medical Oncology
(ESMO), the American Society of Clinical Oncology (ASCO) annual
meeting and San Antonio Breast Cancer Symposium (SABCS)
Meeting abstracts were searched using the terms “Breast cancer
and pregnancy “; papers considered relevant for the aim of this
review were selected.
Biology of PABC
Pregnancy is associated with an increased risk of breast
cancer in the short time, as well as with a long-term protective
effect [11]. The molecular mechanism underlying this process is
poorly understood. The mammary gland is a dynamic organ that
suffers significant changes during the menstrual cycle, preg-
nancy, and lactation, these mechanisms are controlled by
mammary stem cells (MaSCs) [12]. Despite, the MaSCs lack
estrogen/progesterone receptor expression, the functions of
these cells are controlled by oestrogen and progesterone
hormone signalling, both hormones are well-established risk
factor for breast cancer [13].
Multiple studies and a meta-analysis have shown that patients
diagnosed with breast cancer during pregnancy have a worse
prognosis, especially those diagnosed shortly after pregnancy [14].
This could be due to an increase of female hormones during
pregnancy that might modulate the microenvironment of the
mammary gland and stimulate the aggressive growth of mammary
cells. During pregnancy there is an increased in MaSC number,
therefore, this provides a cellular basis for the short-term increase
in breast cancer incidence that accompanies pregnancy. Another
hypothesis considered is that the mammary involution processes
occurring after childbirth could activate angiogenesis, inflamma-
tion and alterations of the extracellular matrix, resulting in a more
aggressive biology of breast cancer [15].
Pregnancy has different effects on MaSC that give rise to
luminal versus basal breast cancers. An early first pregnancy has a
protective effect against breast cancer risk because the breast has
accumulated few mutated cells, however this applies mainly to
luminal breast cancer that develop after menopause [16]. In fact,
risk for an aggressive tumor as basal-like (triple negative and
BRCA1) breast cancer, may be increased even at early ages and with
lack of breastfeeding [11,17,18].
On the other hand, breastfeeding reduces the risk of breast
cancer. The longer women breast feed the more they are protected,
it has been described that breastfeeding for 1 or 2 years reduces the
risk by 32% and 49%, respectively [19,20]. This is because of
episodes of breast-feeding differentiate a proportion of the MaSC
and thereby deplete the pool of stem cells. During this period there
are hormonal changes, specially a reduction in endogenous
oestrogen and progesterone levels and/or increased prolactin
levels, and a delay in the establishment of regular ovulation.
However, in BRCA mutation, breastfeeding protects among women
with a BRCA1, but not with a BRCA2 mutation. Thus, differences
between pathological features of BRCA1 and BRCA2 tumors may
also reflect differences in risk factor association.
Other mechanism that take place is the maternal immunologi-
cal tolerance to allow the semi-allogeneic fetus to grow within. The
immune profile of pregnant patients is modified, this condition
may be used by pro-tumorigenic mechanisms that allow cancer
development. For example, immunosuppressive cells such as
regulatory T and B cells have been implicated in facilitating
immune tolerance, and ultimately, cancer escape [21].
223
As in the general population, invasive ductal carcinoma is the
most frequent PABC (between 71 and 100%) [15,22–26], although
these tumors are larger, with higher histological grade, with
vascular and lymphatic invasion and greater affectation of the
axillary nodes than in non-pregnant patients of the same age.
Different causes have been postulated for this, including a delay in
the diagnosis of PABC [27–29].
In 2014, Azim and colleagues published a study evaluating
whether pregnancy is associated with a change in the biology of
breast cancer. The authors study the breast tumors of 54 pregnant
women and compare them with 113 tumors of non-pregnant
women. Finally, they conclude that there are no differences in the
classic pathological characteristics, the pattern of mutations or the
molecular subtypes of breast cancer. However, they show that
tumors diagnosed during pregnancy are associated with different
patterns of gene expression and activate signalling pathways such
as the serotonin receptor pathway. Nevertheless, these findings are
not significant due to the small population studied [15].
Diagnosis
Patients with PABC are usually diagnosed with more advanced
disease. This has been attributed mainly to a delay in diagnosis. In
different series of patients, a delay in diagnosis of 5–10 months has
been reported, compared with 1–4 months in non-pregnant
patients [30,31].
Often, a delay in the cancer diagnosis is secondary to pregnancy
and lactation, due to the increase in the size and density of the
breast tissue in this period. The pregnant woman may present
similar findings in the physical examination to patients with non-
pregnant breast cancer, such as a mass or a palpable thickening of
the breast tissue. During pregnancy occurs a proliferation of
glandular tissue and differentiation of secretory units by pregnan-
cy-related hormones to prepare the breast for the lactation
process. All these processes are manifested in an increase in the
volume and density of the breast. All these mammary changes
make mammary exploration very complicated and this fact can
delay the identification of a suspicious mass [32,33].
With the intention of reducing delays in diagnosis, palpable
masses that persist for more than 2 weeks during pregnancy and
lactation should be investigated. Finally, around 80% of breast
biopsies during pregnancy will be benign [8].
Regarding complementary tests, mammography during preg-
nancy should be performed with adequate abdominal protection.
Exposure to radiation for the fetus is estimated at 0.4 cGy. The
sensitivity of mammography to detect breast cancer in pregnant
women ranges between 63 and 78% [34,35]. However, breast
ultrasound is probably the best technique for the diagnosis of
breast cancer during pregnancy, for several reasons: it is useful to
distinguish between solid and cystic breast masses and it is also
the most effective method to identify axillary metastases, does
not entail any risk of fetal exposure to radiation and also makes it
possible to perform percutaneous biopsies easily [36]., There are
no prospective data on the safety of breast MRI to diagnose breast
masses in pregnant women, due to the use of gadolinium contrast
that could cause fetal abnormalities. Therefore, this test is not
recommended in this population [37]. During breastfeeding, the
safety of MRI with contrast has been demonstrated because
the contrast doses excreted in breast milk are very small, and the
risk of complications, such as direct toxicity or allergic reactions,
is very low. In some cases, as is the concern of the mother, it is
recommended to abstain from breastfeeding for 12–24 h after
administration of the contrast with gadolinium [31]. It is
important to note that a biopsy of any clinically suspicious mass
should be performed, even if mammography and ultrasound are
inconclusive.
224 M.T. Martínez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 222–227
If the biopsy confirms the existence of breast cancer, the initial
staging should include a complete history and a physical
examination; a chest x-ray with adequate abdominal shielding
and an ultrasound of the liver could also be performed. CT scans
and bone scans are not recommended because of the risk of fetal
radiation exposure [38]. Regarding the use of PET Scan, we know
that the doses of fetal radiation are higher at the beginning of
pregnancy than at the end of it, and also that there is significant
variability between the subjects. Fetal dosimetry values from 18F-
FDG administration, estimated with realistic voxelwise anthropo-
morphic phantoms, are 2.5E–02 mGy/MBq in early pregnancy,
1.3E–02 mGy/MBq in the late part of the first trimester, 8.5E–
03 mGy/MBq in the second trimester, and 5.1E–03 mGy/MBq in the
third quarter. The ideal PET procedure during pregnancy is PET/
MRI because it is not associated with radiation for correction of
attenuation and allows more accurate dosimetric calculations
[39,40].
PABC treatment
Pregnancy itself should not modify the effective treatment of
breast cancer, although the treatments should be selected and
ordered to ensure the safety of the fetus. The therapeutic strategies
must be determined by the biology and staging of the tumour as
well as the preferences of the patient.
Patients diagnosed with PABC are usually young women, in
most cases with ages below 35 years, so they should be referred to
a genetic counseling unit, to assess the probability that they have a
mutation in BRCA genes according to family history or tumor
histological characteristics. We should also point out that young
women with PABC in many cases after chemotherapy develop
infertility (a very important problem for women who probably
wanted to have more children in the future). All this can cause side
effects and has a significant impact on the quality of life, often
leading to long-term psychological imbalances [41,42]. For all these
reasons, women diagnosed with PABC should be evaluated by a
multidisciplinary team that includes medical oncologists, breast
surgeons, radiotherapy oncologists, fertility gynecologists, obste-
tricians, paediatricians, etc. Since, this pathology, at this early age,
with its own psychosocial characteristics such as the maintenance
of fertility, sexual health, genetic counseling, and its differential
tumor characteristics, requires a multidisciplinary assessment
[31].
The general recommendations for the breast cancer manage-
ment during pregnancy are that surgery can be performed in all
trimesters, chemotherapy in the second and third trimesters, and
radiotherapy only in the postpartum period. These are considered
safe options in most PABC patients. In the case of patients with
advanced stage disease (stages III and IV) during the first trimester,
the interruption of pregnancy is advised, because chemotherapy at
this stage is likely to harm the fetus. [43].
In patients treated with systemic therapy, evaluation of fetal
viability and confirmation of fetal age should be carried out before
administration of chemotherapy. The patient should be examined
by an obstetrician prior to each cycle of chemotherapy, with strict
fetal monitoring with a morphometric and umbilical artery
Doppler ultrasound. Chemotherapy should not be administered
beyond 2 weeks before delivery to avoid neutropenia in the mother
and potentially in the fetus and should not be given after week 34–
35 of pregnancy, given the risk of spontaneous delivery in these
weeks [8].
Breast surgery
There is an extensive experience with surgery during pregnan-
cy, therefore mammary surgery should follow the same guidelines
used in non-pregnant patients. Both radical modified mastectomy
and breast conserving surgery with lymph node dissection can
safely be performed during all trimesters of pregnancy with
minimal risk to the fetus. However, surgery in the first trimester is
often delayed many surgeons will choose to wait until after week
12 of gestation when the risk of spontaneous abortion decreases.
[9]
The data available in the literature on the performance of
sentinel lymph node (SLN) biopsy in pregnant women are scarce
and controversial. In current practice, SLN mapping is performed
by injection of 99 m-Technetium (99-Tc), injection of blue dye, or
both. Fetal well-being has to be considered, the potential problems
around SLN include fetal harm from maternal anaphylaxis to
isosulfan blue dye, radiation, and teratogenicity. There are limited
data describing the safety of this procedure. However, given the
relatively small number of patients, the strongest data available
come from cohort studies. Based on this, SLN appears to be
accurate and safe procedure for pregnant breast cancer patients
[44].
Because of some studies proposing the safety of 99-Tc for fetal,
there is an increased preference for use this. Despite theoretical
safety of blue dye, some aspects must be taken into consideration.
First, isosulfan blue has been described to cause allergic reaction.
And second, both isosulfan blue and methylene blue are pregnancy
class C drug, with an unknown potential for teratogenicity. Finally,
another concern is that physiological modifications of breast
lymphatic drainage during pregnancy may decrease the precision
of lymphatic mapping [45,46].
Radiotherapy
The use of radiotherapy as a treatment for supradiaphragmatic
neoplasia in pregnant women exposes the developing fetus to
scattered and leakage radiation despite the exclusion of the
planned tumor volume from the unborn child. This exposure to
fetal radiation can be associated with a high probability of fetal
malformations. Regarding the time interval between breast
surgery and irradiation, different authors agree that it should
not take more than 8–12 weeks, given that delays in local
radiotherapy of the breast are related to an increase in local
recurrence [47]. These data imply that breast cancer radiation
therapy at the third trimester of gestation should be postponed
until after delivery, due to the risk of damage to fetal organogenesis
[48,49]. The use of a 5-cm-thick lead lateral shield is recommended
to avoid the maternal and fetal irradiation mainly during the first
and second trimesters of pregnancy, to avoid both the determin-
istic effects for the fetus and the cancer risk from radiation therapy
[50,51]. RT’s acute effect on maternal lactation has not been
studied, so it is not recommended. [31]
Systemic therapy
Chemotherapy
The published data show that exposure to chemotherapy
during the first trimester is associated with a 14–19% risk of fetal
malformations, while from the second trimester onwards the risk
of fetal malformation is 1.3%; therefore, chemotherapy should not
be administered in the first trimester of pregnancy. In fact, if
chemotherapy is required in the first 12 weeks of amenorrhea,
termination of pregnancy should be considered [3].
Regarding chemotherapeutic agents, the most commonly used
are anthracyclines and alkylating agents [52,53].
In 2006, the latest update of the largest prospective cohort of
pregnant patients treated with a standardized chemotherapy
protocol was published. In this study, 57 pregnant women were
treated with 5-fluorouracil 500 mg/m2 (intravenously on days 1
 M.T. Martínez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 222–227 225

and 4), doxorubicin 50 mg/m2 (continuous infusion for 72 h) and
cyclophosphamide 500 mg/m2 (intravenously on day 1) (FAC). A
median of four cycles were administered during pregnancy
without significant incidences in the mother or the fetus. The
mean gestational age at the time of delivery was 37 weeks [54].
As new case reports continue to be published, more evidence is
appearing that taxanes can also be safe in the second and third
trimesters of pregnancy. However, Mir et al. describe that of 42
children born to 40 patients exposed to taxanes during pregnancy,
one had a malformation possibly related to the use of taxanes.
Therefore, further expansion of these data is required to confirm
the safety of chemotherapy regimens containing taxanes after the
first trimester of pregnancy [55,56]. Thus, currently the use of this
drug is not recommended until the birth of the child, and it is likely
that this will remain so until more safety data is available. Taxanes
could be an option for tumors that do not respond to
anthracyclines [57].
Existing data on the safety of other chemotherapeutic agents
during pregnancy are scarce (Table 1).
Biologic agents
Due to the few existing data in the literature about the safety of
biological agents in pregnancy, routine administration is not
recommended. One of the agents for which we have more data is
trastuzumab. Fetal Oligohydramnios has been frequently reported
with use of trastuzumab [58,59], as well as cases of fetal
respiratory insufficiency and fetal heart failure [60,61]. Treatment
with trastuzumab should therefore be delayed until the birth of the
child, although its use in emergency situations could be assessed
and the risk/benefit of its administration studied in each case.
Endocrine therapy
Endocrine therapy is not recommended during pregnancy.
Tamoxifen has been shown to cause birth defects, spontaneous
abortions, and fetal demise [62,63].
Breastfeeding
Breastfeeding is not recommended during the administration of
chemotherapy, biological therapy, endocrine therapy and radio-
therapy, since many of these agents are excreted into breast milk
[3,8].
Short and long-term complications in the newborn
Although the data are scarce, given the few pregnant patients
included in the different studies, all these studies confirm an
absence of significant neonatal complications.
Likewise, there is no extensive cohort in the literature
evaluating long-term complications including cardiac or neuro-
cognitive disorders in the child. Aviles et al. carried out a follow-up
for 18.7 years in 84 children born to mothers who received
chemotherapy during pregnancy for hematologic malignancies.
These children did not have any neurocognitive, physical or
psychological complications [64].
Prognosis
Conducting an exhaustive review of the literature, we find
controversial data. In some articles PABC is shown to have a poorer
prognosis [14,15], while in others it is shown that women who
were pregnant at the time of diagnosis or were diagnosed within
one year after delivery, did not have a higher locoregional
recurrence rate, distant metastasis or worse overall survival rate
[65–68].
In 2014 Michieletto et al. [29], performed a study in 26 patients
with PABC to evaluate the prognosis and the biological data, such
as p53, Ki67 and BRCA mutations. They reported that the
histopathological and immunohistochemical findings of breast
cancer in pregnancy are similar to those in non-pregnant subjects.
They showed that pregnant women had a high rate of distant
relapse (23%) within one year and 25% of patients had died after an
approximately 5-year follow-up. It is not possible to draw
definitive conclusions due to the few patients that have been
studied.
Recently, Johansson and collaborators, published an article
where they show, after studying 778 patients with PABC, that these
patients and especially those diagnosed 0–12 months after
delivery, had higher proportions of HER2 positive and triple
negative tumors and higher proportion of tumors large and lymph
node involvement [69].
It is important to underline two poor prognostic aspects related
to PABC: first age, as breast cancer in young patients has worse
prognosis, and delayed diagnosis that allows the tumour more
time to grow, increasing the metastatic potential of the disease
[15,63].
However, Beadled et al. conducted a study in 2009 to evaluate
the impact of pregnancy on breast cancer in young women
(35 years). They concluded that women who were pregnant at
the time of diagnosis or were diagnosed within 1 year after
delivery, did not have a worse prognosis than non-PABC patients
[65].
Conclusions
Breast cancer diagnosed during pregnancy is a rare clinical
situation, but requires close collaboration between all specialists
involved in diagnosis, treatment and monitoring. These patients
require an early diagnosis, since their long-term prognosis will
depend on it and they require close monitoring by their
obstetrician and oncologist to diagnose possible side effects of
the administered treatment. Fertility options and future pregnancy

Table 1
Systemic therapy in PABC. Modified from Azim Jr et al. The Breast 20, 2011.

Systemic agents in pregnant Indications

patients
Anthracyclines The best option if there are no contraindications (cardiac toxicity). Schemes such as FAC/FEC, AC/EC can be considered.
Paclitaxel The second-best option in case of metastatic disease when patients are not candidates for anthracycline-based regimens. The weekly
treatment seems attractive, since it facilitates monitoring and control of pregnancy
Docetaxel Less safety data than Paclitaxel. Neutropenia is frequent, so there is a lack of data to confirm its safety during pregnancy
Vinorelbine There are only sporadic case data, all without any problem. It could be considered as a treatment option if it is not possible to administer
anthracyclines or Paclitaxel.
Platinum salts Carboplatin appears to be less toxic during pregnancy than cisplatin.
Trastuzumab High risk of oligohydramnios with prolonged exposures. Best avoided until the end of pregnancy
Tamoxifen Must be completely avoided

FAC:5florouracil,doxorubicin,cyclophosphamide;FEC:5florouracil,epirubicin,cyclophosphamide;AC:doxorubicin,cyclophosphamide;EC:epirubicin,cyclophosphamide.
226 M.T. Martínez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 222–227
plans should be discussed with the patient before starting systemic
therapies. Therapeutic decisions should be based on the stage of
the disease, tumour biology, gestational age at diagnosis and
possible maternal-fetal risk. Chemotherapy should not be admin-
istered before week 12 of pregnancy or after weeks 34–35.
Anthracycline-based regimens are the treatment of choice during
pregnancy for their proven fetal safety.
In recent years we are evidencing an increase in PABC which
could be explained by an increase in the age of first pregnancy,
more evident in developed countries. The diagnosis of breast
cancer during pregnancy causes a tremendous psychological and
biological impact on these patients. All this should lead us to
increase our efforts to reduce delays in the diagnosis of these
patients, (performing an exhaustive study of all breast masses in
pregnant patients or during breastfeeding, as well as biopsy of any
lesion suspected of malignancy) as well to increase our knowledge
of the biology of these tumors to be able to offer more effective and
targeted treatments that are safe for both mother and child.
Competing interests
“The authors declare that they have no competing interests”.
Acknowledgements
This study is part of the Biomedical Cancer Network Research
Center (CIBERONC), an initiative of the Carlos III Health Institute.
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