Introduction

Pregnancy and cancer result in two diametrically opposing emotional reactions in

young women. The first leads usually to a joyous elation, whilst the other to
dismay and horror. When the two occur together, the patient is inevitably
distraught and terrified, whilst her obstetrician and medical advisers are faced
with a therapeutic dilemma involving surgical, perinatal, obstetric, psychological
and moral issues. (Mowafi)
Breast cancer is the most common cancer encountered in pregnant women
occurring in about 1 in 3,000 pregnancies. This incidence is expected to increase
as more women choose childbearing at a later age.(Mowafi) Only 10% of patients
diagnosed with breast cancer at under 40 years of age develop the disease during
pregnancy (martinex)
Although pregnancy-associated breast cancer (PABC, breast cancer diagnosed in
pregnancy or during the first 12 months post-partum) (6) is frequently diagnosed
at a more advanced stage than in breast cancer in non-pregnant women, PABC
patients often present a different tumor profile at diagnosis compared with non-
pregnant breast cancer patients. This may lead to more aggressive tumor growth
(11), advanced stage, and more frequent metastases (12).(froehlich)
Pregnancy is associated with an increased risk of breast cancer in the short time,
as well as with a long-term protective effect (martinex).
Pregnancy induces both proliferation and differentiation of the mammary
epithelium. Both lobular and alveolar growth occur. Differentiation of the alveoli
into mature milk-producing cells requires the stimulus of cortisol, insulin, and
7
prolactin. Prolactin is the major stimulus for galactopoiesis, and prolactin levels
are markedly elevated during the later trimesters of pregnancy and lactation. The
weight of the breasts approximately doubles with a 180% increase in blood flow.
The increase in size, weight, vascularity, and density makes detection of mass
lesions difficult both clinically and mammographically. (mowafi)
The molecular mechanism underlying this process is poorly understood. The
mammary gland is a dynamic organ that suffers significant changes during the
menstrual cycle, pregnancy, and lactation, these mechanisms are controlled by
mammary stem cells (MaSCs). 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 (martinex)
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 (Kotsopoulos J, Lubinski J, Salmena L, Lynch
HT, Kim-Sing C, Foulkes WD, Ghadirian P, Neuhausen SL, Demsky R, Tung N,
Ainsworth P, Senter L, Eisen A, Eng C, Singer C, Ginsburg O, Blum J, Huzarski
T, Poll A, Sun P, Narod SA, Hereditary Breast Cancer Clinical Study Group:
Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation
carriers. Breast Cancer Res 2012, 14: R42.)

Hormonal factors appear to play an important role early on in development of

breast cancer; however, pregnancy itself does not look clearly to influence the
outcome of an established breast cancer. (mowafi)
Through the 1950s and 1960s, concerns regarding the hormonal stimulation tumor
growth, poor survival, and the lack of effective systemic therapy for breast cancer
led many clinicians to advocate therapeutic abortions when breast cancer was
diagnosed during pregnancy. (mowafi)

Hence, management of pregnant women with cancer diagnosis should be

performed in specialised centres with experience and all cases should be discussed
in multidisciplinary meetings composed of multiple specialists (medical
oncologists, obstetricians, surgeons and paediatricians).(zagouri)

diagnosis
During pregnancy occurs a proliferation of glandular tissue and differentiation of
secretory units by pregnancy-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 (Framarino-Dei-Malatesta M, Piccioni MG, Brunelli R, Iannini I,
Cascialli G, Sammartino P. Breast cancer during pregnancy: a retrospective study
on obstetrical problems and survival. Eur J Obstet Gynecol Reprod Biol. 2014
Feb;173:48-52.).

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 (martinex)

therapy
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.(martinex)
Traditionally, chemotherapy is avoided in the first trimester due to the 14% risk of
major malformations versus the baseline risk of 3% in the general population in
the United States. Treatment with cytotoxic chemotherapy in the second or third
trimester appears to be safer with a risk of major fetal malformation similar to
baseline, although the rate of stillbirth is higher (2% versus 0.3%)
According to Lambertini et al, fetal exposure to 5-FU in the first trimester can
cause spontaneous abortion and major malformations including skeletal defects.
However, second trimester exposure has not been associated with birth defects (
Lambertini M, Kamal NS, Peccatori FA, Del Mastro L, Azim HA Jr. Exploring
the safety of chemotherapy for treating breast cancer during pregnancy. Expert
Opin Drug Saf. 2015; 14: 1395-408.)
The general recommendations for the breast cancer management 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. (Loibl S, von Minckwitz G, Gwyn K, et al. Breast carcinoma
during pregnancy. Cancer 2006;106(2): 237–246.246)

The administration of chemotherapy is possible during the second and third

trimester of pregnancy. Chemotherapy can be given from the 12 to 14th week of
pregnancy until a gestational age of 35e37 weeks. Chemotherapy is relatively safe
because of two reasons. Firstly, chemotherapy is administered after the first
trimester, which is the period of organogenesis. Chemotherapy is associated with
an allor-nothing phenomenon during the implantation and induces malformations
between the second and eighth week of pregnancy. This risk of malformation is
estimated to be 10e20%. Some organs are more vulnerable including the eyes, the
ears, the hematopoietic system, and the cerebral nervous system [Amant F, Han
SN, Gziri MM, et al. Chemotherapy during pregnancy. Curr Opin Oncol
2012;24:580e6.].
Aviles et al. described 54 patients treated by chemotherapy during the first
trimester of pregnancy without an increase of malformations and they explained
this observation by a different renal and hepatic function and metabolism during
the first trimester [Aviles A, Neri N, Nambo MJ. Hematological malignancies and
pregnancy: treat or no treat during first trimester. Int J Cancer
2012;131:2678e83.]. However, the timing of chemotherapy administration was
poorly documented Therefore, chemotherapy is advised only after the 12the14th
week of pregnancy because of teratogenicity risks . [Han SN, Gziri MM, Van
Calsteren K, et al. Is chemotherapy during the first trimester of pregnancy really
safe? Int J Cancer 2013;132:1728.].

Secondly, the placenta is a barrier and protects the fetus. For all investigated
drugs, lower fetal concentrations were encountered. The transfer of chemotherapy
is analyzed in animal models and in vitro [48e53], and it depends on maternal
pharmacokinetics, placental blood flow, and the physicochemical drug properties
[54]. The placenta is an active organ where placental transporters guide the
transplacental passage of drugs. This passage can be low (paclitaxel, 0e1%),
intermediate (anthracyclines, 5e7%), or high (carboplatin, 60%) [50,51]. Although
most cytotoxic drugs can be used during pregnancy, trastuzumab (Herceptin_)
crosses the placenta and binds the Her-2 receptors of kidney epithelium, resulting
in reduced amniotic fluid, lung hypoplasia, and fetal death [55]. Currently, no
guidelines exist regarding chemotherapy dosages during pregnancy and the same
dosages are used for nonpregnant and pregnant patients. If corticosteroids are
administered as co-medication, methylprednisolone is preferred over
dexa/betamethasone as placental metabolization results in less transplacental
transfer [56].

The knowledge that chemotherapy can be used during pregnancy has three clinical
implications. Firstly, the need for chemotherapy is not a reason to terminate the
pregnancy. Secondly, the potential to administer chemotherapy allows a timely
maternal treatment without delay. Thirdly, the use of chemotherapy during
pregnancy adds in the prevention of iatrogenic prematurity. Despite this, more
Jchildren need to be followed up for a longer duration in order to provide more
solid safety data.(amant 2015)

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. (Litton JK 2009)
A regular fetal monitoring by ultrasound for growth and fetal well-being is
required. Special attention is required for fetal growth, preterm contractions, and
potential fetal anemia or cardiotoxicity after (anthracycline-based) chemotherapy
(Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an
analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J
Clin Oncol 2010;28:683e9)
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 (Litton JK, Theriault RL, Gonzalez-Angulo AM. Breast cancer
diagnosis during pregnancy. Womens Health (Lond Engl). 2009 May; 5(3): 243–
249.).

A term delivery should be aimed for as prematurity (and also late prematurity) is
associated with a significant neonatal and long-term morbidity . If chemotherapy
treatment is ongoing, delivery should be planned at least 3 weeks after the last
cycle given during pregnancy to avoid drug accumulation in the neonate, and to
avoid problems associated with hematopoietic suppression during delivery. For
the same reason, chemotherapy should not be administered after 35e37 weeks as
spontaneous labor becomes more likely. (amant 2015)

Berry published a standardized protocol for breast cancer during pregnancy that
utilizes a multidisciplinary team approach, including surgery for those women
with operable disease and systemic chemotherapy with cyclophosphamide,
doxorubicin, and 5-fluorouracil (FAC regimen). In their study of 22 women, no
unusual neonatal complications were seen. (Berry DL, Theriault RL, Holmes FA,
Parisi VM, Booser DJ, Singletary SE, et al. Management of breast cancer during
pregnancy using a standardized protocol. J Clin Oncol. 1999; 17: 855-61.)
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 (G, Pavlidis N, Peccatori FA:Prognosis of pregnancy-associated breast
cancer: a meta-analysis of 30 studies. Cancer Treatment Rev 2012, 38:834–842).

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
(Beadle BM, Woodward WA, Middleton LP, Tereffe W, Strom EA, Litton JK,
Meric Bernstam F, Theriault RL, Buchholz TA, Perkins GH.. The impact of
pregnancy on breast cancer outcomes in women less than 35 years. Cancer
2009;115(6):1174–1184.1184 [PubMed: 19204903)
Azim HA Jr, Santoro L, Russell-Edu W, Pentheroudakis

Diskusi
Pregnancy favors processes that promote tumor progression including “intense
modifications in cell proliferation and survival” and “tissue angiogenesis and
remodeling” [2].Physiological changes in breast during pregnancy, including
engorgement, hypertrophy, nodularity, and discharge, make the diagnosis difficult
and delayed, leading to poorer prognosis compared to nonpregnant patients (I.
Krishna and M. Lindsay, “Breast cancer in pregnancy,” Obstetrics & Gynecology
Clinics of North America, vol. 40, no.3, pp. 559–571, 2013.)

Both fine needle aspiration and core needle biopsy can be used for evaluation;
however, the latter is preferred as it provides information on histology, hormone
receptor status, and HER2 analysis. Chest X-ray, ultrasound of the liver, and bone
MRI without contrast are recommended to investigate the metastasis of breast
cancer [F. Amant, S. Loibl, P. Neven, and K. Van Calsteren, “Breast cancer in
pregnancy,”TheLancet, vol. 379, no. 9815, pp. 570–579, 2012.].
Kesimpulan:

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 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 administered 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