Breast cancer in pregnant patients: A review of the literature

Accepted Manuscript Title: BREAST CANCER IN PREGNANT PATIENTS: A REVIEW OF THE LITERATURE Authors: Mar´ıa Teresa Mart´ınez, Bego˜na Bermejo, Cristina Hernando, Valentina Gambardella, Juan Miguel Cejalvo, Ana Lluch PII: DOI: Reference:

S0301-2115(18)30201-X https://doi.org/10.1016/j.ejogrb.2018.04.029 EURO 10339

To appear in:

EURO

Received date: Revised date: Accepted date:

3-1-2018 16-4-2018 22-4-2018

Please cite this article as: Mart´ınez Mar´ıa Teresa, Bermejo Bego˜na, Hernando Cristina, Gambardella Valentina, Cejalvo Juan Miguel, Lluch Ana.BREAST CANCER IN PREGNANT PATIENTS: A REVIEW OF THE LITERATURE.European Journal of Obstetrics and Gynecology and Reproductive Biology https://doi.org/10.1016/j.ejogrb.2018.04.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

TITLE BREAST CANCER IN PREGNANT PATIENTS: A REVIEW OF THE LITERATURE AUTHORS María Teresa Martínez1, Begoña Bermejo1, Cristina Hernando1, Valentina Gambardella1, Juan Miguel Cejalvo1, Ana Lluch1.

IP T

FILIATION:

1.Medical Oncology and Hematology Unit, Health Research Institute INCLIVA,

SC R

University of Valencia, Spain, and the Centre of Networked Biomedical Cancer Research (CIBERONC). ABSTRACT

U

Breast cancer diagnosed during pregnancy is a rare occurrence at present; however, in

N

recent years a trend towards delayed childbirth is generating an increase in its incidence. This situation requires a multidisciplinary approach involving obstetricians, oncologists

A

and surgeons.

M

In this review we analyse diagnostic methods, different possible treatments and long-term patient prognosis. We conducted a search for articles published in PubMed, or in abstract

ED

form from the San Antonio Breast Cancer Symposium (SABCS), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO) annual meeting, using the search terms:

PT

“Breast cancer and pregnancy”.

Breast cancer occurring during pregnancy requires extra effort to offer patients the best

CC E

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-

A

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.

KEYWORDS: Breast cancer, Pregnancy, Diagnosis, Treatment, Prognosis.

1. Introduction 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

IP T

very young, and the disease constitutes 5 to 7% of all cancer deaths in these young women (2).

SC R

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

U

breast cancer at under 40 years of age develop the disease during pregnancy (3).

A

pregnancy or within one year of delivery (4).

N

Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during

Based on the European records on PABC, the average age of onset is 33 years, and the

M

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

ED

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

PT

progressive increase in age of first pregnancy (8). There are few published works about the treatment of PABC, but all of them support the

CC E

continuation of pregnancy during treatment. Therefore, a greater understanding of the biological mechanisms, anatomopathological characteristics and different treatment options are essential.

A

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 the treatments that are considered safe for both the mother and the fetus.

2. 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

IP T

Symposium (SABCS) Meeting abstracts were searched using the terms “Breast cancer

SC R

and pregnancy “; papers considered relevant for the aim of this review were selected.

3. Biology of PABC

Pregnancy is associated with an increased risk of breast cancer in the short time, as well

U

as with a long-term protective effect (11). The molecular mechanism underlying this

N

process is poorly understood. The mammary gland is a dynamic organ that suffers

A

significant changes during the menstrual cycle, pregnancy, and lactation, these mechanisms are controlled by mammary stem cells (MaSCs) (12). Despite, the MaSCs

M

lack estrogen/progesterone receptor expression, the functions of these cells are controlled by oestrogen and progesterone hormone signalling, both hormones are well-established

ED

risk factor for breast cancer (13).

Multiple studies and a meta-analysis have shown that patients diagnosed with breast

PT

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

CC E

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

A

cancer incidence that accompanies pregnancy. Another hypothesis considered is that the mammary involution processes occurring after childbirth could activate angiogenesis, inflammation 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

IP T

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

SC R

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.

U

Thus, differences between pathological features of BRCA1 and BRCA2 tumors may also

N

reflect differences in risk factor association.

Other mechanism that take place is the maternal immunological tolerance to allow the

A

semi-allogeneic fetus to grow within. The immune profile of pregnant patients is

M

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

ED

have been implicated in facilitating immune tolerance, and ultimately, cancer escape (21). As in the general population, invasive ductal carcinoma is the most frequent PABC

PT

(between 71 and 100%) (15,22-26), although these tumours are larger, with higher histological grade, with vascular and lymphatic invasion and greater affectation of the

CC E

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).

A

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 tumours of 54 pregnant women and compare them with 113 tumours 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 tumours 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).

4. 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 to 10 months has been reported, compared with 1 to 4 months in non-

IP T

pregnant patients ( 30, 31).

Often, a delay in the cancer diagnosis is secondary to pregnancy and lactation, due to the

SC R

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

U

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

N

processes are manifested in an increase in the volume and density of the breast. All these

A

mammary changes make mammary exploration very complicated and this fact can delay

M

the identification of a suspicious mass (32,33).

With the intention of reducing delays in diagnosis, palpable masses that persist for more

ED

than 2 weeks during pregnancy and lactation should be investigated. Finally, around 80% of breast biopsies during pregnancy will be benign (8).

PT

Regarding complementary tests, mammography during pregnancy should be performed with adequate abdominal protection. Exposure to radiation for the fetus is estimated at

CC E

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

A

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 hours 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. If the biopsy confirms the existence of breast cancer, the initial staging should include a

IP T

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

SC R

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

U

voxelwise anthropomorphic phantoms, are 2.5E-02 mGy / MBq in early pregnancy, 1.3E-

N

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

A

pregnancy is PET / MRI because it is not associated with radiation for correction of

5. PABC treatment

ED

M

attenuation and allows more accurate dosimetric calculations (39,40).

Pregnancy itself should not modify the effective treatment of breast cancer, although the

PT

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

CC E

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

A

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, obstetricians, 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 management during pregnancy are that surgery can be performed in all trimesters, chemotherapy in the second and third

IP T

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

chemotherapy at this stage is likely to harm the fetus. (43).

SC R

III and IV) during the first trimester, the interruption of pregnancy is advised, because

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

U

be examined by an obstetrician prior to each cycle of chemotherapy, with strict fetal

N

monitoring with a morphometric and umbilical artery Doppler ultrasound. Chemotherapy should not be administered beyond 2 weeks before delivery to avoid neutropenia in the

A

mother and potentially in the fetus and should not be given after week 34-35 of pregnancy,

M

given the risk of spontaneous delivery in these weeks (8). 5.1. Breast Surgery.

ED

There is an extensive experience with surgery during pregnancy, therefore mammary surgery should follow the same guidelines used in non-pregnant patients. Both radical

PT

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.

CC E

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)

A

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

IP T

modifications of breast lymphatic drainage during pregnancy may decrease the precision

SC R

of lymphatic mapping (45, 46).

5.2. Radiotherapy

The use of radiotherapy as a treatment for supradiaphragmatic neoplasia in pregnant

U

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

N

radiation can be associated with a high probability of fetal malformations. Regarding the

A

time interval between breast surgery and irradiation, different authors agree that it should

M

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

ED

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-cmthick lead lateral shield is recommended to avoid the maternal and fetal irradiation mainly

PT

during the first and second trimesters of pregnancy, to avoid both the deterministic effects for the fetus and the cancer risk from radiation therapy (50,51). RT’s acute effect on

CC E

maternal lactation has not been studied, so it is not recommended. (31) 5.3. Systemic therapy

A

A. 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 and 4), doxorubicin 50 mg/m2 (continuous infusion for 72 h) and cyclophosphamide 500 mg /

IP T

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

SC R

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

U

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

N

of these data is required to confirm the safety of chemotherapy regimens containing

A

taxanes after the first trimester of pregnancy (55, 56). Thus, currently the use of this drug

M

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

ED

respond to anthracyclines (57).

Existing data on the safety of other chemotherapeutic agents during pregnancy are scarce

PT

(Table 1). B. Biologic agents

CC E

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

A

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.

C. Endocrine therapy Endocrine therapy is not recommended during pregnancy. Tamoxifen has been shown to cause birth defects, spontaneous abortions, and fetal demise (62,63).

6. Breastfeeding Breastfeeding is not recommended during the administration of chemotherapy, biological therapy, endocrine therapy and radiotherapy, since many of these agents are excreted into

IP T

breast milk (3, 8).

SC R

7. 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.

U

Likewise, there is no extensive cohort in the literature evaluating long-term complications including cardiac or neurocognitive disorders in the child. Aviles et al. carried out a

N

follow-up for 18.7 years in 84 children born to mothers who received chemotherapy

A

during pregnancy for hematologic malignancies. These children did not have any

M

neurocognitive, physical or psychological complications (64). 8. Prognosis

ED

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

PT

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

CC E

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

A

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 012 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

IP T

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).

SC R

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

U

have a worse prognosis than non-PABC patients (65).

N

9. Conclusions

Breast cancer diagnosed during pregnancy is a rare clinical situation, but requires close

A

collaboration between all specialists involved in diagnosis, treatment and monitoring.

M

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

ED

possible side effects of the administered treatment. Fertility options and future pregnancy plans should be discussed with the patient before starting systemic therapies. Therapeutic

PT

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

CC E

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

A

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.

DECLARATIONS Competing interests "The authors declare that they have no competing interests"

IP T

Acknowledgements

SC R

This study is part of the Biomedical Cancer Network Research Center (CIBERONC), an initiative of the Carlos III Health Institute.

REFERENCES

A

CC E

PT

ED

M

A

N

U

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9. 2. Cardoso F, Loibl S, Pagani O, Graziottin A, Panizza P, Martincich L, Gentilini O, Peccatori F, Fourquet A, Delaloge S, Marotti L, Penault-Llorca F, Kotti-Kitromilidou AM, Rodger A, Harbeck N; European Society of Breast Cancer Specialists. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. Eur J Cancer 2012; 48:3355-77 3. Azim HA, Jr., Del Mastro L, Scarfone G, Peccatori FA. Treatment of breast cancer during pregnancy: regimen selection, pregnancy monitoring and more. Breast 2011; 20:1-6 4. Petrek JA, Dukoff R, Rogatko A. Prognosis of pregnancy-associated breast cancer. Cancer 1990; 67:869e72. 5. Navrozoglou I, Vrekoussis T, Kontostolis E, Dousias V, Zervoudis S, Stathopoulos EN, et al. Breast cancer during pregnancy: a mini-review. Eur J Surg Oncol 2008; 34:837e43. 6. Cullinane CA, Lubinski J, Neuhausen SL, Ghadirian P, Lynch HT, Isaacs C, et al. Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer 2005; 117:988e91. 7. Valentini A, Lubinski J, Byrski T, Ghadirian P, Moller P, Lynch HT, Ainsworth P, Neuhausen SL, Weitzel J, Singer CF, Olopade OI, Saal H, Lyonnet DS, Foulkes WD, Kim-Sing C, Manoukian S, Zakalik D, Armel S, Senter L, Eng C, Grunfeld E, Chiarelli AM, Poll A, Sun P, Narod SA; Hereditary Breast Cancer Clinical Study Group.; Hereditary Breast Cancer Clinical Study Group. The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation. Breast Cancer Res Treat. 2013 Nov;142(1):177-85 8. Litton JK, Theriault RL, Gonzalez-Angulo AM. Breast cancer diagnosis during pregnancy. Womens Health (Lond Engl). 2009 May; 5(3): 243–249. doi:10.2217/whe.09.2. 9. Polyak K. Pregnancy and breast cancer: the other side of the coin. Cancer Cell 2006; 9:151e3 10. Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer 2006; 6:281e91.

A

CC E

PT

ED

M

A

N

U

SC R

IP T

11. Albrektsen G, Heuch I, Tretli S, Kvale G: Breast cancer incidence before age 55 in relation to parity and age at first and last births: a prospective study of one million Norwegian women. Epidemiology 1994, 5:604–611. 12. C Ercan. PJ van Diest and M Vooijs. Mammary Development and Breast Cancer: The Role of Stem Cells. Curr Mol Med 2011 13. Asselin-Labat ML, Vaillant F, Sheridan JM, Pal B, Wu D, Simpson ER, Yasuda H, Smyth GK, Martin TJ, Lindeman GJ, Visvader JEControl of mammary stem cell function by steroid hormone signalling. Nature 2010. 14. 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. 15. Azim HA Jr, Santoro L, Russell-Edu W, Pentheroudakis G, Pavlidis N, Peccatori FA: Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies. Cancer Treatment Rev 2012, 38:834–842. 16. Murphy H, Sherman ME, Browne EP, et al. Potential of Breastmilk Analysis to Inform Early Events in Breast Carcinogenesis: Rationale and Considerations. Breast Cancer Res Treat 2016 17. Li CI, Beaber EF, Tang MT, Porter PL, Daling JR, Malone KE: Reproductive factors and risk of estrogen receptor positive, triple-negative, and HER2-neu overexpressing breast cancer among women 20–44 years of age. Breast Cancer Res Treat 2013, 137:579–587. 18. Shinde SS, Forman MR, Kuerer HM, Yan K, Peintinger F, Hunt KK, Hortobagyi GN, Pusztai L, Symmans WF: Higher parity and shorter breastfeeding duration: association with triple-negative phenotype of breast cancer. Cancer 2010, 116:4933–4943. 19. Redondo CM, Gago-Domínguez M, Ponte SM, Castelo ME, Jiang X, García AA, Fernández MP, Tomé MA, Fraga M, Gude F, Martínez ME, Garzón VM, Carracedo Á, Castelao JE: Breast feeding, parity and breast cancer subtypes in a Spanish cohort. PLoS One 2012, 7: e40543. 20. Collaborative Group on Hormonal Factors in Breast Cancer Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002 21. Guzman-Genuino RM and Diener KR. Regulatory B Cells in Pregnancy: Lessons from Autoimmunity, Graft Tolerance, and Cancer. Front Immunol 2017 22. Schedin P: Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer 2006, 6:281–291. 23. Bonnier P, Romain S, Dilhuydy JM, Bonichon F, Julien JP, Charpin C, et al. Influence of pregnancy on the outcome of breast cancer: a case-control study. Societe Francaise de Senologie et de Pathologie Mammaire Study Group. Int J Cancer 1997; 72:720e7. 24. Petrek JA, Dukoff R, Rogatko A. Prognosis of pregnancy-associated breast cancer. Cancer 1990; 67:869e72. 25. Ishida T, Yokoe T, Kasumi F, Sakamoto G, Makita M, Tominaga T, et al. Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: analysis of case-control study in Japan. Jpn J Cancer Res 1992; 83:1143e9. 26. Ruiz R, Herrero C, Strasser-Weippl K, Touya D, St Louis J, Bukowski A, Goss PE. Epidemiology and pathophysiology of pregnancy-associated breast cancer: A review. Breast. 2017 Oct;35:136-141 27. Shousha S. Breast carcinoma presenting during or shortly after pregnancy and lactation. Arch Pathol Lab Med 2000; 124:1053e60.

A

CC E

PT

ED

M

A

N

U

SC R

IP T

28. Elledge RM, Ciocca DR, Langone G, McGuire WL. Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients. Cancer 1993; 71:2499e506. 29. Michieletto S, Saibene T, Evangelista L, Barbazza F, Grigoletto R, Rossi G, Ghiotto C, Bozza F. Preliminary monocentric results of biological characteristics of pregnancy associated breast cancer. Breast. 2014 feb;23(1):19-25. doi: 10.1016/j.breast.2013.10.001. Epub 2013 Nov 1 30. Azim HA Jr, Brohée S, Peccatori FA, Desmedt C, Loi S, Lambrechts D, Dell'Orto P, Majjaj S, Jose V, Rotmensz N, Ignatiadis M, Pruneri G, Piccart M, Viale G, Sotiriou C. Biology of breast cancer during pregnancy using genomic profiling. Endocr Relat Cancer. 2014 Aug;21(4):545-54. doi: 10.1530/ERC-14-0111. Epub 2014 May 13 31. Shachar SS, Gallagher K, McGuire K, Zagar TM, Faso A, Muss HB, Sweeting R, Anders CK. Multidisciplinary Management of Breast Cancer During Pregnancy. Oncologist. 2017 Mar;22(3):324-334. 32. 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. 33. Navrozoglou I, Vrekoussis T, Kontostolis E, Dousias V, Zervoudis S, Stathopoulos EN, et al. Breast cancer during pregnancy: a mini-review. Eur J Surg Oncol 2008; 34:837e43. 34. Jones AL. Management of pregnancy-associated breast cancer. Breast 2008; 17:213. 35. Rimawi BH, Green V, Lindsay M. Fetal Implications of Diagnostic Radiation Exposure During Pregnancy: Evidence-based Recommendations. Clin Obstet Gynecol. 2016; 59:412-8. 36. Nicklas A, Baker M. Imaging strategies in the pregnant breast cancer patient). Semin. Oncol 2000;27 (6):623–632. [PubMed: 11130469]. 37. Yang WT, Dryden MJ, Gwyn K, Whitman GJ, Theriault R. Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy. Radiology 2006;239(1):52– 60.60 [PubMed: 16484353] 38. Webb JAW, Thomsen HS, Morcos SK. The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur. Radiol 2005;15(6):1234–1240. 39. Zanotti-Fregonara P, Chastan M, Edet-Sanson A, Ekmekcioglu O, Erdogan EB, Hapdey S, Hindie E, Stabin MG. New Fetal Dose Estimates from 18F-FDG Administered During Pregnancy: Standardization of Dose Calculations and Estimations with Voxel-Based Anthropomorphic Phantoms. J Nucl Med. 2016 Nov;57(11):1760-1763. Epub 2016 Jun 3. 40. Zanotti-Fregonara P, Laforest R, Wallis JW. Fetal Radiation Dose from 18F-FDG in Pregnant Patients Imaged with PET, PET/CT, and PET/MR. J Nucl Med. 2015 Aug;56(8):1218-22. doi: 10.2967/jnumed.115.157032. Epub 2015 Jun 18. 41. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review. J Natl Cancer Inst 2012;104(5):386e405 42. Gerstl B, Sullivan E, Ives A, Saunders C, Wand H, Anazodo A. Pregnancy Outcomes After a Breast Cancer Diagnosis: A Systematic Review and Meta-analysis. Clin Breast Cancer. 2018 Feb;18(1):e79-e88 43. Loibl S, von Minckwitz G, Gwyn K, et al. Breast carcinoma during pregnancy. Cancer 2006;106(2): 237–246.246 [PubMed: 16342247] 44. Gropper AB, Calvillo KZ, Dominici L, Troyan S, Rhei E, Economy KE, Tung NM, Schapira L, Meisel JL, Partridge AH, Mayer EL. Sentinel Lymph Node Biopsy in Pregnant Women with Breast Cancer. Ann Surg Oncol (2014) 45. NCCN guidelines 2017. www.nccn.org

A

CC E

PT

ED

M

A

N

U

SC R

IP T

46. Michieletto S, Saibene T, Evangelista L, Barbazza F, Grigoletto R, Rossi G, Ghiotto C, Bozza F. Preliminary monocentric results of biological characteristics of pregnancy associated breast cancer. Breast. 2014 feb;23(1):19-25. doi: 10.1016/j.breast.2013.10.001. Epub 2013 Nov 1. 47. Toesca, A., Gentilini, O., Peccatori, F., Azim, H. A. and Amant, F. Locoregional treatment of breast cancer during pregnancy. Gynecol. Surg. 11, 279 –284 (2014). 48. Mazonakis M, Varveris H, Damilakis J, Theoharopoulos N, Gourtsoyiannis N. Radiation dose to conceptus resulting from tangential breast irradiation. Int. J. Radiat. Oncol. Biol. Phys 2003;55(2): 386–391. [PubMed: 12527052] 49. Loibl S, Schmidt A, Gentilini O, Kaufman B, Kuhl C, Denkert C, von Minckwitz G, Parokonnaya A, Stensheim H, Thomssen C, van Calsteren K, Poortmans P, Berveiller P, Markert UR, Amant F. Breast Cancer Diagnosed During Pregnancy: Adapting Recent Advances in Breast Cancer Care for Pregnant Patients. JAMA Oncol. 2015 Nov;1(8):1145-53 50. Mazonakis M, Damilakis J. Estimation and reduction of the radiation dose to the fetus from external-beam radiotherapy. Phys Med. 2017 Nov;43:148-152. doi: 10.1016/j.ejmp.2017.09.130. Epub 2017 Sep 21. 51. Mazonakis M, Tzedakis A, Damilakis J. Monte Carlo Simulation of Radiotherapy for Breast Cancer in Pregnant Patients: How to Reduce the Radiation Dose and Risks to Fetus? Radiat Prot Dosimetry. 2017 Jun 1;175(1):10-16. doi: 10.1093/rpd/ncw260. 52. Amant F, Loibl S, Neven P, Van Calsteren K. Breast cancer in pregnancy. Lancet 2012; 379:570e9. 53. Van Calsteren K, Heyns L, De Smet F, Van Eycken L, Gziri MM, Van Gemert W, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol 2010; 28:683e9. 54. Hahn KM, Johnson PH, Gordon N. Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 2006;107(6):1219– 1226.1226 55. Gadducci A, Cosio S, Fanucchi A, Nardini V, Roncella M, Conte PF, Genazzani AR. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and review of the literature. Anticancer Res 2003; 23:5225–5230]. 56. Mir O, Berveiller P, Goffinet F, Treluyer JM, Serreau R, Goldwasser F, Rouzier R. Taxanes for breast cancer during pregnancy: a systematic review. Ann Oncol (2010) 21(2):425–426 57. Meisel JL, Economy KE, Calvillo KZ, Schapira L, Tung NM, Gelber S, Kereakoglow S, Partridge AH, Mayer EL. Contemporary multidisciplinary treatment of pregnancyassociated breast cancer. Springer plus. 2013 Jul 3;2(1):297. doi: 10.1186/2193-1801-2297. Print 2013 Dec. 58. Sekar R, Stone PR. Trastuzumab use for metastatic breast cancer in pregnancy. Obstet. Gynecol 2007;110(2):507–510. [PubMed: 17666645] 59. Bader AA, Schlembach D, Tamussimo KF, Pristauz G, Petru E. Anhydramnios associated with administration of trastuzumab and paclitaxel for metastatic breast cancer during pregnancy. Lancet Oncol 2007;8(1):79–81. [PubMed: 17196514] 60. Shrim A, Garcia-Bournissen F, Maxwell C, Farine D, Koren G. Trastuzumab treatment for breast cancer during pregnancy. Can. Fam. Physician 2008;54(1):31–32. [PubMed: 18208949] 61. Witzel ID, Müller V, Harps E, Janicke F, Dewit M. Trastuzumab in pregnancy associated with poor fetal outcome. Ann. Oncol 2008;19(1):191–192. [PubMed: 18084047] 62. Isaacs RJ, Hunter W, Clark K. Tamoxifen as systemic treatment of advanced breast cancer during pregnancy - case report and literature review. Gynecol. Oncol 2001;80(3):405–408. [PubMed: 11263941]

A

CC E

PT

ED

M

A

N

U

SC R

IP T

63. Guidroz JA, Scott-Conner CE, Weigel RJ. Management of pregnant women with breast cancer. J Surg Oncol 2011; 103:337e40. 64. Aviles A, Neri N. Hematologic malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin. Lymphoma 2001;2(3):173–177.177 65. Beadle BM, Woodward WA, Middleton LP, Tereffe W, Strom EA, Litton JK, MericBernstam 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 66. Litton JK, Theriault RL, Gonzalez-Angulo AM. Breast cancer diagnosis during pregnancy. Womens Health (Lond Engl). 2009 May; 5(3): 243–249. doi:10.2217/whe.09.2. 67. Shlensky V, Hallmeyer S, Juarez L, Parilla BV. Management of Breast Cancer during Pregnancy: Are We Compliant with Current Guidelines. AJP Rep. 2017 Jan;7(1): e39e43. doi: 10.1055/s-0037-1599133 68. Lee GE, Mayer EL, Partridge A. Prognosis of pregnancy-associated breast cancer. Breast Cancer Res Treat. 2017 Jun;163(3):417-421 69. Johansson ALV, Andersson TM, Hsieh CC, Jirström K, Cnattingius S, Fredriksson I, Dickman PW, Lambe M. Tumor characteristics and prognosis in women with pregnancyassociated breast cancer. Int J Cancer. 2018 Apr 1;142(7):1343-1354. doi: 10.1002/ijc.31174. Epub 2017 Dec 4

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

Systemic agents in pregnant patients

Indications

Anthracyclines

The best option if there are no contraindications

AC / EC can be considered.

IP T

(cardiac toxicity). Schemes such as FAC / FEC, The second-best option in case of metastatic

Paclitaxel

disease when patients are not candidates for

SC R

anthracycline-based regimens. The weekly treatment seems attractive, since it facilitates monitoring and control of pregnancy Docetaxel

U

Less safety data than Paclitaxel. Neutropenia is frequent, so there is a lack of data to confirm its

N

safety during pregnancy Vinorelbine

A

There are only sporadic case data, all without

M

any problem. It could be considered as a

PT

Platinum salts

ED

treatment option if it is not possible to

CC E

Trastuzumab

Carboplatin appears to be less toxic during pregnancy than cisplatin. High risk of oligohydramnios with prolonged exposures. Best avoided until the end of pregnancy Must be completely avoided

A

Tamoxifen

administer anthracyclines or Paclitaxel.

FAC:5florouracil,doxorubicin,cyclophosphamide;FEC:5florouracil,epirubicin,cyclophosphamid e;AC:doxorubicin,cyclophosphamide;EC:epirubicin,cyclophosphamide