Although rare, it is one of the more common malignancies encountered during pregnancy, accounting for 10% of breast cancer cases in patients under 40 years.^1,2 As women in the developed world delay childbearing, the incidence appears to be increasing.³

The complexities related to management arise particularly in patients diagnosed in the gestational period. There is a relative paucity of data to guide treatment decisions. Current knowledge is garnered from retrospective series, case reports and limited prospective studies as randomised trials are not feasible for ethical reasons.⁴ This review explores the management of PABC and the existing challenges relating to diagnosis, treatment, obstetric management and maternal and foetal outcomes. 

Clinical and pathology features

Patients with PABC usually present with a breast mass. Rarely, they present with bloody nipple discharge⁵ or failure of an infant to feed referred to as the ‘milk rejection sign’.⁶ The pathological characteristics of PABC appear to be influenced by age as opposed to the pregnancy itself. As such, PABC tends to present with invasive ductal carcinoma, more advanced stage tumours, nodal involvement and more aggressive biology. Higher grade tumours and increased rates of hormone receptor-negative and HER2-positive tumours are regularly observed.^2,4 Patients with a known BRCA 1 or 2 mutation or a family history of breast cancer do not appear to have an increased breast cancer risk during the gestational period.^7,8 

Diagnostic imaging

Breast imaging in pregnancy can be challenging due to the physiological changes of the breast. Ultrasound is the initial modality of choice due to the lack of ionizing radiation and its high diagnostic sensitivity and specificity. Mammography is indicated following ultrasound if a suspicious mass is identified or a core biopsy demonstrates an invasive carcinoma. It can be useful in determining multifocality or bilateral disease and is relatively safe during pregnancy. The foetal dose of radiation is less than 3mGy, which lies well below the accepted teratogenic threshold dose of 50mGy. Lead shielding of the abdomen is thought to reduce the radiation dose by a further 50%.⁹ Gadolinium-enhanced MRI is not recommended during pregnancy due to an increased risk of stillbirth and neonatal death.¹⁰ Non-contrast MRI or MRI with other contrast agents such as gadobenate dimeglumine is feasible but should only be considered when other diagnostic imaging is inadequate.⁴

Where systemic staging is indicated, chest x-ray with abdominal shielding poses little risk to the foetus and liver ultrasound is safe but less sensitive and specific than CT or MRI.¹¹ Non-contrast skeletal MRI can be performed to detect bone metastases as there is no associated radiation. Whole body MRI with diffusion weighted imaging (DWI) has high sensitivity and appears to be a feasible technique for single-step locoregional and systemic staging in pregnancy.¹²

MRI has traditionally been avoided in the first trimester due to concerns of foetal tissue overheating by radiofrequency fields during organogenesis. Ray et al did not adduce an increased risk of foetal harm overall with exposure to non-contrast MRI in the first trimester. However, in a sub-analysis of foetuses at five to 10 weeks gestation, a slightly higher risk of vision loss was observed.¹⁰ CT abdomen and pelvis and PET/CT are generally avoided during pregnancy due to exposure of the foetus to high radiation doses.¹³

Locoregional treatment

Surgery and radiation therapy

Definitive locoregional treatment of breast cancer in the pregnant patient is similar to the non-pregnant patient. Surgery can usually be safely performed in any trimester and anaesthesia is not associated with a major risk to the foetus.^14,15 The choice of breast conservation or mastectomy depends on the disease stage and both are associated with similar survival outcomes.^2,16,17 Retrospective series suggest that sentinel lymph node biopsy (SLNB) during pregnancy is safe and the radiation exposure inconsequential. Technetium 99m-labelled sulphur colloid is preferred due to the risk of maternal anaphylaxis with blue dye.¹⁸ Delaying reconstruction until after pregnancy is often advised as achieving a satisfactory cosmetic outcome can be limited by the physiological engorgement of the breast during pregnancy.^19,20 

The timing of radiation therapy usually coincides with the postpartum period as most PABC patients require chemotherapy. A dilemma generally only arises in patients with small low-risk tumours who present early in pregnancy. These patients may opt for mastectomy if radiation therapy is to be delayed. The delivery of radiotherapy more than 12 weeks after surgery could be deleterious in reducing the risk of locoregional recurrence.^2,16,17 

If a patient is particularly keen for breast conservation surgery, radiation could be considered in the 1st or early 2nd trimester after a careful discussion of the benefit-risk profile. Foetal risks from radiation include death, restricted growth, major congenital abnormalities, and intellectual disability. 

The embryo is most susceptible to the teratogenic effects of radiation in the first trimester. However, as it lies deep in the pelvis, it is estimated that exposure is 0.1% of the total dose (0.05Gy or less). In contrast, later in pregnancy, the foetus lies closer to the radiation field and can be exposed to doses up to 2Gy which are known to be harmful.^{4,21,22,23,24}

Chemotherapy and HER2-targeted agents

(Neo)adjuvant therapy can be safely administered after the first trimester of pregnancy, the period during which organogenesis occurs. Cytotoxic therapy administered during this period has been associated with a 20% risk of congenital malformation.²⁵ The incidence of malformations is low in the second and third trimester but it is an important period for maturation and development. As a result, intrauterine chemotherapy exposure can be associated with intrauterine growth restriction (IUGR) and prematurity.²⁶

The pharmacokinetic properties of cytotoxic drugs are thought to be altered during pregnancy due to several factors including increased cardiac output, increased plasma volume and accelerated hepatic and renal clearance. It is theorised that with body surface area-based dosing, plasma drug concentrations would be reduced in the gestational period.²⁷ To date, this supposition has not definitely translated into a difference in chemosensitivity²⁸ or survival outcome between pregnant and non-pregnant breast cancer patients.²⁹ Therefore, doses based on actual weight are used.⁴

Medical oncologists can use standard treatment regimens containing anthracyclines, cyclophosphamide or 5-fluorouracil as they would in a non-pregnant patient. Although there is limited evidence available, dose dense regimens do not appear to be associated with detrimental foetal outcomes.³⁰ The use of taxanes in the second and third trimester has been reported and the risk to the foetus appears low. However, there is limited safety data in relation to their use compared to anthracyclines.⁴ Methotrexate is not recommended due to its teratogenic potential and propensity for third spacing in the amniotic sac.² The evidence for platinum-based agents is less clear but it is postulated they could be associated with increased toxicity as the physiological reduction in plasma albumin during pregnancy can lead to higher levels of the unbound active drug.³¹

Trastuzumab is contraindicated in the gestational period. A meta-analysis demonstrated a high incidence of oligohydramnios/anhydramnios (61% of pregnancies). Oligohydramnios/anhydramnios is associated with foetal complications such as intra-uterine growth retardation, pulmonary hypoplasia, soft tissue deformities, and perinatal foetal distress. Interestingly, trastuzumab appears to be only toxic in the second and third trimesters in contrast with other agents.³²

The healthy delivery of a baby following exposure to lapatinib in-utero during the first and second trimester has been documented in a single case report.³³ However, it is not part of the treatment paradigm of early-stage HER2-positive breast cancer and in the absence of more definitive evidence on its safety, it is not currently recommended. Similarly, the use of other HER2-directed agents such as pertuzumab or ado-trastuzumab emtansine (TD-M1) are not recommended due to a lack of supportive data. 

Transplacental transfer of cytotoxic agents from mother to foetus has been documented in a few case reports. The passage rates differ according to various drug properties such as molecular weight, lipid solubility and the presence of placental drug transporters. 

A baboon model was previously established to assess the differences between plasma levels of chemotherapeutic agents in the maternal and foetal circulations. Foetal plasma concentrations of carboplatin, cyclophosphamide and trastuzumab averaged 57%, 25% and 85% of maternal levels, respectively. However, the foetal concentrations of doxorubicin and paclitaxel were found to be lower at 7.5% and 1.5% respectively. Docetaxel was not detected at all in the foetus. This emphasises the fastidious nature of the placenta in safeguarding the foetus from the toxic effects of chemotherapy.^34,35 

Endocrine therapy

Tamoxifen is not recommended during pregnancy due to increased risk of congenital anomalies, ambiguous genitalia and foetal death.³⁶ Similarly, aromatase inhibitors in combination with ovarian suppression are contraindicated.^2,4 

Obstetric and postpartum care

Prenatal care should be co-ordinated in a high-risk obstetric centre due to the increased risk of preterm births in this setting. Patients should be counselled that early termination of pregnancy is not associated with improved survival outcomes. However, some patients may choose termination on the basis of maternal prognosis or concern about foetal toxicity during treatment. 

Special attention should be paid towards the identification of intrauterine growth restriction (IUGR) and risk of preterm labour during chemotherapy. Timing of delivery depends on treatment schedule and on the development of the foetus. Chemotherapy should be stopped approximately three weeks prior to delivery to avoid maternal or foetal myelosuppressive complications. Usually full-term birth is advised (>37 weeks) as preterm births are associated with poorer cognitive outcomes.^2,4 Chemotherapy can be resumed immediately after a vaginal delivery and one week after an uncomplicated caesarean section.⁴ 

Placental metastases have been described³⁷ but there are no published case reports of vertical transmission of breast cancer to the foetus. Breastfeeding is not recommended during chemotherapy or tamoxifen treatment in the absence of safety data. However, if a patient has completed their breast cancer treatment, there is no evidence that breastfeeding leads to inferior maternal or neonatal outcomes.^38,39,40 

Maternal and foetal outcomes

PABC may be associated with inferior overall survival, although this appears to be more pronounced in the postpartum setting. A meta-analysis published in 2016 analysed survival outcomes of 4,929 breast cancer patients who became pregnant up to five years before, during or five years after their diagnosis and compared them to 61,041 non-pregnant controls with breast cancer. An overall increased risk of death was demonstrated in the whole group compared to non-pregnant controls [Hazard Ratio (HR) 1.57; 95 % CI 1.35–1.82]. Subgroup analyses showed poor survival outcomes in patients diagnosed with breast cancer during pregnancy [HR 1.47; 95 % CI 1.04–2.08] and patients diagnosed up to five years postpartum [HR 1.79; 95 % CI 1.39–2.29]. In contrast, patients with breast cancer who subsequently became pregnant up to five years following their diagnosis had a reduced risk of death [HR 0.63; 95% CI 0.51–0.79].⁴¹

A previous meta-analysis in 2012 compared 3,628 PABC patients (diagnosed during pregnancy or one year postpartum) with 37,100 controls. Similarly, it found that PABC patients had a higher risk of death compared to non-pregnant controls (HR 1.44; 95% CI [1.27–1.63]), although this was only significant in the postpartum setting (HR: 1.84; 95% CI [1.28–2.65].¹

The largest study included in both meta-analyses is the combined retrospective and prospective series of patients diagnosed with BCP from the Breast International Group/German Breast Group (BIG/GBG). Their prognosis was similar to that of the controls (HR 1.19, 95% CI [0.73-1.93]).²⁹ 

It is not clear whether poorer prognosis in PABC is related to more advanced stage or more aggressive tumour biology. Traditionally, it was theorised that the disparity in survival rates were partly accounted for by delayed or suboptimal treatment during pregnancy as well as increased levels of oestrogen, progesterone and insulin-like growth factor. 

If postpartum breast cancer is the main driver behind the overall increased risk of death, one hypothesis is that the involution in the postpartum breast is associated with pro-inflammatory and wound healing mechanisms, leading to a mammary micro-environment that promotes tumour growth and metastatic potential, as demonstrated in rodent/pre-clinical models.⁴²

A subject for further research is whether anti-inflammatory medications would downgrade this response.⁴³ Genomic analysis of tumours of pregnant patients with breast cancer has been performed. No particular mutation was associated with PABC. However, the G protein-coupled receptor pathway and the serotonin receptor pathway were found to be upregulated (both P<0.0001). Higher expression of PD1 (p=0.015), PDL1 (p=0.014), and gene sets related to SRC (p=0.004), IGF1 (p=0.032), and β-catenin (p=0.019) was also observed. These could be potential treatment targets in the future.⁴⁴

DeHaan et al evaluated neonatal outcomes in 1,170 patients with cancer during pregnancy retrospectively and prospectively over a 20-year period. Nearly 40% of patients received chemotherapy in the gestational period, the most common agent being an anthracycline (78%). Of singleton pregnancies, 2% ended in miscarriage. The rate of intrauterine death and perinatal death of viable pregnancies was 1%. Preterm deliveries accounted for half of the births of which 88% were iatrogenic. Over one-fifth of neonates were small for gestational age. The incidence of major congenital malformations was 2% (similar to that observed in the general population).²⁶

Other small prospective studies have demonstrated that exposure to chemotherapy in the prenatal period is not associated with an increased risk of general health complaints, audiological dysfunction or impaired cardiac, neurological or cognitive development during infancy, childhood or adolescence as compared to the general population. Prematurity was associated with poorer cognitive outcomes, but this was irrespective of whether the child had in-utero exposure to treatment or not.^45,46 

Conclusion

Despite the seemingly complex clinical and ethical dilemma posed, the management of pregnancy-associated breast cancer is similar to that of the non-pregnant patient. A strong multidisciplinary approach is imperative to ensure satisfactory maternal and foetal outcomes. Surgery is possible throughout all trimesters and most standard chemotherapy regimens can be administered from 14 weeks of gestation onwards. Intrauterine exposure to chemotherapy after 14 weeks does not appear to be linked to an excess risk of foetal deaths or congenital abnormalities. Iatrogenic preterm birth should be avoided as it is associated with delayed cognitive development in childhood. Obstetric care should be co-ordinated in a high-risk maternity centre. 

Patients with PABC may have inferior survival outcomes compared to an age matched breast cancer population although this appears to more significant in the postpartum period. Results from ongoing prospective studies are welcomed to gain further insight and guide future decision making. Therapies that target the inflammatory milieu of the lactating involuting breast may be a strategy in the future for impeding tumour growth and metastases. Several prospective registry studies have now been established and with a global collaborative effort it is likely that progress will be made in the treatment of this vulnerable and complex patient group. 

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