Breast cancer during pregnancy is a dramatic event that interrupts one the most joyful aspects of the life of a woman. The diagnostic/therapeutic setting is deeply affected by the presence of a second individual (the fetus) during its intrauterine development. For this reason, the most common decisional pathways need to be modified to minimize collateral effects. Termination of pregnancy is a possible issue that has to be discussed, although currently no evidence is available regarding any benefit in terms of improved survival.

A multidisciplinary diagnostic setting is likely to reduce the chance of exposing the fetus to excessive radiation. Similarly, all the treatments need to be discussed and planned in order to be, as much as possible, in keeping with the most advanced therapeutic strategies for nonpregnant women and be tailored to the gestational age.

Breast cancer develops in women at an average age between 32 and 38 years old, it is the most common cancer during pregnancy and after delivery, occurring in about 1 in 3,000 pregnant women. Delays in diagnoses are common, with an average reported delay of 5 to 15 months from the onset of symptoms [1]. A clinical diagnosis is often hustled by the typical gestational changes that makes the mammary gland tender and painful. This may cause a diagnostic delay (approximately between one and two months from clinical onset) with cancer detection at a later stage in comparison to a nonpregnant age-matched population [2].

For this reason, pregnant women should undergo regular breast examination during prenatal consultations. Breast cancer during pregnancy normally arises as a discrete nonpainful lump without any other specific characteristic. Nipple discharge is often present during pregnancy and is not only associated with breast cancer [3].

We suggest that any family history of breast cancer is investigated as this has been reported in approximately 48% of cases while a BRCA1–2 mutation has been reported in 9% of the population.

Ultrasound (US) is the most appropriate radiologic method for evaluating breast disorders in women during pregnancy and lactation; it has a high sensitivity (nearly 98%) and specificity for the diagnosis of breast cancer. It is used as a guide to cytology or histological confirmation and to monitor the response to chemotherapy [4]. Therefore, US is the gold standard for the evaluation of a palpable breast mass during pregnancy [5].

The increase in size, vascularization and glandular density of the breasts in a pregnant woman is translated to an increase in radiographic density. At mammography, the gland appears very dense, heterogeneously coarse, nodular, and confluent, with a marked decrease in adipose tissue and a prominent ductal pattern [6]. The sensitivity of mammography in detecting malignant lesions during gestation is less than 70%. However, it is the only method for studying suspicious microcalcifications [7].

The impact of prenatal exposure to ionizing radiation depends on three factors: radiation dose, anatomic distribution of radiation, and stage of fetal development at the time of exposure. On the first and second month of pregnancy (organogenesis), the fetus is the most susceptible to radiation-induced malformations (congenital lesions, growth retardation, perinatal death, and postnatal neoplasias) [8]. Malformations occur with exposure to more than 0.05 Gy of radiation, a dose which is much higher than a fetal radiation exposure in a standard two view mammography (0.004 Gy) [9].

The role of magnetic resonance imaging (MRI) is still controversial because lactational parenchyma, shows rapid enhancement following the intravenous administration of contrast material, followed by an early plateau. In late pregnancy, it is difficult for the patient to assume the prone position [10].

MRI with contrast agents is possible during pregnancy, but should only be used when other clinical decision making methods and ultrasonography are inadequate. No well-designed studies of the efficacy and safety of MRI of the breast during pregnancy have been reported, and results of some studies have shown that gadolinium- based MRI contrast agents pass through the placental barrier and enter fetal circulation. The European Society of Radiology recently stated that use of gadolinium during pregnancy is probably safe because the quantity expected to cross the placenta is low, and it is rapidly eliminated by the kidneys. MRI with contrast can be used during lactation; because a small amount of gadolinium is excreted into breast milk, it is not prudent to breastfeed for 48 hours after the examination [11]. The routine use of MRI in the evaluation and treatment of pregnant patients is not appropriate. No results of breast MRI specificity and sensitivity in pregnant patients have yet been reported.

Fine-needle aspiration is not an adequate diagnostic procedure during pregnancy or lactation due to the high number of false positive results because of physiological epithelial hyperplasia. Therefore, this procedure is not recommended during pregnancy. The standard examination to obtain a histological diagnosis is a core biopsy under local anaesthesia, which can be done safely during pregnancy with a sensitivity of around 90%. Lactation should be suppressed prior to biopsy in order to reduce the risk of abscesses and milk fistulas [12]. Beyond mammography, ultrasonography and biopsy examination, others staging examinations should be guided by the clinical stage of the disease.

A metastatic preoperative work-up, including a chest x-ray with shielding and liver function tests, is needed in order to determine the feasibility of surgical treatment. In a woman with symptomatic advanced bony disease a noncontrast MRI of the thoracic and lumbar spine to exclude bone metastases could be carried out. MRI can also be used to scan the brain and the liver. The bone scan is the only staging examination contraindicated in pregnancy.

From the pathological viewpoint it has been reported that breast carcinomas occurring in pregnancy share histopathological and immunohistochemical findings similar to those occurring in nonpregnant women who are younger than 35 years [13]. The predominant reported histology is of invasive ductal carcinomas (71–100%) [14], whereas invasive lobular carcinoma has been diagnosed infrequently [15]. Carcinomas are often associated with aggressive behavior such as high incidence of grade 3 tumors (40–95%) and lymphovascular invasion [16]. Moreover, gestational breast cancer usually involves larger tumors and shows a higher incidence of nodal involvement (53–71%) than in nonpregnant patients [17].

As far as the hormone status in breast carcinomas occurring in pregnancy is concerned, it has been reported that most tumors are hormone-independent, as demonstrated in all series investigated. In a prospective series by Middleton et al. [18], 28% of the tumors occurring in pregnancy were estrogen receptor [ER]-positive and 24% were progesterone receptor [PR]-positive compared with 45% and 36%, respectively, of nonpregnant young women with breast carcinoma. This is in keeping with the concept that hormone-positive disease is age-related and is seen more often in postmenopausal women. Results of HER2 expression studies are inconclusive, although data on more than 300 patients showed HER2 positivity in 42%, which is much the same (39%) as recorded in nonpregnant patients with breast cancer who are younger than 35 years [19].

It seems that pathological features of breast cancer do not change as an effect of pregnancy, but are determined by age. Thus, it is more likely that age at diagnosis rather than the pregnancy determines the biologic features of the tumor. Whether increase in mammary stem cells, which are highly responsive to steroid signaling, despite the absence of hormone receptors, may play a role in the pregnancy setting is still unknown [20].

When a pregnant woman is diagnosed with breast cancer, the treatment options are complex; they depend on age of gestation, on the extent of malignancy, and, on patient preferences. We would advise the acquisition of as much information as possible on the biological characteristics of the lesion before starting any treatment; this may allow the expected prognosis of the disease to be determined and could be helpful in taking complex decisions regarding treatments and termination of the pregnancy. The pregnant woman should be assisted by an extended multidisciplinary team that ideally should include obstetrics, pediatrics, and geneticists.

Termination of pregnancy has not been demonstrated to have any beneficial effect on breast cancer outcome and is not usually considered as a therapeutic option. However, this can be discussed for moral or personal reasons, and once pregnancy has been terminated, all standard treatment for non-breast cancer patients can be undertaken [21].

All treatments should conform as much as possible to standard treatment for nonbreast cancer patients. Surgery can be usually performed safely at any stage of pregnancy. Breast-conserving surgery can be performed safely as long as postoperative radiotherapy can be performed after delivery. If mastectomy is required due to extensive multicentric carcinoma breast-reconstruction with implants can be performed safely. Flap-based reconstructions should be delayed after delivery [22].

The axillary staging can include sentinel node biopsy although no evidence has been provided regarding sensitivity and specificity in the setting of pregnancy. The procedure needs to be performed with 99m labeled technetium [23] as blue dye is associated with a risk of anaphylaxis. The standard dose of radionuclide absorbed by the fetus is approximately 0°00045 Gy, which is fair amount below the thresholds of 0.1–0.2 Gy [24].

Administration of cytotoxic drugs or hormones during pregnancy threatens the normal progress of the pregnancy, and generates ethical and psychological issues. We must consider the opportunity to anticipate the childbirth and the administration of systemic treatment after the birth of the baby. Two key factors should be taken into account when considering chemotherapy in pregnant women: changes in maternal physiology and the stage of fetal development.

For instance significant alterations in circulating blood volume, hepatic metabolism, renal plasmatic flow, can affect the clearance of the drugs. Furthermore decreased levels of plasmatic albumin associated with the increase of other proteins with high circulating estrogen levels can alter drug protein bindings [25].

The pregnancy can be divided into three periods: the period from conception to 2 weeks of embryonic life (peri-implant), the period from 3 to 8 weeks, and the period from 9 weeks to the delivery [26]. The peri-implant phase is characterized by a rapid proliferation of embryonic and fetal adnexa. At this stage, the toxic effect of chemotherapy is „all or nothing”, and can determinate either an abortion or no apparent damage. During the first trimester of pregnancy, chemotherapy may interfere with the organogenesis and the teratogenic risk is at a maximum: 10% for a treatment of single-agent chemotherapy, 20% for a polychemotherapy treatment. This risk is thought to increase when chemotherapy is given in conjunction with radiotherapy [27].

During the second and third trimester organogenesis is complete, with the exception of the central nervous system, the heart and the genitals [28]. Even so, chemotherapy after the first trimester is not without risk: as the fetus still needs to grow and mature, and some organ systems, in particular the central nervous system and gonads develop later in fetal life.