The frequency with which breast cancer is diagnosed in pregnant women is low (in the region of 1 in 1000 pregnancies), but the management of these women presents a considerable challenge to those involved in their care. Women frequently present with tumours displaying adverse pathological prognostic features. Initial investigation may be carried out as for non-pregnant women, but with particular attention paid to the risks of exposure to the foetus of ionizing radiation.

Surgery can be carried out with seemingly little increased risk to the mother or foetus, but radiotherapy is usually avoided. In terms of short-term complications chemotherapy may be given relatively safely when administered outside of the first trimester and not around the time of delivery. However, the principle concern with all of these interventions is what the long-term implications for the newborn might be.

Introduction

It has been estimated that up to 3% of breast cancers may be diagnosed in women who are pregnant or lactating.1 However, there is an increasing trend in many developed countries for women to delay childbearing until later in life, and this incidence may therefore rise. The management of these women presents a considerable challenge to those involved in their care. This is partly due to the rarity of the association, and partly because, in contrast to other areas of breast cancer oncology, we do not have large randomized trials to guide our clinical practice. We are forced to rely on assumptions and anecdotes, and that it is a difficult scenario to work in, particularly when the stakes (both medical and emotional) are so high. In this review, the basic principles underlying the management of pregnant women with cancer will be discussed, before moving on to discuss pregnancy-associated breast cancer in more detail.

Principles underlying the oncological management of pregnant women
The first stage of foetal development is implantation, which occurs within 2 weeks post-conception. Physical or pharmacological insults during this period may precipitate foetal loss. Following this, over the next 8 weeks of foetal development, is the period of organogenesis. At the end of this period, despite the tiny size of the foetus (approximately 3 cm) all of the major organ systems have been developed. Insults during this period may manifest themselves as major malformations. However, after this period, because organogenesis is complete, major malformations are unlikely to occur. This does not mean that the foetus if free from risk of harm, it still needs to grow and mature, and be safely delivered. Moreover, some organ systems, such as the gonads and central nervous system continue to develop later through foetal life. However, the greatest risks of harm, and particularly the risks of major malformation are over by the completion of the first trimester.

Pathological features of pregnancy-associated breast cancer

Women who present with breast cancer during pregnancy have been found to frequently present with high-grade tumours, which are often large at the time of diagnosis and exhibit pathological lymph node involvement.2 Up to 60–80% of breast cancers diagnosed in pregnant women may be oestrogen receptor (ER) negative, and between 28% and 58% have been reported to be HER2 positive.3 There has been a lot of debate as to whether these high rates of adverse prognostic features are a specific reflection of pregnancy-associated breast cancer, or whether they simply reflect the patient age-group being studied. Regardless, when pregnant women present with breast cancer they frequently present with adverse pathological features.

Diagnosis and staging
Women who present with a breast lump in pregnancy should be investigated promptly, as historically delays to diagnosis have been reported frequently in this patient group. Atypical cytological features may be observed in the normal breast in pregnant women, therefore the investigation of choice is a core biopsy. In terms of imaging investigations, ultrasounds can be performed as normal, but the greatest concerns surround the risks of exposure of the foetus to ionizing radiation (IR). Quantifying the risks to a foetus of IR exposure is difficult, as we have to extrapolate from data from the atomic bomb survivors, animal studies and children exposed accidentally to radiological investigations in utero. Nonetheless, the foetus is at risk of stochastic effects of IR which may manifest itself as increased risk of cancer and hereditary disease in subsequent generations, and deterministic effects which may become manifest as malformations, foetal loss, and mental retardation.4 The deterministic effects of IR have thresholds for their clinical effects, below which dose of IR the deterministic outcomes do not occur. These thresholds depend on the gestational age. Essentially, early on in foetal life during implantation and organogenesis relatively low doses of IR (thresholds 250–500 mGy) may lead to the deterministic outcomes of foetal loss and malformations. But later on, when organogenesis is complete and the foetus more robust these outcomes are unlikely to occur (thresholds>1000 mGy). Chest X-rays and mammograms expose the foetus to doses of IR well below these thresholds (less than 10 mGy), and the thresholds are only really approached by CT scans of the abdomen and pelvis.4 Therefore, if investigations such as plain X-rays are the only means by which to gain information that will immediately effect management, then such investigations can be considered. However, in reality sufficient information may often be gleaned from tests, which do not utilize IR, such as ultrasound and MRI, and recourse to other radiological investigations is not necessary.

Breast surgery in pregnant women
Surgery is the primary treatment offered to most women with early breast cancer diagnosed in pregnancy. However, the physiological changes associated with pregnancy: such as increased cardiac output, increased oxygen consumption and renal plasma flow, mean that general anaesthesia may be complicated in pregnant women. These changes are, however, predictable and large registry studies suggest that surgery and general anaesthesia can be performed in pregnant women with apparently little increase in risk to the mother or foetus. In the small uncontrolled case series, where breast and axillary surgery has been performed on pregnant women, there do not appear to be a significant excess of surgical or obstetric complications.5

Radiotherapy in pregnant women
The same risks to the foetus of IR exposure exist for radiotherapy as for diagnostic radiology, only with the potential for greater harm owing to the doses of IR employed. However, with careful dosimetry, it may be possible to irradiate some parts of the mother, distant from the pelvis, without significantly irradiating the foetus. The use of radiotherapy to treat the preserved breast or chest wall has been reported in pregnant women.6 Under these circumstances, it is clearly important to weigh up the pros and cons of delaying treatment until after pregnancy, and to consider alternative approaches. However, in the adjuvant setting, the inevitable young age of these women and the high frequency of poor pathological prognostic factors mean that adjuvant chemotherapy is often indicated following surgery. Under these circumstances, it is usually chemotherapy, which becomes indicated following surgery during pregnancy and radiotherapy usually only becomes indicated after delivery.

Alistair Ring
Sussex Cancer Centre, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, UK