Pregnancy and Breast Cancer

Drs. Patridge and Schapira set out to review breast cancer and pregnancy, discuss treatment options for breast cancer during pregnancy, and summarize the available evidence regarding safety of pregnancy after breast cancer. This is a substantial undertaking. They begin by reviewing the epidemiologic data indicating an early increase in risk of breast cancer development after pregnancy and the likely long-term protective effect of pregnancy on breast cancer risks. The subsequent focus of their review is on breast cancer during pregnancy, a relatively rare occurrence. In a study from California, Smith et al indicated that the frequency of breast cancer concurrent with pregnancy was 1.3 per 10,000 live singleton births.[1] The authors note a frequently quoted figure of 1 in 3,000 pregnancies. Initial Evaluation
It is important to establish the diagnosis and extent of disease in a pregnant patient prior to any therapeutic recommendation. At our institution, the evaluation of these patients includes diagnostic mammogram and ultrasound of the breast and nodal basins and contralateral breast diagnostic mammogram. Mammography is safe during pregnancy with the use of abdominal shielding. There are concerns about increased breast density obscuring breast cancer mammographic detection. However, Liberman et al have reported 18 of 23 mammograms to be abnormal during pregnancy.[ 2] Ahn et al reported 13 of 15 patients to have abnormal mammograms, even though patients had radiographically dense breasts. Ahn et al also reported that ultrasonographic evaluation of the breast yielded abnormality in 19 of 19 patients with breast cancer and concurrent pregnancy.[3] The authors recommend ultrasound and/or magnetic resonance imaging (MRI) of the breast. The use of MRI is not supported by evidence. There is a case report of MRI in a lactating patient with diffuse gadolinium uptake noted throughout both breasts. This was felt to be similar to findings associated with malignancy, but no focal abnormality could be determined.[ 4] In fact, MRI of the breast is not recommended during pregnancy because of its undefined role. Gadolinium contrast crosses the placenta and has been shown to cause developmental, skeletal, and visceral abnormalities in rats.[5,6] Diagnosis and Staging
A core biopsy of the primary tumor will establish the histologic diagnosis, hormone-receptor status, and HER2/neu assessment. Fine-needle aspiration can confirm cytologic diagnosis of any suspicious lymph nodes detected by ultrasonography. The majority of tumors are estrogenreceptor (ER)- and/or progesteronereceptor (PR)-negative. They do not appear to have an increased frequency of HER2/neu overexpression. Staging assessment, for determining anatomic extent of disease, is often warranted in this setting because women with concurrent pregnancy and breast cancer present with a more advanced stage.[7] Staging assessment allows for more informed decisionmaking for the patient and physician, especially if the presence of extant metastases are confirmed. A chest radiograph can be accomplished with minimal radiation exposure (ie, between 0.002 and 0.43 mGy.[8] Ultrasonography of the liver determines size, position, and configuration of the liver. However, an ultrasound scan may be difficult to interpret in women with fatty infiltration of the liver due to pregnancy. Computed tomography of the abdomen is contraindicated because of the higher radiation exposure (up to 43.6 mGy in the second and third trimester).[ 9] If further assessment of the liver is warranted, MRI without contrast has been our preferred method. If bone metastases are suspected, MRI of the thoracic and lumbar spine without contrast may be helpful.[10-12] Surgical Considerations
The surgical approach to breast cancer concurrent with pregnancy depends on the stage of disease and the trimester of pregnancy. Kuerer et al have demonstrated that breast-conserving surgery with axillary node dissection is possible, delaying radiation therapy to the postpartum period.[13] Sentinel node biopsy has been reported, and the dose of radiation would appear to be safe. However, the use of blue dye in the sentinel node biopsy procedure is not recommended.[14] Breast and axillary surgery can be performed during pregnancy without significant risk to the developing fetus. Mastectomy is the most frequently used procedure. Systemic Therapy
Exposure to chemotherapy during the first trimester has been associated with increased risks of fetal malformation, as reported by Doll et al and Ebert et al.[15,16] At our institute, we do not treat with chemotherapy during the first trimester because of these concerns. Systemic therapy for primary breast cancer is designed to reduce the risk of recurrence and mortality from primary disease. Since many women who are pregnant with breast cancer have more advanced disease at time of diagnosis and have hormone-receptor-negative tumors, chemotherapy has been the treatment of choice. Careful discussion with the patient regarding the potential risks of chemotherapy and potential fetal risks is necessary. Intrauterine growth retardation, leukopenia, and premature labor have been reported. Nevertheless, a variety of chemotherapy agents have been used during pregnancy. Methotrexate(Drug information on methotrexate) is contraindicated because it is an abortifacient and, during firsttrimester exposure, has been reported to result in severe fetal malformations.[ 15,16] A recent review by Germann et al reported on 160 patients receiving anthracyclines during pregnancy. The majority of patients received doxorubicin or daunorubicin(Drug information on daunorubicin). First-trimester exposure was associated with greater risk of toxicity. Five fetal malformations were reported from the 160 patients exposed, and three of these occurred during first-trimester exposure to anthracyclines.[17] At our institute, we have not observed fetal deaths, stillborns, or fetal malformations with the use of FAC chemotherapy (fluorouracil/doxorubicin [Adriamycin]/cyclophosphamide)- not CAF due to lack of data regarding prolonged daily exposure to oral cyclophosphamide(Drug information on cyclophosphamide)-with infusional doxorubicin(Drug information on doxorubicin) over 72 hours.[18] Drs. Partridge and Schapira note the French study by Giacalone et al, which recorded four premature deliveries, anemia, leukopenia, and fetal death. However, this study was a questionnaire survey sent to more than 40 obstetric units in France, and the time frame for collecting the data is not reported. Moreover, the treatment programs were not standardized, and obstetrical care was not described.[19] As noted by Drs. Partridge and Schapira, endocrine therapy, especially with tamoxifen(Drug information on tamoxifen), has no role during pregnancy. Primarily this is true because the tumors are ER/PR-negative. Postpartum tamoxifen can be used for hormone-receptor-positive tumors. Subsequent Risk
Drs. Partridge and Schapira review pregnancy after breast cancer and present, in tabular form, case control and cohort studies that show no increased risk in recurrence or death from primary breast cancer in women who become pregnant after successful treatment. The authors note the "healthy mother effect."[20] However, a large cohort study reported by Mueller et al has controlled for the healthy mother effect by having all matched controls alive at the date of matching with the study subjects. In addition, Mueller et al control for age, stage of disease, race, and ethnicity.[ 21] While Drs. Partridge and Schapira suggest that the reporting is biased and that there is a lack of "definitive information" about the effects of subsequent pregnancy on breast cancer recurrence risks and mortality, there remains only one study reported in the literature that shows increased risks-that of Bonnier et al.[22] Having undertaken a difficult task, Drs. Partridge and Schapira have clearly highlighted the issues associated with pregnancy and breast cancer.