ABSTRACT: The care of a pregnant breast cancer patient is a challenging clinical situation that historically has placed the welfare of the mother in conflict with that of the fetus. For the woman in this situation, the emotions usually associated with pregnancy can be overshadowed by the emotions aroused by a diagnosis of breast cancer and its subsequent treatment. The majority of published information on the management of breast cancer during pregnancy has consisted of retrospective chart reviews, case reports, and anecdotes. There is a paucity of published data from the prospective study of women who are pregnant at the time of their breast cancer diagnosis. This review will endeavor to address the diagnosis, staging, and subsequent treatment of breast cancer during pregnancy. The limited information available for this group of women on the outcomes of labor, delivery, and neonatal health will also be reviewed. This review will not specifically address pregnancy that occurs after diagnosis and subsequent treatment for breast cancer. However, some data, particularly those of an epidemiologic nature, address breast cancer diagnosed during pregnancy or within the year following delivery. [ONCOLOGY 15(1):39-51, 2001]
Introduction
Although breast cancer is one of the most common cancers associated with pregnancy, it is still an uncommon event, with estimates ranging from 1 in 3,000 to 3 in 10,000 deliveries to women with breast cancer.[1-4] A review of 32 series of reports on pregnancy-associated breast cancer published between 1937 and 1982 estimated that 0.2% to 3.8% of all breast cancers coincided with pregnancy or lactation.[5] The prevalence of pregnancy at diagnosis of breast cancer has been reported to be approximately 1.5% in a large Canadian series of consecutive and unselected patients with breast cancer.[6]
In women 30 years of age or younger, the incidence of pregnancy-associated breast cancer may be quite high, as two case series—one from Memorial Sloan-Kettering Cancer Center and the other from M. D. Anderson Cancer Center—reported prevalences of 9.7% and 25.6%, respectively.[7,8] As more women delay childbearing, it has been postulated that the incidence of pregnancy-associated breast cancer will parallel the increased incidence of breast cancer with age.[9,10]
Diagnosis
The pregnant breast cancer patient usually presents with a mass or thickening in her breast.[11] The physiologic changes that occur in the pregnant woman’s breast—the engorgement and hypertrophy—are believed to contribute to the delay in diagnosis of a breast mass that is common in this unique group of patients.
A number of studies have documented delays of 3 months or longer in pregnant or lactating women.[12,13] In one study, patient-related factors created a 6- vs 4-month delay when pregnant and nonpregnant breast cancer patients were compared. Physician-related factors were responsible for 3- vs 2-month delays, respectively.[14]
Socioeconomic status, cultural background, and other psychosocial factors are thought to contribute to patient-based delays in diagnosis, while education (in particular, familiarity with pregnancy-associated breast cancer) is the key factor thought to contribute to physician-based delays in diagnosis.
Role of Mammography
Although approximately 80% of breast biopsies performed in pregnant women yield benign lesions, a breast mass that persists for 2 to 4 weeks warrants further investigation.[12] The effectiveness of mammography in diagnosing breast cancer during pregnancy is controversial. In a small series reported by Max and Klamer,[15] six of eight pregnant women with a breast mass that subsequently proved to be breast cancer were found to have normal mammograms. The false-negative mammograms were attributed to increased water content and loss of contrasting fat in the pregnant breast.
A slightly larger study of 23 women with pregnancy-associated breast cancer found abnormal mammograms in 18 women.[16] In a small Canadian study of pregnancy-associated breast cancer, five of eight women in the study had abnormal mammographic findings.[17] Although there is some debate as to the accuracy and utility of mammography in the diagnosis of a breast mass in a pregnant patient, the procedure can be performed safely with the use of abdominal shielding and may yield important information.
Breast Ultrasonography
The utility of breast ultrasonography during pregnancy, which may differentiate a solid mass from a cystic mass, has been evaluated in small studies. In the study by Liberman et al,[16] a focal solid mass was seen in six of the six cases examined. However, only two of the four pregnant breast cancer patients who underwent breast ultrasound had lesions that were suspicious for malignancy in the Canadian study.[17] Although these studies were small, breast ultrasound and ultrasound of nodal basins, if clinically indicated, likely play a role in the initial staging of the pregnant patient with a breast mass.
Magnetic Resonance Imaging
Studies evaluating the effectiveness of magnetic resonance imaging (MRI) in the diagnosis of breast masses in pregnant or lactating women have not been published. MRI has been used in pregnancy for fetal imaging, and, among studies published thus far (with limited follow-up of the infants), there do not appear to be any serious sequelae for the fetus.[18,19]
Biopsy
Despite the results of either the mammogram or breast ultrasound, a clinically suspicious breast mass, regardless of whether the patient is pregnant, requires biopsy for definitive diagnosis. A number of small studies have demonstrated the accuracy of fine-needle aspiration in diagnosing pregnancy-associated breast cancer.[20,21,22] The accurate interpretation of a fine-needle aspiration from a pregnant patient with a breast mass requires a pathologist skilled in the diagnosis of breast pathology coincident with the changes seen in the pregnant or lactating breast.
Core biopsies allow for a diagnosis of invasion, but there are rare reports in the literature of the development of milk fistulas.[23] If necessary, either an incisional or excisional biopsy can be performed relatively safely during the first and second trimesters of pregnancy.[24] Ultimately, the nature of a breast mass in a pregnant patient should be established with the least invasive and technically most accurate method(s) available.
Pathologic Features of Breast Cancer During Pregnancy
Few studies have assessed or compared the pathologic features of the primary breast tumor in the pregnant patient with that of the nonpregnant patient.
Hormone Receptors
In their series of pregnant breast cancer patients, Tobon and Horowitz[25] reported infiltrating ductal carcinoma in 13 of 14 patients, negative or very low estrogen-receptor (ER) status in 7 patients, and positive progesterone(Drug information on progesterone)-receptor (PR) status in 5 patients. In another study of 14 pregnant breast cancer patients, 6 women had tumors that were both ER and PR negative, 3 had ER- and PR-positive tumors, and the remaining 5 had tumors that were either ER positive and PR negative or ER negative and PR positive.[26]
A case-control study by Ishida et al[27] found that women diagnosed with breast cancer during pregnancy were significantly less likely to have ER- or PR-positive tumors, compared to nonpregnant controls. Bonnier et al[28] reported that women with pregnancy-associated breast cancer were significantly more likely to have ER- and PR-negative tumors and a diagnosis of inflammatory breast cancer, compared to nonpregnant controls.
In the M. D. Anderson prospective cohort of pregnant breast cancer patients treated with chemotherapy, 65% of tumors were negative for both receptors.[29] However, in a smaller case-control study of 15 pregnant breast cancer patients and their respective nonpregnant controls, no significant difference was seen in ER or PR status when the tumors of these two groups were compared.[30]
Some investigators believe that the ligand-binding assay used to measure ER and PR positivity may be less accurate during pregnancy. The first mechanism by which a ligand-binding assay may produce a false-negative result during pregnancy is associated with the increased estrogen and progesterone levels that downregulate ER levels to the point at which they are no longer detectable. Secondly, the accuracy of the ligand-binding assay depends on the availability of the unbound receptor, and it is possible that all binding sites in a pregnant woman could be occupied as a result of increased estrogen levels.
In the majority of published case-control studies, ER and PR positivity was primarily determined using the ligand-binding assay. In the study by Elledge et al,[30] a greater proportion of the tumors of the pregnant breast cancer patients were found to be ER and PR positive when immunohistochemistry and not the ligand-binding assay was used.
Genetic Factors
In the only published study of HER2/neu expression in pregnant breast cancer patients, 58% of tumors stained positive for HER2/neu in this patient group, compared to 16% of tumors in age-matched nonpregnant controls.[30] In this study, HER2/neu positivity was ascertained using a rabbit polyclonal antiserum generated against the carboxy-terminal synthetic peptide of HER2/neu. It is difficult to draw conclusions about the pathologic profile of tumors for this unique group of breast cancer patients, because the majority of studies are small or retrospective in nature, or use techniques that are not generally employed in the modern analysis of breast tumors.
The effect of BRCA1 and BRCA2 mutations upon the incidence of pregnancy-associated breast cancer is unclear, although a small Swedish study found that significantly more women with BRCA1 vs BRCA2 mutations had pregnancy-associated breast cancer.[31] However, another small study compared women with pregnancy-associated breast cancer and no history of familial breast cancer to women with sporadic breast cancer and found a higher rate of allelic deletion at the BRCA2 locus in women with pregnancy-associated breast cancer (88% vs 20%).[32]
Staging
For women with breast cancer, regardless of whether they are pregnant at the time of diagnosis, the tumor/node/metastasis (TNM) system is used to stage the disease. The TNM system can also be used to assess prognosis and to formulate a treatment plan. A number of case series and case-control studies have reported that, compared to nonpregnant breast cancer patients, women with pregnancy-associated breast cancer present with more advanced-stage disease, larger tumors, and an increased likelihood of positive lymph nodes and metastatic disease.[7,27,28,33,34] The patient’s stage of disease at the time of diagnosis may have significant psychosocial implications, particularly if the pregnant patient presents with metastatic disease.
Initial staging of the pregnant breast cancer patient involves a thorough physical examination of the breast and regional lymph node-bearing areas, with careful documentation of all abnormalities. Regional nodal disease that is clinically suspicious for metastases should be evaluated further using ultrasound and subsequent fine-needle aspiration for cytologic confirmation.
Metastatic disease must also be ruled out, particularly in the lung, liver, or bone—the three most common sites of metastases. There are no contraindications for chest radiography in the pregnant patient, but abdominal shielding should be used. The ability to evaluate the lower lung parenchyma with chest radiography later in the pregnancy, when the gravid uterus is pressing against the diaphragm, may be more difficult. Abdominal ultrasound for the evaluation of liver metastases is obviously safe, but the results may be more difficult to interpret if the patient has developed fatty infiltration of the liver during pregnancy.
Computed tomography (CT) scanning of the abdomen and pelvis is generally not used during pregnancy because of the risk of fetal exposure to radiation. MRI may be useful when further visceral organ evaluation is required, as there have been no reports of harm to the fetus from exposure to MRI.[18,19] Although it has been reported that bone scans can be performed safely during pregnancy if there is adequate hydration and an indwelling catheter is used for 8 hours to prevent retention of radioactivity in the bladder, a screening MRI of the thoracic and lumbosacral spine may be a more palatable option in patients with no complaints suggestive of bony metastases outside the spine.[35]
When data from 12 studies were evaluated, a 3% and 7% true-positive yield of bone metastases was found on routine bone scans in patients with stage I and II breast cancer, respectively.[36] In patients with clinical stage III breast cancer, however, a 25% true-positive yield has been reported. Since it is not uncommon for pregnant breast cancer patients to present with later-stage disease, one should appropriately stage the patient, recognizing that some modifications need to be made to protect the fetus.
Monitoring the Pregnancy
The pregnant breast cancer patient requires careful and continuous monitoring of her pregnancy by a medical team highly skilled in the management of maternal and fetal health. This team, in conjunction with the oncologist, will assess and monitor the health of the mother and fetus.
Ultrasonography should be used to determine gestational age and the expected date of delivery, as both of these dates play a significant role in treatment planning. As the pregnancy progresses, fetal maturity should be monitored by ultrasound. In some cases, amniocentesis may be necessary to determine pulmonary maturity, particularly if induction of labor is being considered. Amniocentesis may also be recommended in the initial assessment of the pregnant breast cancer patient if the patient is felt to be at higher than average risk for karyotype abnormalities or if there are abnormalities detected by ultrasound that warrant further investigation.
