Breast Cancer in a Pregnant Woman
Illustrative Case Series
Breast Cancer in a Pregnant Woman
By William B. Ershler, MD
A 31-year-old g1p0 caucasian woman in the seventh month of pregnancy is referred for management of her T2N0Mx "triple-negative" breast cancer. She had discovered a breast mass, and underwent ultrasound-guided, fine-needle biopsy, followed by modified mastectomy and axillary lymph-node dissection. The breast tumor was 2.5 cm in diameter and was found to be poorly differentiated, infiltrating ductal adenocarcinoma. The tumor was estrogen- and progesterone-receptor negative, and HER2 negative. Eleven resected axillary nodes were negative for breast cancer.
She had previously been well and, prior to pregnancy, she had no known illness and was taking no medications. She works as an accountant and maintains a healthy lifestyle that includes hiking, yoga, and dance. She occasionally drinks wine and does not smoke. There is no family history of breast or ovarian cancer.
On physical examination, she appeared well. Her blood pressure was 110/70 and pulse 80/min. There was slight pallor. Chest was clear to auscultation and the heart was regular, with a low-grade systolic murmur. The mastectomy site was healing nicely and was without evidence for residual disease. There was abdominal distention consistent with third-trimester pregnancy, and fetal movement was palpable.
The patient was referred for consideration of additional diagnostic studies and management.
Gestational Breast Cancer
Although certainly not common, breast cancer is the most common cancer associated with pregnancy.1 Epidemiologic studies have suggested that pregnancy itself might transiently increase the risk for breast cancer for a period that might last as long as 10 years.2 This is despite the protective effect of multiple pregnancies on breast cancer occurring later in life. The physiological changes in the breast during pregnancy make interpretation of physical and imaging findings difficult and, as a result, delays of two or more months in diagnosis are relatively common. This alone might account for larger tumor size and greater nodal involvement at the time of diagnosis.3-5 However, compared with breast cancer occurring in non-pregnant women of the same age, the cases occurring during pregnancy are more likely to have poorly differentiated tumors with a lower frequency of ER/PR positivity6 and a greater likelihood of overexpression of HER2.7
Work-up
Although breast changes occur regularly with pregnancy, a mass that persists beyond two weeks should be investigated, acknowledging that most masses will prove benign. Ultrasonography is useful to determine if a mass is cystic or solid. Furthermore, axillary ultrasound, with or without fine-needle aspiration, is useful in staging, and assessment of treatment does not expose the fetus to radiation. Mammography sensitivity may be reduced during pregnancy or lactation, but current studies indicate detection rates approaching 90%.8 When abdominal shielding is used, fetal exposure to radiation is negligible. Magnetic resonance imaging (MRI) may be more sensitive, but optimal studies require gadolinium contrast, and this has not been suitably tested in pregnant women. Core or excisional biopsies also may be performed safely, preferably under local anesthesia. For patients with large primary tumors (T3 or T4) or clinically positive axillary node involvement, staging should include chest X-ray (with abdominal shielding) and abdominal ultrasound (for liver evaluation). Skeletal evaluation could be performed by either "low-dose" bone scan9 or by skeletal MRI (without gadolinium).
Managing Pregnancy
The optimal management of breast cancer during pregnancy requires active collaboration between the obstetrician and oncologist. An accurate estimation of gestational age and delivery date are critical. Decisions regarding diagnosis, staging, and treatment must all be made while balancing the risks to the developing fetus, as well as the risks to the mother associated with delay in treatment.
Treatment Strategy
Breast and axillary surgery may be performed with minimal fetal risk. Mastectomy with axillary node dissection remains the most commonly selected procedure, as breast-conserving surgery would require additional radiation therapy, and this should be avoided if at all possible during pregnancy. However, breast-conserving surgery is possible for women who are diagnosed late in pregnancy, or require chemotherapy with radiation to be delivered post-partum. The safety of the sentinel node biopsy procedure has yet to be determined in pregnant patients.
The same criteria used to determine adjuvant systemic therapy in a non-pregnant patient should be applied to a pregnant woman. Adjuvant therapy is usually indicated in patients with ER/PR/HER2 negative or "triple-negative" tumors, HER2 positive tumors, large tumors, or evidence of lymph-node involvement. Genomic predictors, such as the 21-gene recurrence score,10 adjuvantonline (www.adjuvantonline.com), and other tools are often incorporated into the adjuvant chemotherapy decision. When indicated, chemotherapy should be administered, with doses adjusted as weight increases. Most chemotherapeutic agents are teratogenic, particularly in the first trimester. However, chemotherapy administered in the second and third trimesters of pregnancy has been associated with a very low rate of congenital malformations.11-15 Nonetheless, chemotherapy administered in the second and third trimesters has been associated with low birth weight in approximately one-half of exposed infants.13
Although it would be impossible in this brief review to provide a comprehensive list of drugs that have proven effective and safe during pregnancy, a few caveats are worth mentioning. Cyclophosphamide, fluorouracil, and doxorubicin have been commonly prescribed in this setting, and are relatively safe. There has been concern raised about fetal cardiotoxicity with certain anthracyclines and, for this reason, doxorubicin is preferred over idarubicin or epirubicin for use during pregnancy.13 Taxanes probably will turn out to be relatively safe during the second and third trimester,16 but there have been recommendations to avoid their use until more data are available.17 Methotrexate should not be used, and trastuzumab only given under emergent conditions, for each has been associated with severe neonatal toxicity. Tamoxifen, and other hormonal approaches, should be reserved until post-partum. Because many of these drugs, including Tamoxifen, will enter breast milk, patients should be advised not to breast-feed during treatment.
Current Case Management
The patient presented above is entering her third trimester of pregnancy and has recently had a mastectomy and axillary node dissection for Stage IIA (T2N0Mx) breast cancer. Additional workup would not be warranted in light of the low likelihood of finding distant metastases. Her 10-year risk of recurrence is 40%-45%, per adjuvantonline.com, most likely due to the poorly differentiated "triple-negative" biology. A third-generation regimen, such as doxorubicin and cyclophosphamide for four cycles followed by paclitaxel for four cycles, would most likely result in a 50% relative risk reduction. For example, one or possibly two cycles of AC (doxorubicin/cyclophosphamide) prior to delivery, keeping in mind there should be no chemotherapy in the four weeks prior to delivery to avoid transient neonatal myelosuppression, sepsis, or hemorrhage secondary to thrombocytopenia. Filgrastim, dexamethasone, promethazine, or ondasetron may be used for supportive care during pregnancy.
It is common for patients to request delaying chemotherapy until after delivery. However, delays in initiating chemotherapy, particularly for those at high risk, have clearly been shown to be associated with significantly worse disease-free survival compared to patients who do not experience delays.18
After delivery, the patient should complete her adjuvant chemotherapy and undergo monitoring, per American Society of Clinical Oncology (ASCO) guidelines. She should not breast-feed while undergoing chemotherapy. Genetic counseling and testing should be performed due to young age at diagnosis. She should be advised not to become pregnant for at least two years after completion of chemotherapy, as most recurrences of breast cancer would occur in the first two years. After that, there is at least some data that would suggest becoming pregnant does not increase risk of recurrence, and may even be protective.19
References
1. Antonelli NM, et al. Cancer in pregnancy: A review of the literature. Part I. Obstet Gynecol Surv. 1996;51:125-134.
2. Albrektsen G, Heuch I, Kvale G. The short-term and long-term effect of a pregnancy on breast cancer risk: a prospective study of 802,457 parous Norwegian women. Br J Cancer. 1995;72:480-484.
3. Lethaby AE, et al. Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Auckland Breast Cancer Study Group. Int J Cancer. 1996;67:751-755.
4. von Schoultz E, et al. Influence of prior and subsequent pregnancy on breast cancer prognosis. J Clin Oncol. 1995;13:430-434.
5. Reed W, et al. Pregnancy and breast cancer: A pop-ulation-based study. Virchows Arch. 2003;443:44-50.
6. Middleton LP, et al. Breast carcinoma in pregnant women: Assessment of clinicopathologic and immunohistochemical features. Cancer. 2003;98:1055-1060.
7. Elledge RM, et al. Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients. Cancer. 1993;71:2499-2506.
8. Yang WT, et al. Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy. Radiology. 2006;239:52-60.
9. Baker J, et al. Bone scanning in pregnant patients with breast carcinoma. Clin Nucl Med. 1987;12:519-524.
10. Paik S. Development and clinical utility of a 21-gene recurrence score prognostic assay in patients with early breast cancer treated with tamoxifen. Oncologist. 2007;12:631-635.
11. Berry DL, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol. 1999;17:855-861.
12. Kuerer HM, et al. Conservative surgery and chemotherapy for breast carcinoma during pregnancy. Surgery. 2002;131:108-110.
13. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004;5:283-291.
14. Germann N, Goffinet F, Goldwasser F. Anthracyclines during pregnancy: Embryo-fetal outcome in 160 patients. Ann Oncol. 2004;15:146-150.
15. Ring AE, et al. Chemotherapy for breast cancer during pregnancy: An 18-year experience from five London teaching hospitals. J Clin Oncol. 2005;23:4192-4197.
16. Mir O, et al. Taxanes for breast cancer during pregnancy: A systematic review. Ann Oncol. 2010;21:425-426.
17. Gainford MC, Clemons M. Breast cancer in pregnancy: Are taxanes safe? Clin Oncol (R Coll Radiol). 2006;18:159.
18. Buzdar AU, et al. Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat. 1982;2:163-169.
19. Ives A, et al. Pregnancy after breast cancer: Population based study. BMJ. 2007;334:194.
A 31-year-old g1p0 caucasian woman in the seventh month of pregnancy is referred for management of her T2N0Mx "triple-negative" breast cancer.Subscribe Now for Access
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