Pregnancy and Breast Cancer

Investigators have long sought to understand how a woman's pregnancy history affects breast cancer risk, as well as the safety of pregnancy after treatment for breast cancer. Although rare, breast cancer diagnosed during pregnancy remains a challenge for clinicians who may need to make recommendations for treatment without the usual evidence on which to base decisions. Research to date has shown that the relationship between pregnancy and breast cancer is quite complex.[1] There is a paucity of available information, particularly for women diagnosed with breast cancer during pregnancy or for women desiring to become pregnant after a diagnosis of breast cancer, which complicates decisionmaking for many young women and their physicians. The goals of this article are to review what is known and what remains unknown about the complex association between pregnancy and breast cancer, discuss treatment options for women diagnosed with breast cancer during pregnancy, and summarize the available evidence regarding the safety of pregnancy after breast cancer. Epidemiologic Relationship Between Breast Cancer and Pregnancy The effect of pregnancy on risk of subsequent breast cancer appears to be related to the age of the woman at the time of pregnancy and the period of risk under consideration. Large epidemiologic studies indicate that earlier age at first live birth has a long-term protective effect on the lifetime risk of breast cancer. For example, having a pregnancy before age 20 reduces a woman's likelihood of developing breast cancer in her lifetime by approximately 50%. However, pregnancy appears to have a dual effect on the risk of breast cancer: It transiently increases the risk immediately following childbirth for 3 to 15 years postpartum but reduces the risk in later years.[2-5] The excess transient early risk of breast cancer is most pronounced among women who are older at the time of their first delivery. Thus, pregnancy has a protective effect for postmenopausal breast cancer and is a risk factor for premenopausal breast cancer, particularly for older premenopausal women. It has been hypothesized that pregnancy increases the short-term risk of breast cancer by stimulating the growth of cells that have undergone the early stages of malignant transformation (likely occurring with increasing frequency in older women) but that it confers longterm protection by inducing the differentiation of normal mammary stem cells that have the potential for neoplastic change.[5] Breast Cancer During Pregnancy Breast cancer complicates approximately 1 in 3,000 pregnancies.[6,7] Patients typically present with a breast mass, swelling, or nipple discharge. Delays in diagnosis occur frequently, likely due in part to the confounding physiologic changes taking place in the breast during pregnancy that may mask changes from a cancer. Furthermore, women of childbearing years are often not undergoing regular mammographic screening. Indeed, the threshold for initiating a referral for testing in this population is often high. A diagnosis can be made using ultrasound and/or magnetic resonance imaging (MRI), followed by fineneedle aspiration or biopsy. Pregnancy- associated tumors are frequently aggressive tumors that present at an advanced stage and have poor histologic and prognostic features. Tumors are frequently estrogen- and/or progesterone(Drug information on progesterone)-receptor-negative, HER2/neu-positive, and high grade. Whether breast cancer and concurrent pregnancy result in a worse outcome remains unclear when controlling for other prognostic factors.[8-10] Treatment Considerations
Optimal management for a woman diagnosed while pregnant requires a multidisciplinary team willing to respect the patient's preferences for treatment, and weigh the risks and benefits of each option with regard to both the patient and her unborn child. These perspectives can best by articulated by multidisciplinary conversations among the obstetrician, neonatologist, and oncology team- with active participation from the patient and her spouse or partner. Breast cancer treatment in a pregnant woman usually depends on the stage of the cancer as well as the gestational age of the fetus. Because of concerns about the effects of radiation on the fetus, staging is limited to ultrasound and sometimes MRI. Although there have been reports of the use of sentinel node biopsy in pregnancy, there are concerns about both the safety and accuracy of the procedure in this setting. The safety of sentinel node biopsy during pregnancy has not been fully evaluated. Isosulphan blue dye should not be administered during pregnancy. However, radiolabelled colloids are most likely safe because of the rapid uptake into the reticuloendothelial system of any material that enters circulation. Recent data demonstrate that the dose of radiation to the fetus is minimal during sentinel lymph node biopsy, allowing reasonable consideration of the procedure during pregnancy.[11]

• Timing of Therapy-Treatment delays are often entertained in an effort to minimize the danger to the fetus. Another strategy involves early delivery of the fetus with careful obstetric monitoring to allow the mother to proceed with therapy for her malignancy. In weighing the relative merits of these options, one must consider the probability of increasing a woman's risk of developing recurrent disease by delaying treatment. Published mathematic models have predicted that the daily increased risk of axillary metastases is 0.028% for tumors with moderate doubling times of 130 days and 0.057% for tumors with rapid doubling times of 65 days.[12] This means that for a breast cancer with a fast doubling time, a 1- month delay increases the risk of axillary node involvement by 1.8%; a 3-month delay, by 5.2%; and a 6- month delay, by 10.2 %. Because axillary lymph nodes are the most important prognostic indicator for survival in breast cancer, this increased risk of nodal disease may translate into increased risk of systemic recurrence and possibly decreased survival in this setting. These figures can help guide decision-making and frame the "cost" of treatment delay for the pregnant patient.
• Choice of Therapy-The choice of local therapy is influenced by the fact that radiotherapy is contraindicated during pregnancy due to the risk of radiation to the developing fetus.[ 2,13] Thus, mastectomy is the therapy of choice for many patients who present early in pregnancy with early-stage disease. The risks of anesthesia and surgery are generally dependent on the age of the fetus.[14] Breast conservation may be an option for patients who will deliver soon, or for those who will undergo chemotherapy during pregnancy followed by radiation shortly after delivery.
• Chemotherapy-Related Risks- In principle, chemotherapy should be expected to be harmful to a developing fetus because most chemotherapy is specifically designed to cause genetic damage or disrupt cell division. Effects of chemotherapy on the pregnant patient as well as the developing fetus warrant consideration.[15] Risks to the fetus include early effects such as spontaneous abortion, teratogenesis, organ toxicity, premature birth, intrauterine growth retardation, and low birth weight. Potential late effects include carcinogenesis, gonadal dysfunction, infertility, retarded physical and neuropsychological development, organ damage, mutagenesis of germ-line tissue, and teratogenicity and carcinogenesis in subsequent generations.[16] Animal studies have revealed that various chemotherapeutic agents have a wide range of effects, which are primarily associated with the precise timing during which the exposure occurred. Human data regarding the effects of chemotherapy on a developing fetus are limited to case reports and small series. These publications are further limited by likely publication bias as well as a bias toward intervention (eg, the investigators tried this chemotherapy and it caused this problem or no problem). Most available reports comprise patients with various cancers, and effects of a given treatment may be confounded by effects of concurrent radiation, multiple drug exposures, and underlying maternal illness. Drugs such as methotrexate(Drug information on methotrexate) are contraindicated during pregnancy because of the substantial risk of teratogenicity.[15] When chemotherapy is administered during the period of organogenesis early in pregnancy, there is an increased risk of inducing an abortion, causing malformations, or compromising fetal viability. Beyond the first trimester, studies have found that the risk of fetal abnormalities does not appear to be significantly increased.[ 15] Concerns about the timing of delivery are also legitimate, as both maternal and neonatal blood counts may be low and thus increase the risk of bleeding and infection. Whenever possible, it is best to administer the final prenatal course of chemotherapy at least 4 weeks prior to the planned delivery. In discussing possible long-term effects of chemotherapy on the fetus, it is important to note there is still little known regarding longterm outcomes in the children.[16]

• Chemotherapy Studies-Despite these concerns, adjuvant chemotherapy can be administered to pregnant women with early breast cancer. The largest single-institution published experience using a uniform chemotherapy protocol for pregnant patients comes from the University of Texas M. D. Anderson Cancer Center. Berry and colleagues reported their experience with a protocol of adjuvant CAF (cyclophosphamide, doxorubicin [Adriamycin], fluorouracil(Drug information on fluorouracil) [5-FU]) for pregnant women with early breast cancer.[17] Twenty-four pregnant women began CAF chemotherapy in their second and third trimester, receiving cyclophosphamide(Drug information on cyclophosphamide) at 500 mg/m², doxorubicin(Drug information on doxorubicin) at 50 mg/m², and 5-FU at 1,000 mg/m² for a median of 4 cycles (range: 1-6). In this series, there were no reported unexpected antepartum maternal complications, and none of the 24 neonates-born at a median gestational age of 38 weeks-had unusual complications or evidence of malformation. This study provided no details on the health or developmental status of children after the neonatal period. In contrast to this reassuring study, French investigators found 20 cases of breast cancer treatment during pregnancy in a nationwide survey.[18] From this sample of women who received various chemotherapy regimens beginning at a mean gestational age of 26 weeks, the investigators reported several adverse fetal outcomes including one fetal demise, four premature deliveries, anemia and leukopenia in one infant each, two infants with respiratory distress at birth, one case of intrauterine growth retardation, and one neonatal death due to unclear causes at 8 days postpartum. Thus, while women can be treated for early breast cancer during pregnancy, there is no entirely safe cytotoxic drug or timing of exposure for the developing fetus. Chemotherapy during pregnancy should be considered only in situations where the risk to the fetus appears to be outweighed by the risk of delays in therapy for the mother.
• Tamoxifen-Studied as an abortifacient, tamoxifen(Drug information on tamoxifen) is generally contraindicated in pregnancy.[16] There have been case reports of in utero exposure to tamoxifen being associated with fetal anomalies including ambiguous genitalia. Furthermore, there is concern about the long-term effects of tamoxifen on the progeny. However, at least 85 women have become pregnant on tamoxifen with subsequent delivery of an ostensibly normal infant.[16] Thus, in utero exposure to tamoxifen, although not recommended, does not always have adverse effects on the fetus.
• Conclusions-In summary, treatment of breast cancer during pregnancy requires a multidisciplinary care team and careful consideration of the risk of the disease and gestational age of the fetus, in conjunction with the patient's preferences. If it cannot be avoided without potential detriment to the mother, chemotherapy should be deferred beyond the first trimester. Agents of choice include cyclophosphamide and doxorubicin, with or without 5-FU. There are few data regarding the use of the taxanes in pregnancy, and trastuzumab(Drug information on trastuzumab) (Herceptin) and tamoxifen are contraindicated in light of concerns of toxicity to the fetus. Ondansetron(Drug information on ondansetron) (Zofran) has been used in the general obstetrics population and appears to be safe to use for chemotherapy-related emesis. Furthermore, pregnant patients should be monitored carefully for dehydration and infection during treatment, and maternal and fetal pancytopenia near delivery should be avoided in an effort to avoid associated complications.