Pregnancy and Breast Cancer

The relationship between pregnancy and breast cancer is complex, and a paucity of available data further complicates decision-making for many women diagnosed with breast cancer during pregnancy or desiring to become pregnant after such a diagnosis. 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. Chemotherapy should be deferred beyond the first trimester. There is no evidence that pregnancy in a breast cancer survivor will decrease long-term survival; in fact, studies suggest a potential protective effect of pregnancy after breast cancer in terms of the risk of recurrence. However, the available studies are limited by substantial potential biases, and concerns remain for some women and their doctors about the risks of pregnancy after breast cancer. This article reviews what is known about the association between pregnancy and breast cancer, discusses treatment options for women diagnosed with the disease during pregnancy, and summarizes evidence regarding the safety of pregnancy after 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-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]

• 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 [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 at 500 mg/m², 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 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 (Herceptin) and tamoxifen are contraindicated in light of concerns of toxicity to the fetus. 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.

Pregnancy After Breast Cancer In light of the high estrogen and progesterone milieu of pregnancy, there have been concerns that pregnancy after breast cancer may stimulate micrometastases and increase the risk of disease recurrence, particularly in women with a history of hormone- receptor-positive breast cancer. Several studies have attempted to evaluate the risk of pregnancy after breast cancer.[19-25] Available large studies are presented in Table 1. To date, there is no evidence that a breast cancer survivor who goes on to have a child is harming her chances for long-term survival. In fact, the studies suggest a potential protective effect of pregnancy after breast cancer in terms of the risk of recurrence. For example, Danish investigators identified 173 pregnancies following diagnosis among 5,725 women in their national breast cancer database.[21] Women who became pregnant tended to have a more favorable prognosis, including smaller tumors and fewer involved nodes. When adjusting for known prognostic variables, they found that the relative risk of death for a woman who had a pregnancy after breast cancer was 0.55 (95% confidence interval = 0.28-1.06, P = .08). When their analysis was restricted to a subgroup of low-risk patients, they also found a nonsignificant relative risk reduction. In light of the mostly historical use of high-dose estrogen as a treatment modality for breast cancer, some investigators have speculated that pregnancy produces a biologic protective effect via high levels of estrogen. It is important to recognize, however, that studies in this setting are all limited by significant biases, including selection biases and what has been called the "healthy mother effect": Only women who are alive, healthy, and disease-free will generally go on to become pregnant after breast cancer.[ 20] It is difficult to avoid this bias, and certainly not appropriate or ethically sound to consider a randomized clinical trial (randomizing women to pregnancy or not) to evaluate more fully the safety of breast cancer after pregnancy. Thus, despite the lack of evidence of harm in available studies, the lack of definitive information about the effects of a subsequent pregnancy on breast cancer prognosis remains problematic for many women. Ongoing prospective studies will hopefully provide additional information about the safety of breast cancer following pregnancy. Ultimately, the decision to have a child after treatment for breast cancer remains difficult for a patient with an uncertain future. Conventional wisdom is to wait until at least 2 years have passed from time of diagnosis in order to get through the period of early recurrence risk. It is important to note, however, that there are no data to suggest there is any harm in a lower-risk patient becoming pregnant sooner.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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