Breast Cancer in Pregnancy | 7 |
Ewa Mrozek, Susan B. Kesmodel, and Katherine H. R. Tkaczuk
INTRODUCTION
The incidence of pregnancy-associated breast cancer (PABCa) has been increasing during the last few decades because of the rising breast cancer incidence and the delay in childbearing to the fourth decade of life (1). PABCa is defined as breast cancer diagnosed during pregnancy or within 1 year of delivery; however, the primary difficulty in managing these patients occurs when they are diagnosed during pregnancy. Pregnant and lactating women should undergo a breast examination as part of the routine prenatal examination. All palpable breast masses should be evaluated by imaging studies, and biopsy of suspicious masses should be performed without delay. Management of breast cancer during pregnancy requires a careful balance between using standard therapies to effectively treat the mother while minimizing the potential toxicities to the fetus. PABCa should be treated according to guidelines for young nonpregnant patients in highly qualified and experienced centers (2,3). A multidisciplinary collaboration between the surgical oncologist, medical oncologist, radiologist, obstetrician specializing in high-risk pregnancies, and perinatologist is required due to concerns for congenital malformations, effects of treatment on fetal growth, preterm delivery, and long-term side effects from cancer treatments in children.
EPIDEMIOLOGY
Breast cancer, the most common cancer in pregnant women, occurs in approximately 1 in 3,000 pregnant women (4). It is estimated that 10% of breast cancers in women ≤40 years of age are pregnancy-related, and approximately 1 in 5 breast cancers diagnosed in women aged 25 to 29 years is associated with a pregnancy (5).
No specific risk factors for breast cancer in pregnancy are known. Genetic and environmental risk factors are similar to those for age-adjusted breast cancer in the general population.
PABCa presents in more advanced stages with larger primary tumors and more frequent lymph node involvement when compared to nonpregnant women (6). However, the largest cohort study of 313 patients showed that after controlling for stage, prognostic factors, and adjuvant treatment, the disease-free survival and overall survival were similar for patients with breast cancer diagnosed during pregnancy compared to nonpregnant patients with breast cancer (7). In contrast, a large meta-analysis of 30 studies showed that the diagnosis of breast cancer in the postpartum period was associated with significantly poorer outcomes compared to diagnosis during pregnancy (8).
PABCa has more unfavorable histological features: high tumor grade, lower rate of hormone receptor expression, and higher rate of HER2 expression (9).
FETAL RISKS DURING PREGNANCY
A maternal fetal medicine consultation and follow-up is necessary to document fetal growth and development, as well as fetal age. Consultation should also include the review of antecedent maternal risks such as hypertension, diabetes, and complications during prior pregnancies. Estimation of the date of delivery is necessary to plan for systemic chemotherapy and breast surgery.
Fetal exposure to chemotherapy in the first trimester, especially during the gestational age of 2 to 8 weeks when organogenesis occurs, is associated with an increased risk of spontaneous miscarriage, fetal death, and major birth defects (10). First-trimester exposure to cytotoxic drugs has been associated with a 10% to 20% risk of major malformations (11). After organogenesis, several organs including the eyes, genitals, hematopoietic system, and the central nervous system remain vulnerable to chemotherapy (12).
The use of chemotherapy in the second and third trimesters of pregnancy does not increase the risk of fetal malformations, but is associated with intrauterine growth retardation (IUGR), prematurity, lower birthweight, and higher rate of stillbirth (13). The international registry data, which included 197 pregnant women with breast cancer who received chemotherapy during the second and third trimesters of pregnancy, showed that chemotherapy in utero lowered birthweight, with a slight increase in the incidence of premature deliveries and obstetric and neonatal adverse events compared to women who were not treated with chemotherapy while pregnant (14).
A significantly higher incidence of IUGR observed with chemotherapy given during pregnancy indicates a potentially toxic influence on placental development via incomplete trophoblast invasion into the uterus, resulting in a decreased transfer of nutrients to the fetus (15). Data on transplacental transfer rates of cytotoxic drugs are very limited in humans. Animal models indicate that the placenta acts as a barrier for the transfer of most chemotherapeutic drugs, reducing fetal exposure (16). Ionizing radiation greatly interferes with cell proliferation. Fetal exposure and damage can occur during diagnostic imaging studies and therapeutic radiotherapy. Timing of the exposure to radiation relative to the gestational age of the fetus is more important than the actual dose of radiation delivered (17). Radiation exposure >0.1 Gy during the first trimester may lead to congenital malformations, mental retardation, and increased relative risk of carcinogenesis (18). These risks are the reasons that pregnancy is an absolute contraindication to the use of therapeutic radiation.
The data on long-term outcomes of children exposed to chemotherapy in utero are limited, and there are currently no specific guidelines for monitoring such children (19). A recently published multicenter case–control study showed that prenatal exposure to maternal cancer and treatment with chemotherapy did not impair the cognitive, cardiac, or general development of children in early childhood (20).
Medical termination of pregnancy may be discussed when a diagnosis of PABCa is made early in the pregnancy. Generally, however, we do not recommend termination of pregnancy, as in most cases it is acceptable to delay surgery and chemotherapy until the patient is in her second trimester of pregnancy. In some cases neoadjuvant chemotherapy can be given to patients in the second or third trimester while surgery and radiation are performed after delivery. We typically recommend delaying chemotherapy until ≥20 weeks of pregnancy. The patient and her partner should be informed about the different treatment options and the physician should explain that termination of pregnancy has not been shown to improve the overall outcome of the cancer (21).
CHEMOTHERAPY
Since many pregnant patients present with biologically aggressive and/or large, locally advanced tumors, chemotherapy, given either before or after breast surgery, is often required. Unless the woman is diagnosed with breast cancer in the late third trimester of pregnancy, postponing chemotherapy treatment until after delivery is not recommended. Data in pregnant young women indicate that delaying or postponing chemotherapy might increase the risk of relapse (22).
The physiological alterations associated with pregnancy, such as changes in plasma volume, serum albumin, increased hepatic and renal clearance, and third spacing of drugs in the amniotic sac fluid, result in lower maximal concentrations of chemotherapy and a lower area under the concentration–time curve (23). The increased activity of major enzymes involved in the metabolism of taxanes and anthracyclines (including cytochrome p450 isoforms, such as CYP3A4 and CYP2C8) observed during the late trimesters of pregnancy, can further decrease the drug exposure (24). Despite those concerns, the same dose of chemotherapy is recommended for pregnant women compared to nonpregnant women. The dosing should be based on actual bodyweight and body surface area (25).
There are no randomized controlled trials evaluating the safety of the various chemotherapy regimens in breast cancer. There is only one single-institution prospective study published on pregnant patients with breast cancer, who were treated with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) (26). The study enrolled 81 patients and showed that pregnant women with breast cancer can be treated safely with FAC during the second and third trimesters without concerns for serious complications or short-term health concerns for their offspring.
Anthracyclines, cyclophosphamide, and taxanes, the standard adjuvant or neoadjuvant combination that is recommended for nonpregnant patients, is also recommended for treatment of PABCa after the first trimester (26–29). Taxanes are substrates for the P glycoprotein (Pgp/MDR1/ABCB1), which is highly expressed on the maternal compartment of the placenta (30). The Pgp protects the fetus against xenobiotics and might therefore reduce the transplacental transfer of taxanes. There are limited data on the use of taxanes during pregnancy; however, a published review of literature that included 23 publications describing 40 women—27 with breast cancer, 10 with ovarian cancer, and 3 with non–small-cell lung cancer—and 42 neonates showed that taxanes do not appear to increase the risk of fetal or maternal complications when administered in the second and third trimesters of pregnancy (27). Paclitaxel was administered in 21 cases, docetaxel in 16 cases, and both drugs in 3 cases; except for 2 cases, taxanes were administered concomitantly or sequentially with other cytotoxic agents such as anthracyclines, cyclophosphamide, and platinum derivatives.
The use of anthracycline- or taxane-free regimens is not considered to be standard in nonpregnant women and therefore is not recommended in pregnant women. Since a recently published study found that fluorouracil does not add any benefit to an anthracycline–taxane-based regimen, it is no longer indicated for breast cancer therapy (31). In view of the third-space effect of methotrexate, the combination of this drug with cyclophosphamide and fluorouracil should not be used in pregnant women (32). Currently, there are limited reports of use of dose dense regimens for PABCa (33).
Targeted therapy. Trastuzumab use is not recommended during pregnancy. HER2 is strongly expressed in the fetal renal epithelium (34). A recent review identified 18 reports in the literature of trastuzumab use during pregnancy (35). The most frequent adverse effect, occurring in 33% of reported cases, was oligohydramnios and anhydramnios. Most of the pregnancies ended prematurely and four of the newborns died from complications of prematurity (mainly respiratory failure). However, the use of trastuzumab may be discussed in special, high-risk situations. In the neoadjuvant setting, treatment with pertuzumab in addition to trastuzumab and chemotherapy increases the pathological complete response rate in patients with HER2-positive breast cancer, but currently there are no data on use of pertuzumab during pregnancy and we would not recommend this approach in pregnant women. New breast cancer drugs, such as tyrosine kinase inhibitors, should not be used in pregnant patients because they have not been tested in this group. For HER2-positive pregnant patients receiving neoadjuvant therapy we typically recommend initiating standard chemotherapy before delivery and delaying the anti-HER2 therapy until after delivery, at which point a full course of trastuzumab +/− pertuzumab every 3 weeks for 17 cycles can be completed.
Supportive treatment for chemotherapy can be given to pregnant women according to general recommendations. The typical side effects and risks of chemotherapy in pregnant women are similar to those risks in nonpregnant women. There is consensus on the safe use of antiemetics like metoclopramide, the 5-HT-3 antagonist ondansetron, and corticosteroids during pregnancy (36,37). No data are available on the use of neurokinin 1 (NK-1) antagonists. Regarding corticosteroids, the use of methylprednisolone or hydrocortisone is preferred over dexa/betamethasone. Hydrocortisone and methylprednisolone are extensively metabolized in the placenta, so relatively small amounts of these drugs cross into the fetal compartment (38).
Granulocyte colony stimulating factor (G-CSF) is frequently used in nonpregnant patients to manage chemotherapy-induced neutropenia. The effectiveness and safety profile of G-CSF are not clearly established in pregnancy. Although data on the use of G-CSF in pregnant women are limited, we found no conclusive evidence that G-CSF use increases the rates of fetal death or congenital malformations, but feel that G-CSF should only be recommended when chemotherapy is recommended with curative intent after consideration of the overall risks and benefits. In an observational study in women with cyclic, idiopathic, or autoimmune neutropenia, the use of G-CSF during pregnancy was associated with no significant increase in adverse events, considering all pregnancies or individual mothers and adverse events in the neonates were similar between pregnancies with or without G-CSF therapy (39). Filgrastim carries the Food and Drug Administration (FDA) pregnancy category C and is not recommended unless the benefit outweighs the risk to the developing fetus. This generally means that animal studies have showed some evidence of maternal toxicity, embryolethality, and fetotoxicity; there are no controlled data in human pregnancy. Women who become pregnant during treatment with filgrastim should enroll in Amgen’s Pregnancy Surveillance Program—1-800-77-AMGEN (1-800-772-6436). Nonetheless, the administration of G-CSF in pregnancy should only be considered when the benefits of managing maternal neutropenia outweigh the unknown fetal risks.
Chemotherapy should be avoided after 35 weeks of gestation due to the risk of spontaneous delivery before the recovery of bone marrow. In addition, delivery postponement after chemotherapy will facilitate fetal drug clearance via the placenta. This is most important in preterm babies who have immature liver and kidneys and thus limited capacity to metabolize and excrete the drugs.
HORMONAL THERAPY
Tamoxifen is the standard hormonal agent used for the treatment of premenopausal women with endocrine-responsive breast cancer, but it is a teratogenic agent. Studies using adjuvant hormonal therapy for breast cancer in pregnant women are very limited. Animal models have shown that tamoxifen can cause genitourinary developmental defects (40). Other birth defects associated with use of tamoxifen include Goldenhar syndrome (oculoauriculovertebral dysplasia), ambiguous genitalia, and Pierre Robin sequence, the triad of small mandible, cleft palate, and glossoptosis (41,42). A review of Astra Zeneca files identified 50 cases that were exposed to tamoxifen during pregnancy, with 10 congenital defects identified (43). Therefore, hormonal therapy should be started after delivery and after completion of chemotherapy. Delaying hormonal treatment will not reduce the efficacy of tamoxifen.
SURGERY IN PREGNANCY
Surgery can be performed during all trimesters of pregnancy (43). However, in the first trimester there is an increased risk of pregnancy loss and concern for potential exposure of the fetus to teratogens. The risk of miscarriage and preterm labor is lowest in the second trimester and increases during the third trimester.
When performing surgery in pregnant women, it is important to maintain venous return to the heart, which may be compromised due to pressure from the uterus. Patients who are at 20 weeks or greater gestation should be positioned in a left lateral tilt position to reduce compression on the inferior vena cava.
Surgical options that are available to pregnant women are the same as those that are available to nonpregnant patients and depend on the size of the tumor and extent of lymph node involvement. If breast conserving surgery is performed during pregnancy then adjuvant radiation therapy needs to be delayed until after delivery.
For early-stage breast cancer patients having surgery during pregnancy, sentinel lymph node biopsy typically with radiotracer alone may be considered (44). The radiation exposure to the fetus is low with this procedure. However, the options of sentinel lymph node biopsy and axillary lymph node dissection and the risks of each procedure should be clearly discussed with the patient. We currently discuss the option of sentinel lymph node biopsy using low-dose (10 MBq) lymphoscintigraphy using (99m)Tc human serum albumin nanocolloids, radiotracer alone with pregnant patients who have clinically negative lymph nodes (45).
For patients with locally advanced tumors, we consider neoadjuvant systemic therapy, when appropriate, prior to surgery.
It is always important for the surgeon to speak with anesthesia and maternal fetal medicine so that a plan for anesthesia and fetal monitoring (when necessary) can be discussed and arranged prior to surgery.
