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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1567-1569 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.0309
Treatment of Breast Cancer With Trastuzumab During PregnancyDivision of Hematology/Oncology, Comprehensive Breast Health Services, James Cancer Hospital and Solove Research Institute, The Ohio State University Medical Center, Columbus, OH
Department of Obstetrics and Gynecology, The Ohio State University Medical Center, Columbus, OH
Division of Surgical Oncology, Comprehensive Breast Health Services, James Cancer Hospital and Solove Research Institute, The Ohio State University Medical Center, Columbus, OH
Division of Hematology/Oncology, Comprehensive Breast Health Services, James Cancer Hospital and Solove Research Institute, The Ohio State University Medical Center, Columbus, OH To the Editor: The human epidermal growth factor receptor 2 (HER-2) is a member of the epidermal growth factor receptor family of tyrosine kinases.1 Trastuzumab,2 a monoclonal antibody targeting the extracellular domain of the HER-2 protein, either alone or in combination with chemotherapy, improves the outcome of women with metastatic breast cancer.3,4 This benefit extends to the adjuvant setting with phase III randomized controlled trials demonstrating a statistically significant improvement in disease-free and overall survival with the addition of trastuzumab to adjuvant chemotherapy.2,5,6 Cardiac dysfunction occurs in 2% to 4% of women treated with trastuzumab,7 but information about the effects on the developing human fetus is limited. Herein describes a woman with HER-2–overexpressing metastatic breast cancer who became pregnant while receiving trastuzumab, and the drug was continued during all three trimesters of pregnancy. A 30-year-old woman was referred to the clinic for evaluation of a 4-month-old mass in the right breast. She palpated the mass during the first trimester of her third pregnancy. She had a miscarriage at 13 weeks gestation; however, the mass persisted, and subsequent core biopsy revealed invasive ductal cancer, grade 2/3, estrogen and progesterone receptor–negative. A right-modified radical mastectomy revealed a 0.9 cm invasive ductal cancer with two of 28 lymph nodes containing metastases. She received adjuvant chemotherapy from August 1998 to January 1999 on Cancer and Leukemia Group B protocol 9741 with sequential cyclophosphamide 600 mg/m2, doxorubicin 60 mg/m2, and paclitaxel 175 mg/m2, each drug administered every 2 weeks for four cycles with filgrastim support. She retained normal menstrual function after chemotherapy, and after 2 years subsequently conceived and delivered her third healthy child. Two years later a chronic cough prompted a chest x-ray that revealed patchy opacity in the apex of the right lung. Soft tissue nodules in the right lung were imaged on computed tomography, and fine needle aspirate was consistent with adenocarcinoma of breast origin. Evaluation of original tumor was HER-2–positive 3+ by immunohistochemistry. She received paclitaxel and trastuzumab with near complete resolution of pulmonary nodules; after 8 months of this treatment, she was switched to single-agent trastuzumab. She was on single-agent therapy for 3 months when she reported a lack of menses and was found to be 14 weeks pregnant by ultrasound. After weighing the uncertain fetal risks of trastuzumab during the first trimester versus the expectation of trastuzumab providing ongoing benefit, the patient and her husband elected to continue pregnancy and receive trastuzumab. The maternal-fetal service provided obstetric care and close fetal surveillance. During weeks 14 to 24, fetal growth and viability was within normal limits. Beginning at 25 weeks gestation, low amniotic fluid volume was noted with an index of 8.1 cm. Weekly assessment of amniotic fluid index continued in the low normal range for 7 weeks. Estimated fetal growth remained normal at the 33rd percentile. A follow-up ultrasound at 32 weeks revealed frank oligohydroaminos with an index of 3.7. Premature rupture of membranes was ruled out by speculum examination. She was admitted to the hospital, and antenatal steroids were administered to promote fetal lung maturation. Labor was induced with delivery of a viable female infant at 32+1 weeks’ gestational age and birth weight of 1,810 g. The infant exhibited normal Apgar scores, urine output and serum creatinine. A renal ultrasound and echocardiogram were normal. The infant was intubated for 3 days for surfactant delivery, and after extubation there were no further respiratory or other medical problems. The child is now 5 years old with normal growth and development. The mother is currently receiving lapatinib and capecitabine for metastatic breast cancer. Experience with trastuzumab during pregnancy is limited (Table 1), and there is one case report of lapatinib during pregnancy.8-14 The current report is unique in that trastuzumab was administered before and during all three trimesters of pregnancy, and now the child has been observed for 60 months, and has had normal growth and development. The majority of the women exposed to trastuzumab developed oligo- or anhydraminos, and increases in amniotic fluid were observed when the drug is discontinued.8,12 It is presently unknown whether trastuzumab directly causes a decrease in amniotic fluid, or if it does by what mechanism, but one hypothesis relates to the role of epidermal growth factor receptor (EGFR) in fetal kidney development.8,10 First, a critical question is whether trastuzumab crosses the placenta. Although direct evidence from humans is lacking, maternal-placental transfer of immunoglobulin-G1 antibodies such as rituximab occurs,14,15 and studies in cynomologus monkeys show placental transfer of trastuzumab during early and late gestation.16
Nephrons derive from proliferating metanephric mesenchyme beginning about the fifth to sixth week of gestation.17 Increased epidermal growth factor (EGF), EGFR, and EGFR activation occurs in the rat fetal kidney,18 and EGFR expression is relatively high in the human fetal kidney.17,19 Furthermore, EGF increases and anti-EGFR antibody decreases DNA synthesis in human fetal kidney cells.20 With specific reference to HER-2, both protein and mRNA expression are found in human adult and fetal kidney tissues.21 Vascular endothelial growth factor (VEGF) regulates the production and reabsorption of amniotic fluid by altering the permeability of fetal membranes.22 As trastuzumab inhibits VEGF expression,23,24 it is plausible that trastuzumab affects amniotic fluid by altering VEGF expression. EGFR signaling, in particular erbB2 (or HER-2), is required for normal myocardial and neural development in models using transgenic mice.25,26 It is somewhat surprising that trastuzumab is classified as category B,27 and use of trastuzumab in pregnancy is indicated if the potential benefit to the mother exceeds the potential harm to the fetus.16 Trastuzumab was started between 3 and 52 weeks before pregnancy in four women, and the drug was continued throughout the first trimester in three of them (Table 1). These cases, in addition to the studies of fetal cynomologus monkeys regarding the safety of trastuzumab when administered early in gestation,16 may provide a modicum of reassurance to the woman who inadvertently becomes pregnant while receiving trastuzumab and is considering maintaining the pregnancy. Surveys of young women with breast cancer suggest preservation of fertility and menopausal concerns are of major importance, yet up to one third of these women do not recall having had any discussions about these issues.28-30 With reference to contraception, more than 50% of women reported that their questions were not answered at the time of the initial treatment, and nearly 20% of them reported their questions were still unanswered at the time of the survey.29 This suggests that issues surrounding contraceptive practices before, during, and after treatment may not be optimally addressed. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U’ are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Charles L. Shapiro, Genentech (C) Stock Ownership: None Honoraria: None Research Funding: Charles L. Shapiro, Genentech Expert Testimony: None Other Remuneration: None
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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