- Email: [email protected]
Treatment of Metastatic Breast Cancer with Trastuzumab and Vinorelbine During Pregnancy
case
report Treatment of Metastatic Breast Cancer with Trastuzumab and Vinorelbine During Pregnancy Michelle A. Fanale,1 Anne R. Uyei,2 Richard L. Theriault,2 Karolina Adam,3 Rachel A. Thompson4 Abstract The management of breast cancer during pregnancy is a crucial clinical issue. It is important to evaluate the impact of chemotherapy on a woman and her fetus. Studies from our institution have demonstrated the safety and efficacy of treating women with adjuvant 5-fluorouracil/doxorubicin/cyclophosphamide during the second or third trimester of pregnancy. However, the literature regarding the treatment of metastatic breast cancer in a pregnant patient is scarce. In this article, we describe the successful treatment of a woman at 27 weeks of pregnancy with recurrent HER2/neu–overexpressing breast cancer who was symptomatic from multiple liver metastases. Per our review of the literature and to our knowledge, she is the first patient to be treated with weekly vinorelbine plus trastuzumab. Our patient had near complete resolution of her disease and delivered a healthy male infant at 34 weeks of gestation. Clinical Breast Cancer, Vol. 6, No. 4, 354-356, 2005 Key words: Chemotherapy, Cyclophosphamide, 5-Fluorouracil, Magnetic resonance imaging, Trastuzumab
Introduction Although breast cancer during pregnancy is an unusual circumstance, it is the second most common malignancy associated with pregnancy.1,2 Exposure to chemotherapy during the first trimester carries the greatest fetal risk.3 Data suggest that chemotherapy in the second or third trimester may be associated with fetal prematurity but not with increased rate of congenital malformations.4 A prospective cohort study at The University of Texas M. D. Anderson Cancer Center (MDACC), has evaluated 39 women treated for primary breast cancer during their second or third trimester with FAC (5-fluorouracil [5-FU]/doxorubicin/cyclophosphamide) for a median of 4 cycles.5 This regimen has not resulted in maternal or fetal death. Poten1Lymphoma and Myeloma 2Breast Medical Oncology
The University of Texas M. D. Anderson, Houston 3Obstetrics and Gynecology, Maternal Fetal Medicine,
The Methodist Hospital, Houston, TX 4Obstetrics and Gynecology
Houston Women’s Care Associates, Houston, TX Submitted: Sep 8, 2004; Revised: Oct 22, 2004; Accepted: Nov 12, 2004 Address for correspondence: Michelle A. Fanale, MD, The University of Texas M. D. Anderson Cancer Center, Department of Lymphoma and Myeloma, 1515 Holcombe Blvd, Box #429, Houston, TX 77030-4009 Fax: 713-794-5656; e-mail: [email protected]
tial side effects noted included preterm labor, preeclampsia, hyaline membrane disease, transient hypoxia, transient leukopenia without infection, and low birth weight.6 Data concerning the treatment of metastatic breast cancer (MBC) during pregnancy are scarce. To our knowledge, we provide the first report of the use of trastuzumab plus vinorelbine. The Institutional Review Board at The University of Texas MDACC has approved the reporting of these data.
Patient A 26-year-old white woman presented with stage IIB (T2N1M0) multicentric left infiltrating ductal breast cancer; she had estrogen receptor–negative and progesterone receptor–negative, and HER2/neu–overexpressing disease by fluorescent in situ hybridization. The patient underwent an excisional biopsy of 2 tumors (1.3 cm and 1.4 cm) and then came to MDACC. She was found to have a 3.1 cm left axillary lymph node that was malignant by fine needle aspiration and a residual 1.8 cm tumor in the left axillary tail. She was treated on a clinical trial with trastuzumab plus neoadjuvant chemotherapy. She received paclitaxel 225 mg/m2 every 3 weeks for 4 cycles followed by FEC (5-FU 500 mg/m2 on days 1 and 4, epirubicin 75 mg/m2 on day 1, and cyclophosphamide 500 mg/m2 on day 1) every 3 weeks for 4 cycles without trastuzumab. After the fourth cycle of paclitaxel, she had a decrease in tumor size to 0.8 cm in both
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
354 • Clinical Breast Cancer October 2005
Figure 1 Magnetic Resonance Imaging of the Liver Showing Metastases Before Treatment
Figure 2 Magnetic Resonance Imaging of the Liver Showing Resolution of Metastases After Treatment
Pretreatment MRI of the liver shows extensive breast cancer metastases involving the liver.
Magnetic resonance imaging showing near resolution of breast cancer metastases to the liver 3 months after beginning combined treatment with vinorelbine and trastuzumab.
the left axillary tail tumor and the left axillary lymph node. However, after the second cycle of FEC, the left axillary tail tumor had increased to 1.7 cm. Chemotherapy was halted, and a left modified radical mastectomy was performed. Pathology confirmed a modified Black’s nuclear grade 3 infiltrating ductal carcinoma measuring 2.5 cm, with 1 positive axillary lymph node of 15 examined. She then received radiation therapy of 50 Gy plus a 10 Gy boost. Fourteen months after the original diagnosis, she presented at the 27th week of pregnancy with right upper quadrant pain and an Eastern Cooperative Oncology Group performance status (PS) of 2. Staging evaluations, including a chest radiograph, magnetic resonance imaging (MRI) of the brain/thoracic and lumbar spine/abdomen, and ultrasound of the abdomen, documented multiple hepatic metastases (Figure 1). Laboratory assessment indicated increased liver function tests and cancer antigen 27-29 level. After detailed deliberation and discussion, she began treatment with vinorelbine and trastuzumab. A loading dose of 4 mg/kg of trastuzumab and weekly doses of 2 mg/kg was prescribed. Vinorelbine was initiated at 25 mg/m2 weekly for 3 weeks followed by a week of rest. The patient was seen weekly by our department and a high-risk obstetrician for fetal monitoring. Oligohydramnios was noted, so intravenous fluids were given with each treatment. The oligohydramnios was thought to be secondary to fluid shifts or to direct side effects of the systemic therapy. After 5 weeks of treatment the patient’s hepatic pain resolved, laboratory values normalized, and PS improved to 1. Fetal development was reported to be normal; however, despite extra hydration, the amniotic fluid indexes were low. At 34 weeks and 5 days the patient noted decreased fetal movement. Although the fetus had only mild occasional car-
diac decelerations, the patient underwent induction of labor and delivered, per vaginum, a healthy male infant who weighed 5 pounds, 11 ounces and was 19.5 inches long with an Apgar score of 9/9/10. No immediate postpartum maternal or neonatal complications were noted. The patient remains on vinorelbine plus trastuzumab therapy. An MRI of the liver 3 months after initiation of therapy showed near complete resolution of disease (Figure 2). Her 6-month-old infant is reported to be healthy and developing normally.
Discussion Data on the treatment of MBC in pregnancy are limited. Patients with stage IV breast cancer have treatment goals of palliation and prolongation of life. However, if there is rapid progression with involvement of vital organs, it is likely that delay in treatment will result in death for the mother and fetus. Vinorelbine is a vinca alkaloid and is classified as pregnancy risk category D by the Food and Drug Administration (FDA). Several case reports document its use in the treatment of breast cancer in pregnant patients alone and in combination with 5-FU. All 8 patients were in their second trimester or later. The only fetal side effect noted was anemia. All babies were delivered at 32-40 weeks with normal development on follow-up ≤ 3 years.7-9 Vinorelbine treatment during pregnancy has also been reported for non–small-cell lung cancer10 and non-Hodgkin’s lymphoma.11 Trastuzumab is a recombinant monoclonal antibody against HER2/neu and is approved for the treatment of MBC. When given with chemotherapy, including vinorelbine, response rates and survival are increased.12-16 It is classified as FDA Pregnancy Risk Category B. Reproduction studies in cynomolgus monkeys have been conducted using 25 times
Clinical Breast Cancer October 2005 • 355
Treatment of Metastatic Breast Cancer During Pregnancy the standard human dose. Transfer of the antibody in the milk was noted, but no adverse effects on the offspring were reported even though HER2/neu receptors are present in cardiac and neural tissues.17,18 In our judgment, without treatment this patient would not have survived to deliver her baby. To our knowledge, this is the first case that provides evidence regarding the use of vinorelbine plus trastuzumab treatment for MBC in a pregnant patient. It adds to the current evidence supporting the use of vinorelbine in pregnant patients and provides some support for the use of trastuzumab in this dire clinical circumstance.
References 1. Wallack MK, Wolf JA Jr, Bedwinek J, et al. Gestational carcinoma of the female breast. Curr Probl Cancer 1983; 7:1-58. 2. Smith LH, Dalrymple JL, Leiserowitz GS, et al. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol 2001; 184:1504-1512. 3. Ebert U, Loffler H, Kirch W. Cytotoxic therapy and pregnancy. Pharmacol Ther 1997; 74:207-220. 4. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and pregnancy. Semin Oncol 1989; 16:337-346. 5. Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17:855-861. 6. Gwyn K, Theriault R, Sahin A., et al. Treatment of breast cancer during pregnancy ssing a standard protocol: update of the M.D. Anderson experience. Proc Am Soc Clin Oncol 2001; 18b (Abstract #1821). 7. De Santis M, Lucchese A, De Carolis S, et al. Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer Care (Engl) 2000; 9:235-237.
356 • Clinical Breast Cancer October 2005
8. Cuvier C, Espie M, Extra JM, et al. Vinorelbine in pregnancy. Eur J Cancer 1997; 33:168-169. 9. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy: a French national survey. Cancer 1999; 86:22662272. 10. Janne PA, Rodriguez-Thompson D, Metcalf DR, et al. Chemotherapy for a patient with advanced non-small-cell lung cancer during pregnancy: a case report and a review of chemotherapy treatment during pregnancy. Oncology 2001; 61:175-183. 11. Rodriguez JM, Haggag M. VACOP-B chemotherapy for high grade non-Hodgkin’s lymphoma in pregnancy. Clin Oncol (R Coll Radiol) 1995; 7:319-320. 12. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in the first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20:719-726. 13. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safey of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639-2648. 14. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-792. 15. Jahanzeb M, Mortimer JE, Yunus F, et al. Phase II trial for weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancer. Oncologist 2002; 7:410-417. 16. Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21:2889-2895. 17. Genetech Pharmaceuticals Website. Full Prescribing Information of Herceptin (Trastuzumab)--Precautions. 2003. Available at: http://www.gene.com/gene/products/information/oncology/herceptin/in sert.jsp. Accessed October 22, 2004. 18. Lee KF, Simon H, Chen H, et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995; 378:394-398.
report Treatment of Metastatic Breast Cancer with Trastuzumab and Vinorelbine During Pregnancy Michelle A. Fanale,1 Anne R. Uyei,2 Richard L. Theriault,2 Karolina Adam,3 Rachel A. Thompson4 Abstract The management of breast cancer during pregnancy is a crucial clinical issue. It is important to evaluate the impact of chemotherapy on a woman and her fetus. Studies from our institution have demonstrated the safety and efficacy of treating women with adjuvant 5-fluorouracil/doxorubicin/cyclophosphamide during the second or third trimester of pregnancy. However, the literature regarding the treatment of metastatic breast cancer in a pregnant patient is scarce. In this article, we describe the successful treatment of a woman at 27 weeks of pregnancy with recurrent HER2/neu–overexpressing breast cancer who was symptomatic from multiple liver metastases. Per our review of the literature and to our knowledge, she is the first patient to be treated with weekly vinorelbine plus trastuzumab. Our patient had near complete resolution of her disease and delivered a healthy male infant at 34 weeks of gestation. Clinical Breast Cancer, Vol. 6, No. 4, 354-356, 2005 Key words: Chemotherapy, Cyclophosphamide, 5-Fluorouracil, Magnetic resonance imaging, Trastuzumab
Introduction Although breast cancer during pregnancy is an unusual circumstance, it is the second most common malignancy associated with pregnancy.1,2 Exposure to chemotherapy during the first trimester carries the greatest fetal risk.3 Data suggest that chemotherapy in the second or third trimester may be associated with fetal prematurity but not with increased rate of congenital malformations.4 A prospective cohort study at The University of Texas M. D. Anderson Cancer Center (MDACC), has evaluated 39 women treated for primary breast cancer during their second or third trimester with FAC (5-fluorouracil [5-FU]/doxorubicin/cyclophosphamide) for a median of 4 cycles.5 This regimen has not resulted in maternal or fetal death. Poten1Lymphoma and Myeloma 2Breast Medical Oncology
The University of Texas M. D. Anderson, Houston 3Obstetrics and Gynecology, Maternal Fetal Medicine,
The Methodist Hospital, Houston, TX 4Obstetrics and Gynecology
Houston Women’s Care Associates, Houston, TX Submitted: Sep 8, 2004; Revised: Oct 22, 2004; Accepted: Nov 12, 2004 Address for correspondence: Michelle A. Fanale, MD, The University of Texas M. D. Anderson Cancer Center, Department of Lymphoma and Myeloma, 1515 Holcombe Blvd, Box #429, Houston, TX 77030-4009 Fax: 713-794-5656; e-mail: [email protected]
tial side effects noted included preterm labor, preeclampsia, hyaline membrane disease, transient hypoxia, transient leukopenia without infection, and low birth weight.6 Data concerning the treatment of metastatic breast cancer (MBC) during pregnancy are scarce. To our knowledge, we provide the first report of the use of trastuzumab plus vinorelbine. The Institutional Review Board at The University of Texas MDACC has approved the reporting of these data.
Patient A 26-year-old white woman presented with stage IIB (T2N1M0) multicentric left infiltrating ductal breast cancer; she had estrogen receptor–negative and progesterone receptor–negative, and HER2/neu–overexpressing disease by fluorescent in situ hybridization. The patient underwent an excisional biopsy of 2 tumors (1.3 cm and 1.4 cm) and then came to MDACC. She was found to have a 3.1 cm left axillary lymph node that was malignant by fine needle aspiration and a residual 1.8 cm tumor in the left axillary tail. She was treated on a clinical trial with trastuzumab plus neoadjuvant chemotherapy. She received paclitaxel 225 mg/m2 every 3 weeks for 4 cycles followed by FEC (5-FU 500 mg/m2 on days 1 and 4, epirubicin 75 mg/m2 on day 1, and cyclophosphamide 500 mg/m2 on day 1) every 3 weeks for 4 cycles without trastuzumab. After the fourth cycle of paclitaxel, she had a decrease in tumor size to 0.8 cm in both
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
354 • Clinical Breast Cancer October 2005
Figure 1 Magnetic Resonance Imaging of the Liver Showing Metastases Before Treatment
Figure 2 Magnetic Resonance Imaging of the Liver Showing Resolution of Metastases After Treatment
Pretreatment MRI of the liver shows extensive breast cancer metastases involving the liver.
Magnetic resonance imaging showing near resolution of breast cancer metastases to the liver 3 months after beginning combined treatment with vinorelbine and trastuzumab.
the left axillary tail tumor and the left axillary lymph node. However, after the second cycle of FEC, the left axillary tail tumor had increased to 1.7 cm. Chemotherapy was halted, and a left modified radical mastectomy was performed. Pathology confirmed a modified Black’s nuclear grade 3 infiltrating ductal carcinoma measuring 2.5 cm, with 1 positive axillary lymph node of 15 examined. She then received radiation therapy of 50 Gy plus a 10 Gy boost. Fourteen months after the original diagnosis, she presented at the 27th week of pregnancy with right upper quadrant pain and an Eastern Cooperative Oncology Group performance status (PS) of 2. Staging evaluations, including a chest radiograph, magnetic resonance imaging (MRI) of the brain/thoracic and lumbar spine/abdomen, and ultrasound of the abdomen, documented multiple hepatic metastases (Figure 1). Laboratory assessment indicated increased liver function tests and cancer antigen 27-29 level. After detailed deliberation and discussion, she began treatment with vinorelbine and trastuzumab. A loading dose of 4 mg/kg of trastuzumab and weekly doses of 2 mg/kg was prescribed. Vinorelbine was initiated at 25 mg/m2 weekly for 3 weeks followed by a week of rest. The patient was seen weekly by our department and a high-risk obstetrician for fetal monitoring. Oligohydramnios was noted, so intravenous fluids were given with each treatment. The oligohydramnios was thought to be secondary to fluid shifts or to direct side effects of the systemic therapy. After 5 weeks of treatment the patient’s hepatic pain resolved, laboratory values normalized, and PS improved to 1. Fetal development was reported to be normal; however, despite extra hydration, the amniotic fluid indexes were low. At 34 weeks and 5 days the patient noted decreased fetal movement. Although the fetus had only mild occasional car-
diac decelerations, the patient underwent induction of labor and delivered, per vaginum, a healthy male infant who weighed 5 pounds, 11 ounces and was 19.5 inches long with an Apgar score of 9/9/10. No immediate postpartum maternal or neonatal complications were noted. The patient remains on vinorelbine plus trastuzumab therapy. An MRI of the liver 3 months after initiation of therapy showed near complete resolution of disease (Figure 2). Her 6-month-old infant is reported to be healthy and developing normally.
Discussion Data on the treatment of MBC in pregnancy are limited. Patients with stage IV breast cancer have treatment goals of palliation and prolongation of life. However, if there is rapid progression with involvement of vital organs, it is likely that delay in treatment will result in death for the mother and fetus. Vinorelbine is a vinca alkaloid and is classified as pregnancy risk category D by the Food and Drug Administration (FDA). Several case reports document its use in the treatment of breast cancer in pregnant patients alone and in combination with 5-FU. All 8 patients were in their second trimester or later. The only fetal side effect noted was anemia. All babies were delivered at 32-40 weeks with normal development on follow-up ≤ 3 years.7-9 Vinorelbine treatment during pregnancy has also been reported for non–small-cell lung cancer10 and non-Hodgkin’s lymphoma.11 Trastuzumab is a recombinant monoclonal antibody against HER2/neu and is approved for the treatment of MBC. When given with chemotherapy, including vinorelbine, response rates and survival are increased.12-16 It is classified as FDA Pregnancy Risk Category B. Reproduction studies in cynomolgus monkeys have been conducted using 25 times
Clinical Breast Cancer October 2005 • 355
Treatment of Metastatic Breast Cancer During Pregnancy the standard human dose. Transfer of the antibody in the milk was noted, but no adverse effects on the offspring were reported even though HER2/neu receptors are present in cardiac and neural tissues.17,18 In our judgment, without treatment this patient would not have survived to deliver her baby. To our knowledge, this is the first case that provides evidence regarding the use of vinorelbine plus trastuzumab treatment for MBC in a pregnant patient. It adds to the current evidence supporting the use of vinorelbine in pregnant patients and provides some support for the use of trastuzumab in this dire clinical circumstance.
References 1. Wallack MK, Wolf JA Jr, Bedwinek J, et al. Gestational carcinoma of the female breast. Curr Probl Cancer 1983; 7:1-58. 2. Smith LH, Dalrymple JL, Leiserowitz GS, et al. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol 2001; 184:1504-1512. 3. Ebert U, Loffler H, Kirch W. Cytotoxic therapy and pregnancy. Pharmacol Ther 1997; 74:207-220. 4. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and pregnancy. Semin Oncol 1989; 16:337-346. 5. Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17:855-861. 6. Gwyn K, Theriault R, Sahin A., et al. Treatment of breast cancer during pregnancy ssing a standard protocol: update of the M.D. Anderson experience. Proc Am Soc Clin Oncol 2001; 18b (Abstract #1821). 7. De Santis M, Lucchese A, De Carolis S, et al. Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer Care (Engl) 2000; 9:235-237.
356 • Clinical Breast Cancer October 2005
8. Cuvier C, Espie M, Extra JM, et al. Vinorelbine in pregnancy. Eur J Cancer 1997; 33:168-169. 9. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy: a French national survey. Cancer 1999; 86:22662272. 10. Janne PA, Rodriguez-Thompson D, Metcalf DR, et al. Chemotherapy for a patient with advanced non-small-cell lung cancer during pregnancy: a case report and a review of chemotherapy treatment during pregnancy. Oncology 2001; 61:175-183. 11. Rodriguez JM, Haggag M. VACOP-B chemotherapy for high grade non-Hodgkin’s lymphoma in pregnancy. Clin Oncol (R Coll Radiol) 1995; 7:319-320. 12. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in the first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20:719-726. 13. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safey of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639-2648. 14. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-792. 15. Jahanzeb M, Mortimer JE, Yunus F, et al. Phase II trial for weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancer. Oncologist 2002; 7:410-417. 16. Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21:2889-2895. 17. Genetech Pharmaceuticals Website. Full Prescribing Information of Herceptin (Trastuzumab)--Precautions. 2003. Available at: http://www.gene.com/gene/products/information/oncology/herceptin/in sert.jsp. Accessed October 22, 2004. 18. Lee KF, Simon H, Chen H, et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995; 378:394-398.