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Journal of
Oncology Pharmacy Practice
Case Report
Is there any cumulative dose for trastuzumab?
J Oncol Pharm Practice 0(0) 1–3 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214538686 opp.sagepub.com
Hasan Mutlu and Hasan S¸enol Cos¸kun
Abstract Trastuzumab is one of the most important agents that target human epidermal growth factor receptor 2, but its cardiotoxic effect limits to use it. The mechanism of cardiac dysfunction-related trastuzumab is still unclear. In literature, there is no definite information about the cumulative dose of trastuzumab for cardiotoxicity. In presented case, we reported a breast cancer patient who has been receiving long-term trastuzumab. We have not found any cardiac problems for duration of over four years. According to our case and literature review, we may say that trastuzumab is safely used with periodically echocardiographic control in patients with breast cancer.
Keywords Breast cancer, trastuzumab, herceptin, cumulative dose, cardiotoxicity
Introduction Approximately human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of patients with breast cancer (BC). HER2-targeted therapeutic agents have become important in patients with early and metastatic BC. Trastuzumab is one of the most important agents that target HER2 like pertuzumab and lapatinib. Trastuzumab improves survival in patients with HER2-positive early and metastatic breast cancer. Unfortunately, its cardiotoxic effect limits to use it. Cardiotoxicity related to trastuzumab increases in breast cancer patients who previously received anthracycline.1 In previous studies, it was reported that the percent of symptomatic heart failure and asymptomatic decrease in left ventricular ejection fraction (LVEF) were 4 and 8–28 in patients with early or metastatic breast cancer, respectively.2–5 In daily practice, it is recommended to assess LVEF at baseline (before starting trastuzumab) and every three months thereafter for the duration of treatment in patients using trastuzumab. Generally, there is a cumulative dose of cardiotoxic agents such as doxorubicin, epirubicine and mitoxantrone (cumulative dose have been generally recommended as 550 mg/m2, 900 mg/m2 and 140 mg/m2 for doxorubicin, epirubicine and mitoxantrone, respectively).6–8 Trastuzumab is one of most commonly used
agents that has cardiotoxic effect. Unlike other agents, any cumulative dose for trastuzumab was not reported. Here, we report a metastatic BC patient who has been receiving long-term trastuzumab.
Case report A 25-year-old premenopausal woman was diagnosed with breast cancer in 1994. Her disease was stage IIB (T2N1M0). Her estrogen and progesterone receptor were positive. HER2 receptor status was immunhistochemically (+++). After the left-modified radical mastectomy, she received adjuvant six cycles of the combination of cyclophosphamide plus adriablastina plus 5-Fluorouracil (CAF) and tamoxiphen for five years. In 2009, she was admitted with complaints of pain, and then bone scintigraphy was performed, which revealed multiple bone metastases. This time, the combination of trastuzumab and docetaxel was offered as six cycles. Palliative radiotherapy was given
Department of Medical Oncology, Akdeniz University, Antalya, Turkey Corresponding author: ¨ niversitesi, Tıp Faku¨ltesi, Tıbbi Onkoloji Bo¨lu¨mu¨, Hasan Mutlu, Akdeniz U Konyaaltı, 07070 Antalya, Turkey. Email: [email protected]
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[1–3] [INVALID Stage]
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to metastatic painful bone lesions. The patient has received monthly zoledronic acid for two years. After six cycles of the combination of trastuzumab and docetaxel, single-agent trastuzumab (every 21 days) and letrozole (the patient has become postmenopausal this time) were offered. Response state was evaluated as radiologic or marker levels in every two months. Cardiac EF was evaluated echocardiographically in every three months. In last two echocardiographic evaluations performed in November 2013 and January 2014, EFs were 65% and 68%, respectively. She received totally 77 cycles of trastuzumab until now. She is still receiving trastuzumab and letrozole and has no any complaint and visceral metastasis except for bone metastasis.
Discussion Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor. Trastuzumab-related cardiotoxicity is typically manifested by an asymptomatic decrease in LVEF, but sometimes clinical heart failure may occur. The pathophysiology of trastuzumab-related cardiotoxicity is not still defined clearly. Endomyocardial biopsies performed in patients with trastuzumab-related severe cardiaotoxicity showed no evidence of typical anthracycline-related changes on cardiac biopsy material, and vacuolization or myocyte dropout was not observed.9 A likely mechanism of trastuzumab-related cardiotoxicity may be associated with HER2 (also named ErbB-2) signaling pathways. HER2 receptor pathway is a member of ErbB family10 and has an important role in epithelial cell growth and differentiation.11 In a study, it was reported that ErbB2 signaling in cardiomyocytes is essential for the prevention of dilated cardiomyopathy.12 After the discontinuation of trastuzumab in BC patients with cardiotoxicity, the recovery of cardiac dysfunction may be expected with an improving HER2 receptor function which is important for myocyte survival.12,13 However, the mechanism of trastuzumab-related cardiotoxicity remains uncertain. A study reported that the patients with high HER2/ p95 ratio with metastatic BC have longer benefit with trastuzumab-based therapies.14 Also, in same study, it was reported that the time on trastuzumab-based protocols was 38.8 and 25.3 months in two patients with BC.14 Another study reported the use of trastuzumab for 34 months15 Okada et al.16 reported a case who received trastuzumab for four years. Ota et al.17 reported no adverse events over 68 months of trastuzumab treatment. In presented case, the patient has been receiving trastuzumab over 52 months, and there is no
trastuzumab-related cardiac dysfunction. According to cases reported in literature, we may say that trastuzumab is safely used with periodically echocardiographic control in patients with BC. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Farolfi A, Melegari E, Aquilina M, et al. Heart. Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart 2013; 99: 634–639. 2. Dahabreh IJ, Linardou H, Siannis F, et al. Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 2008; 13: 620–623. 3. Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of HER-2-positive early breast cancer: a meta-analysis of published randomized trials (review). BMC Cancer 2007; 7: 153. 4. Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 2008; 26: 1231–1238. 5. Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol 2006; 24: 4107–4115. 6. Brestescher C, Pautier P and Farge D. Chemotherapy and cardiotoxicity. Ann Cardiol Angeiol (Paris) 1995; 44: 443–447. 7. Ryberg M, Nielsen D, Skovsgaard T, et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol 1998; 16: 3502–3508. 8. Avasarala JR, Cross AH, Clifford DB, et al. Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Mult Scler 2003; 9: 59–62. 9. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005; 23: 7820–7826. 10. Linggi B and Carpenter G. ErbB receptors: new insights on mechanisms and biology (review). Trends Cell Biol 2006; 16: 649–656. 11. Klapper LN, Glathe S, Vaisman N, et al. The ErbB-2/ HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A 1999; 96: 4995–5000. 12. Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002; 8: 459–465.
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13. Lee KF, Simon H, Chen H, et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995; 378: 394–398. 14. Montemurro F, Prat A, Rossi V, et al. Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer. Mol Oncol 2014; 8: 20–26. 15. Vaz-Luis I, Seah D, Olson EM, et al. Clinicopathological features among patients with advanced human epidermal growth factor-2-positivebreast cancer with prolonged clinical benefit to first-line trastuzumab-based therapy:
a retrospective cohort study. Clin Breast Cancer 2013; 13: 254–263. 16. Okada N, Narita Y, Nanno Y, et al. Long-term survival of a patient with giant liver metastatic breast cancer treated with trastuzumab. Gan To Kagaku Ryoho 2012; 39: 1399–1402. 17. Ota Y, Ishikawa T, Yamada A, et al. Long-term survival of a breast cancer patient with liver metastasis treated with trastuzumab and Paclitaxel. Gan To Kagaku Ryoho 2010; 37: 1091–1094.
Downloaded from opp.sagepub.com at FLORIDA STATE UNIV LIBRARY on October 27, 2015
(OPP)
[1–3] [INVALID Stage]
Journal of
Oncology Pharmacy Practice
Case Report
Is there any cumulative dose for trastuzumab?
J Oncol Pharm Practice 0(0) 1–3 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214538686 opp.sagepub.com
Hasan Mutlu and Hasan S¸enol Cos¸kun
Abstract Trastuzumab is one of the most important agents that target human epidermal growth factor receptor 2, but its cardiotoxic effect limits to use it. The mechanism of cardiac dysfunction-related trastuzumab is still unclear. In literature, there is no definite information about the cumulative dose of trastuzumab for cardiotoxicity. In presented case, we reported a breast cancer patient who has been receiving long-term trastuzumab. We have not found any cardiac problems for duration of over four years. According to our case and literature review, we may say that trastuzumab is safely used with periodically echocardiographic control in patients with breast cancer.
Keywords Breast cancer, trastuzumab, herceptin, cumulative dose, cardiotoxicity
Introduction Approximately human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of patients with breast cancer (BC). HER2-targeted therapeutic agents have become important in patients with early and metastatic BC. Trastuzumab is one of the most important agents that target HER2 like pertuzumab and lapatinib. Trastuzumab improves survival in patients with HER2-positive early and metastatic breast cancer. Unfortunately, its cardiotoxic effect limits to use it. Cardiotoxicity related to trastuzumab increases in breast cancer patients who previously received anthracycline.1 In previous studies, it was reported that the percent of symptomatic heart failure and asymptomatic decrease in left ventricular ejection fraction (LVEF) were 4 and 8–28 in patients with early or metastatic breast cancer, respectively.2–5 In daily practice, it is recommended to assess LVEF at baseline (before starting trastuzumab) and every three months thereafter for the duration of treatment in patients using trastuzumab. Generally, there is a cumulative dose of cardiotoxic agents such as doxorubicin, epirubicine and mitoxantrone (cumulative dose have been generally recommended as 550 mg/m2, 900 mg/m2 and 140 mg/m2 for doxorubicin, epirubicine and mitoxantrone, respectively).6–8 Trastuzumab is one of most commonly used
agents that has cardiotoxic effect. Unlike other agents, any cumulative dose for trastuzumab was not reported. Here, we report a metastatic BC patient who has been receiving long-term trastuzumab.
Case report A 25-year-old premenopausal woman was diagnosed with breast cancer in 1994. Her disease was stage IIB (T2N1M0). Her estrogen and progesterone receptor were positive. HER2 receptor status was immunhistochemically (+++). After the left-modified radical mastectomy, she received adjuvant six cycles of the combination of cyclophosphamide plus adriablastina plus 5-Fluorouracil (CAF) and tamoxiphen for five years. In 2009, she was admitted with complaints of pain, and then bone scintigraphy was performed, which revealed multiple bone metastases. This time, the combination of trastuzumab and docetaxel was offered as six cycles. Palliative radiotherapy was given
Department of Medical Oncology, Akdeniz University, Antalya, Turkey Corresponding author: ¨ niversitesi, Tıp Faku¨ltesi, Tıbbi Onkoloji Bo¨lu¨mu¨, Hasan Mutlu, Akdeniz U Konyaaltı, 07070 Antalya, Turkey. Email: [email protected]
Downloaded from opp.sagepub.com at FLORIDA STATE UNIV LIBRARY on October 27, 2015
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(OPP)
[1–3] [INVALID Stage]
2
Journal of Oncology Pharmacy Practice 0(0)
to metastatic painful bone lesions. The patient has received monthly zoledronic acid for two years. After six cycles of the combination of trastuzumab and docetaxel, single-agent trastuzumab (every 21 days) and letrozole (the patient has become postmenopausal this time) were offered. Response state was evaluated as radiologic or marker levels in every two months. Cardiac EF was evaluated echocardiographically in every three months. In last two echocardiographic evaluations performed in November 2013 and January 2014, EFs were 65% and 68%, respectively. She received totally 77 cycles of trastuzumab until now. She is still receiving trastuzumab and letrozole and has no any complaint and visceral metastasis except for bone metastasis.
Discussion Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor. Trastuzumab-related cardiotoxicity is typically manifested by an asymptomatic decrease in LVEF, but sometimes clinical heart failure may occur. The pathophysiology of trastuzumab-related cardiotoxicity is not still defined clearly. Endomyocardial biopsies performed in patients with trastuzumab-related severe cardiaotoxicity showed no evidence of typical anthracycline-related changes on cardiac biopsy material, and vacuolization or myocyte dropout was not observed.9 A likely mechanism of trastuzumab-related cardiotoxicity may be associated with HER2 (also named ErbB-2) signaling pathways. HER2 receptor pathway is a member of ErbB family10 and has an important role in epithelial cell growth and differentiation.11 In a study, it was reported that ErbB2 signaling in cardiomyocytes is essential for the prevention of dilated cardiomyopathy.12 After the discontinuation of trastuzumab in BC patients with cardiotoxicity, the recovery of cardiac dysfunction may be expected with an improving HER2 receptor function which is important for myocyte survival.12,13 However, the mechanism of trastuzumab-related cardiotoxicity remains uncertain. A study reported that the patients with high HER2/ p95 ratio with metastatic BC have longer benefit with trastuzumab-based therapies.14 Also, in same study, it was reported that the time on trastuzumab-based protocols was 38.8 and 25.3 months in two patients with BC.14 Another study reported the use of trastuzumab for 34 months15 Okada et al.16 reported a case who received trastuzumab for four years. Ota et al.17 reported no adverse events over 68 months of trastuzumab treatment. In presented case, the patient has been receiving trastuzumab over 52 months, and there is no
trastuzumab-related cardiac dysfunction. According to cases reported in literature, we may say that trastuzumab is safely used with periodically echocardiographic control in patients with BC. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Farolfi A, Melegari E, Aquilina M, et al. Heart. Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart 2013; 99: 634–639. 2. Dahabreh IJ, Linardou H, Siannis F, et al. Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 2008; 13: 620–623. 3. Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of HER-2-positive early breast cancer: a meta-analysis of published randomized trials (review). BMC Cancer 2007; 7: 153. 4. Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 2008; 26: 1231–1238. 5. Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol 2006; 24: 4107–4115. 6. Brestescher C, Pautier P and Farge D. Chemotherapy and cardiotoxicity. Ann Cardiol Angeiol (Paris) 1995; 44: 443–447. 7. Ryberg M, Nielsen D, Skovsgaard T, et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol 1998; 16: 3502–3508. 8. Avasarala JR, Cross AH, Clifford DB, et al. Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Mult Scler 2003; 9: 59–62. 9. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005; 23: 7820–7826. 10. Linggi B and Carpenter G. ErbB receptors: new insights on mechanisms and biology (review). Trends Cell Biol 2006; 16: 649–656. 11. Klapper LN, Glathe S, Vaisman N, et al. The ErbB-2/ HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A 1999; 96: 4995–5000. 12. Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002; 8: 459–465.
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13. Lee KF, Simon H, Chen H, et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995; 378: 394–398. 14. Montemurro F, Prat A, Rossi V, et al. Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer. Mol Oncol 2014; 8: 20–26. 15. Vaz-Luis I, Seah D, Olson EM, et al. Clinicopathological features among patients with advanced human epidermal growth factor-2-positivebreast cancer with prolonged clinical benefit to first-line trastuzumab-based therapy:
a retrospective cohort study. Clin Breast Cancer 2013; 13: 254–263. 16. Okada N, Narita Y, Nanno Y, et al. Long-term survival of a patient with giant liver metastatic breast cancer treated with trastuzumab. Gan To Kagaku Ryoho 2012; 39: 1399–1402. 17. Ota Y, Ishikawa T, Yamada A, et al. Long-term survival of a breast cancer patient with liver metastasis treated with trastuzumab and Paclitaxel. Gan To Kagaku Ryoho 2010; 37: 1091–1094.
Downloaded from opp.sagepub.com at FLORIDA STATE UNIV LIBRARY on October 27, 2015
