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FACULTE DE MEDECINE
Evandro DE AZAMBUJA
Thèse présentée en vue de l’obtention du grade académique de Docteur
en Sciences Médicales
Promoteur de thèse: Professeur Martine Piccart-Gebhart
November 2015
EVALUATION OF CARDIAC TOXICITIES IN BREAST CANCER PATIENTS
TREATED WITH ADJUVANT CHEMOTHERAPY AND/OR ANTI-HER2
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TABLE OF CONTENTS
1. LIST OF TABLES ... 11 2. LIST OF FIGURES... 12 3. LIST OF ABBREVIATIONS ... 134. INTRODUCTION AND RATIONALE ... 16
5. 1.1 Cardiotoxicity related to cytotoxic chemotherapy ... 17
6. 1.1.1. Anthracyclines ... 17
7. 1.1.2. Mechanisms of anthracycline-induced cardiotoxicity ... 20
8. 1.1.3. Other chemotherapeutic agents (non-anthracyclines) ... 21
9. 1.2. Anti-HER2 agents ... 22
10. 1.2.1. Trastuzumab ... 22
11. 1.2.2. Other anti-HER2 agents ... 26
12. 1.2.2.1. Lapatinib ... 26
13. 1.2.2.2. Pertuzumab ... 26
14. 1.2.2.3. Trastuzumab-DM1 (TDM1) ... 27
15. 1.2.2.4. Afatinib and Neratinib ... 27
16. 1.2.3. Dual HER-2 blockade ... 28
17. 1.2.4. Mechanisms of trastuzumab-induced cardiotoxicity ... 33
18. 1.3. The use of cardiac biomarkers ... 34
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20. 1.3.2. Functional imaging ... 37
21. 2. Justification of the thesis... 40
22. CHAPTER 1: long-term cardiotoxicity caused by adjuvant anthracycline-based chemotherapy ... 42
23. Objectives ... 42
24. Discussion chapter 1 ... 52
25. Anthracycline-induced cardiotoxicity: the magnitude of the problem ... 52
26. Cardiac imaging for assessing cardiac damage induced by anticancer drugs ... 56
27. Cardiac biomarkers and 6MWT as screening tools for the detection of long-term cardiac damage from anticancer drugs ... 61
28. Challenges of long-term follow-up ... 64
29. CHAPTER 2: Trastuzumab-induced cardiotoxicity ... 66
30. Chapter 2.1. The incidence and reversibility of trastuzumab-induced cardiotoxicity using clinical data of patients enrolled in the Herceptin Adjuvant (HERA) trial ... 66
31. Objectives ... 67
32. Discussion chapter 2.1 ... 77
33. Trastuzumab-induced cardiotoxicity ... 77
34. The utility of cardiac biomarkers in screening for trastuzumab-induced cardiotoxicity ... 82
35. Chapter 2.2. The incidence of cardiotoxicity when trastuzumab is used concomitantly to neoadjuvant anthracycline-based chemotherapy ... 84
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37. Discussion chapter 2.2. ... 88
38. Cardiotoxicity following trastuzumab combined with anthracycline-based chemotherapy ... 88
39. STRATEGIES TO REDUCE THE RISK OF CARDIOTOXICITY AND SURVEILLANCE ... 90
40. ADDITIONAL THOUGHTS ... 93
41. CONCLUDING REMARKS AND PERSPECTIVES ... 95
42. REFERENCES ... 97
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LIST OF TABLES
Table 1. Risk factors for anthracycline-induced cardiotoxicity ... 18
Table 2. List of chemotherapeutic agents commonly used in breast cancer and
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LIST OF FIGURES
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LIST OF ABBREVIATIONS
AC: doxorubicin, cyclophosphamide
ACE: angiotensin converting enzyme
ASCO: American Society of Clinical Oncology
AV block: atrial ventricular block
BC: breast cancer
BCIRG: Breast Cancer International Research Group
BIG: Breast International Group
BNP: B-type natriuretic peptide
CHF: congestive heart failure
CI: confidence interval
CMF: cyclophosphamide, methotrexate, 5-fluorouracil
CT: chemotherapy
CV: cardiovascular
EC: epirubicin, cyclophosphamide
ECG: electrocardiogram
EF: ejection fraction
DFS: disease free survival
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EGFR: epidermal growth factor receptor
ESC: European School of Cardiology
ESMO: European Society for Medical Oncology
ESV: end systolic volume
FEC: 5-flurouracil, epirubicin, cyclophosphamide
FEC50: 5-flurouracil, epirubicin 50 mg/m², cyclophosphamide
FEC100: 5-flurouracil, epirubicin 100 mg/m², cyclophosphamide
H: trastuzumab (herceptin®)
HDE: high dose epirubicin
HERA: Herceptin Adjuvant trial
HER-2: human epidermal growth factor receptor 2
HF: heart failure
HR: hazard ratio
LGE: late gadolinium enhancement
LLN: lower limit of normal
LV: left ventricle
LVD: left ventricular dysfunction
LVEF: left ventricular ejection fraction
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