Adjuvant combined therapy with trastuzumab in patients with HER2‑positive breast cancer and cardiac alterations: implications for optimal cardio‑oncology care

Abstract

Introduction: Recently, the prognosis of patients with HER2-positive breast cancer (BC) has improved significantly owing to the use of combined treatment modalities. However, systemic treatment is associated with increased risk of cardiotoxicity.

Objectives: We aimed to assess subclinical cardiac alterations during the final stage of adjuvant combined therapy, that is, trastuzumab therapy (TT), as potential predictors of late cardiac complications in patients with HER2-positive BC.

Patients and methods: We enrolled 251 patients with HER2-positive BC treated with a radical local therapy, adjuvant chemotherapy (anthracyclines or anthracyclines + taxanes), and immunotherapy (trastuzumab). Patients underwent 6 echocardiographic examinations: at baseline, during TT, and after TT, with assessment of left ventricular ejection fraction (LVEF), degree of valvular regurgitation, and cardiac chamber diameters.

Results: Valvular fibrosis (28.4% of patients) was associated with older age, hypertension at baseline, and a higher degree of regurgitation during TT. Reduced LVEF, greater regurgitation, and larger cardiac chamber diameters were noted during TT. The patients who received higher anthracycline doses showed a greater degree of aortic insufficiency and a larger right ventricular diameter. Reduced LVEF during TT was associated with radiotherapy or chemotherapy and the degree of valvular regurgitation. Significantly larger diameters were observed in older patients and in those with comorbidities at baseline, high body mass index, and regurgitation.

Conclusions: Asymptomatic subclinical cardiac alterations during TT may predict late cardiac complications; however, longer follow-up is necessary to confirm this hypothesis. Patients with HER2-positive BC should be closely monitored for possible cardiac alterations during and after therapy to ensure optimal care and guide therapeutic decision-making.

What’s new?

In this study, we used echocardiography to identify a number of subclinical cardiac alterations that might serve as predictors of cardiotoxicity and premature cardiac death in women with HER2-positive breast cancer during and a few months after a radical combined treatment (chemotherapy, radiotherapy, immunotherapy, and hormone replacement therapy). Interestingly, we observed that some patients who did not receive radiotherapy developed mitral and / or aortic valve fibrosis with secondary valvular insufficiency. However, patients treated with radiotherapy developed valvular fibrosis earlier than expected. In some patients, we also noted functional mitral regurgitation due to slight enlargement and geometrical changes of the left ventricle and atrium. Finally, we observed development or progression of tricuspid regurgitation. Close monitoring for cardiac alterations during and after radical combined treatment with trastuzumab is strongly recommended to guide therapeutic decisions and ensure optimal care in patients with HER2-positive breast cancer.

Introduction

Over the past 10 years, there have been significant advances in the radical treatment of HER2-positive breast cancer (BC).¹ The use of targeted anti-HER2 therapy in combination with chemotherapy (anthracyclines, taxanes) has vastly improved the prognosis of patients. At the same time, progress in local treatment modalities (surgery, radiotherapy) allowed clinicians to minimize damage to healthy tissues without compromising the efficacy of the radical treatment.^2-4 However, systemic treatment is a known risk factor for early and late cardiac complications, which, in turn, increase the risk of premature cardiac death.⁵

The aim of the study was to use standard echocardiographic examinations to assess subclinical changes in the heart as potential predictors of symptomatic cardiotoxicity and premature cardiac death.

Patients and methods

This was a retrospective cohort study including 251 women with BC treated at the Institute of Oncology in Kraków, Poland, with adjuvant trastuzumab between 2008 and 2019. The inclusion criteria were the diagnosis of HER2-positive BC and absence of contraindications to chemotherapy and radiotherapy. Patients with a left ventricular ejection fraction (LVEF) of less than 50% and significant cardiac contraindications to immunotherapy (eg, acute coronary syndrome, ventricular tachycardia) were excluded.

All patients showed HER2 receptor overexpression, underwent radical surgery (mastectomy or breast-conserving surgery), adjuvant chemotherapy and immunotherapy (trastuzumab) as well as radiotherapy (202 patients, depending on individual indications), and received hormone therapy (in the case of positive hormone receptors). HER2 expression was assessed by immunohistochemistry (HercepTest; F. Hoffmann-La Roche, Basel, Switzerald). If the test results were equivocal, amplification of the ERBB2 gene by fluorescent in situ hybridization was additionally assessed.⁶ According to the protocol, trastuzumab was administered for 12 months. Treatment was discontinued within 1 year since the development of significant cardiac complications. Cardiotoxicity was defined as a reduction in LVEF below 50% or more than 10 percentile points from baseline. In these cases, treatment was always discontinued. For the purpose of this study, the term “significant cardiac complications” was defined as cardiac complications that were considered a significant contraindication to the continuation of trastuzumab therapy (TT), at the physician’s discretion. The women with cardiac complications received treatment with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II-receptor antagonists, β-adrenergic blocking agents, aldosterone inhibitors, and diuretics, as appropriate. Doses were gradually uptitrated according to blood pressure, and electrolyte and creatinine levels. During the therapy, effective contraception (accepted in BC) was recommended in all women.

Our center provides complex cardio-oncology care. Our team includes a highly qualified cardiologist (E.K.) with access to appropriate noninvasive diagnostic equipment as well as experience in managing cardiac complications and consulting complex cases. Other cardiology consultants are also available at our center. In the future, we are going to cooperate with the Department of Cardiology that employs the main consultant for cancer patients requiring hospitalization.

Radiotherapy was applied after completing chemotherapy. For radiotherapy after breast-conserving surgery, tangential fields were used for whole-breast irradiation, while in patients with nodal involvement, the monoisocentric technique was used for breast and regional nodal irradiation. Additionally, all patients received an amended boost to the tumor bed. For radiotherapy administered after mastectomy, the monocentric technique with mixed photon-electron beam was used to irradiate the target volume, including the chest wall with the postoperative scar as well as internal mammary, axillary, supraclavicular, and infraclavicular lymph nodes. The radiotherapy was performed with a linear accelerator with the application of megavoltage photon and electron beams. In all patients, the radiotherapy was planned on the basis of computed tomography scans and a 3-dimensional radiotherapy technique with delineation of the target and organ-at-risk volumes. In the patients with a pacemaker, the device and the electrode were delineated on radiographs, and the dose for these areas was estimated in a radiotherapy plan. Before the radiotherapy, the patients underwent a cardiac consultation and their cardiac function was monitored during the radiotherapy implementation.

Clinical examination

Before the initiation of TT, all patients were assessed for the presence of cardiovascular risk factors (increased body mass index [BMI], hypertension [HA], ischemic heart disease [IHD], diabetes mellitus [DM]) according to our standard protocol. At baseline, all participants underwent subjective and objective clinical examination. HA was defined as a blood pressure of 140/90 mm Hg or higher (on at least 2 separate measurements) or the use of antihypertensive drugs for elevated blood pressure. DM was defined according to the current guidelines.⁷ In all patients, echocardiography was performed.

Echocardiography

Complete echocardiographic examination was performed using a GE VIVID S-6 ECHO unit (GE Medical System, Boston, Massachusetts, United States), equipped with a multifrequency harmonic transducer (2.5–4 MHz). Most patients were examined by the same experienced operator (E.K.). Echocardiography was performed at baseline (before TT), every 3 months during immunotherapy (TT), and a few (3–6) months after TT. The mean values of 3 consecutive measurements were recorded. Left ventricular (LV) systolic function was assessed on the basis of LVEF measurement using the Simpson method. Cardiac chamber quantification was performed according to the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging.⁸ Left atrial (LA) diameter was expressed as body surface area–indexed LA volume. Right atrial (RA) diameter was defined as RA volume calculated using a single-plane area-length or disk summation method in an apical 4-chamber view. LV sizes were expressed as diastolic and systolic dimensions as well as LV volumes normalized by the body surface area. Right ventricular (RV) diameters were obtained in a standard position, and RV systolic function was assessed by tricuspid annular plane systolic excursion as well as tissue Doppler imaging–derived tricuspid lateral annular systolic velocity. Valvular regurgitation was evaluated according to the recommendations of the European Association of Cardiovascular Imaging, in which native valvular regurgitation is classified as mild, mild / moderate, moderate, moderate to severe, or severe.⁹ In our study, all degrees were considered in the analysis in order to assess a patient’s tendency to have either a higher or a lower degree of valvular regurgitation. At baseline, some patients presented with the first or second degree functional mitral insufficiency, tricuspid insufficiency, and aortic insufficiency. Changes in the degree of valvular insufficiency during treatment vs baseline were also assessed. Valvular fibrosis was assessed visually by an experienced cardiologist. The results of all echocardiographic examinations were recorded, and the results of each subsequent examination were compared with baseline. Fibrosis was identified by assessing differences in the echogenicity of the valve leaflets and changes in their mobility. Doubtful cases were examined and discussed by 2 experienced investigators until a consensus was reached.

The primary study end point was defined as subclinical changes in the heart (assessed by echocardiography) during the combined radical treatment of HER2-positive BC. The secondary end point was defined as the occurrence of significant valvular insufficiency and cardiac enlargement during treatment.

Statistical analysis

The following tests were applied for statistical analysis: 1) the Pearson χ² or Fisher test to assess the independence of categorical variables presented using a contingency Table; and 2) the repeated measures analysis of variance (repeated measures ANOVA) for differences in the mean degree of LVEF or cardiac chamber diameter measured at 6 time points (at baseline, every 3 months during TT, and after the therapy) according to variables including the presence of valvular insufficiency, cardiac complications (myocardial dysfunction, cardiac arrhythmias, LVEF reduction <⁠50% or >10 percentile points), DM, HA, IHD, chemotherapy regimen, as well as the use of radiotherapy and hormone replacement therapy; 3) the Friedman test for valvular regurgitation measured at 6 time points and the Mann–Whitney test to assess differences between groups at the same time point (according to variables including age, the presence of valvular insufficiency, HA, chemotherapy regimen). A P value lower than 0.05 was considered significant. The STATISTICA v.10.0 software (StatSoft, Inc., Tulsa, Oklahoma, United States) was used for all calculations.

Ethical issues

The study was approved by the Independent Ethics Committee at the Regional Medical Chamber in Kraków (decision as of December 4, 2013, no. 2013/09/B/NZ5/00764; to J.N.). This was a retrospective study with no direct patient contact, no modification of diagnostic or treatment procedures, and no disclosure of personal patient data. Therefore, the patient consent was not required for this study.

Results

The patients with valvular fibrosis diagnosed at baseline (before TT) or during TT were significantly older than those without fibrosis (P <⁠0.001) (Table 1). Moreover, the absence of valvular fibrosis was the most common in the patients without HA (P = 0.01) (Table 1). Additionally, during TT, we noted a higher degree of mitral regurgitation in women with valvular fibrosis (Table 2). Detailed associations between the clinical parameters and the valvular fibrosis are presented in Table 1.

**Table 1**. Associations between clinical parameters and valvular fibrosis
Parameter^a		Valvular fibrosis
Parameter^a		Absent (n = 180)	Present (n = 71)	P value^e
Age, y, mean (SD)		52.5 (10.1)	59.8 (7.8)	<⁠0.001
Baseline BMI, kg/m², mean (SD)		27.3 (5.0)	27.8 (5.5)	0.51
Cardiac complications^b	Not present	155 (72.1)	60 (27.9)	0.54
Cardiac complications^b	Present	25 (71.4)	10 (28.6)	0.54
Diabetes mellitus	Not present	173 (72.7)	65 (27.3)	0.28
Diabetes mellitus	Present	8 (61.5)	5 (38.5)	0.28
Hypertension^c	Not present	133 (76.9)	40 (23.1)	0.01
Hypertension^c	Present	47 (61.0)	30 (39.0)	0.01
Ischemic heart disease^d	Not present	167 (72.9)	62 (27.1)	0.24
Ischemic heart disease^d	Present	14 (63.6)	8 (36.4)	0.24
Radiotherapy	No	34 (69.4)	15 (30.6)	0.38
Radiotherapy	Yes	147 (72.8)	55 (27.2)	0.38
Chemotherapy	Anthracyclines ≤300 mg/m²	65 (69.1)	29 (30.9)	0.39
	Anthracyclines >300 mg/m²	33 (67.3)	16 (32.7)
	Anthracyclines and taxanes	78 (76.5)	24 (23.5)
Hormone replacement therapy	No	76 (66.1)	39 (33.9)	0.04
Hormone replacement therapy	Yes	105 (77.2)	31 (22.8)	0.04
Data are presented as number (percentage) of patients unless otherwise indicated. a A mismatch in the number of cases results from the lack of data for some parameters. b The following cardiac complications were noted: LVEF reduction by more than 10 percentile points vs baseline or LVEF reduction below 50%; heart failure (NYHA functional class III/IV); grade III/IV (mild / severe) valvular insufficiency; arrhythmia (atrial fibrillation, ventricular arrhythmias); LVEF reduction by more than 10 percentile points vs baseline plus heart failure (NYHA functional class III/IV); and LVEF reduction by more than 10 percentile points vs baseline plus arrhythmia. c All patients with hypertension received ACEIs, β-blockers, and thiazides. d All patients with ischemic heart disease received ACEIs, β-blockers, antiplatelet drugs. e P value from analysis of variance or from the Fisher (2x2 contingency Table) or Person χ² test Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; BMI, body mass index; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association

**Table 2**. Differences in the degree of mitral, tricuspid, and aortic regurgitation at 6 time points during the study in the whole study group, patients with regurgitation during or after trastuzumab therapy, and in those with regurgitation both at baseline and during or after trastuzumab therapy
Parameter		Patients, n	Degree of regurgitation, median (IQR)^a						P value^b	P value^c
			Baseline before TT	During treatment				After TT
			Baseline before TT	3 months	6 months	9 months	12 months	After TT
Whole group		243	0.0 (0.0–0.1)	0.0 (0.0–1.0)	0.0 (0.0–0.1)	1.0 (0.0–0.1)	1.0 (0.0–0.1)	1.0 (0.0–0.1)	–	<⁠0.001
Regurgitation	Present only during and / or after TT	107	0.0^d (0.0–0.0)	0.0^d (0.0–1.0)	1.0^d (0.0–1.0)	1.0^d (0.0–1.5)	1.0^e (0.0–1.0)	1.0^d (0.0–1.0)	^d<⁠0.001; ^e 0.001	<⁠0.001
Regurgitation	Present before and during and / or after TT	63	1.0 (1.0–1.5)	1.0 (1.0–1.75)	1.0 (1.0–2.0)	1.0 (1.0–2.0)	1.0 (1.0–2.0)	1.0 (1.0–2.0)	^d<⁠0.001; ^e 0.001	0.91
Hypertension	No	167	0.0 (0.0–0.0)	0.0 (0.0–1.0)	0.0^f (0.0–1.0)	0.0 (0.0–1.0)	1.0 (0.0–1.0)	0.0^g (0.0–1.0)	^f0.004; ^g 0.03	<⁠0.001
Hypertension	Yes	76	0.0 (0.0–1.0)	0.0 (0.0–1.0)	1.0 (0.0–1.5)	1.0 (0.0–1.0)	1.0 (0.0–1.0)	1.0 (0.0–1.0)	^f0.004; ^g 0.03	<⁠0.001
Age	≤54 years	114	0.0 (0.0–0.0)	0.0 (0.0–1.0)	0.0^d (0.0–1.0)	0.0^d (0.0–1.0)	0.0^d (0.0–1.0)	0.0^a (0.0–1.0)	^d <⁠0.001	<⁠0.001
Age	>54 years	129	0.0 (0.0–0.0)	0.0 (0.0–1.0)	1.0 (0.0–1.5)	1.0 (0.0–1.5)	1.0 (0.0–1.5)	1.0 (0.0–1.5)	^d <⁠0.001	<⁠0.001
Valvular fibrosis	Absent	170	0.0 (0.0–0.0)	0.0 (0.0–1.0)	0.0^e (0.0–1.0)	1.0^h (0.0–1.0)	1.0 (0.0–1.0)	1.0 (0.0–1.0)	^e 0.001; ^h 0.05	<⁠0.001
Valvular fibrosis	Present	69	0.0 (0.0–1.0)	0.0 (0.0–1.0)	1.0 (0.0–2.0)	1.0 (0.0–2.0)	1.0 (0.0–1.5)	1.0 (0.0–1.0)	^e 0.001; ^h 0.05	<⁠0.001
Tricuspid regurgitation (no regurgitation in 159 cases), median (IQR)
Whole group		244	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–1.0)	–	<⁠0.001
Regurgitation	Present only during and / or after TT	70	0.0^ad (0.0–0.0)	0.0^d (0.0–0.0)	0.0ⁱ (0.0–1.0)	1.0^j (0.0–1.0)	1.0 (0.0–1.0)	1.0 (0.0–1.0)	^d<⁠0.001; ⁱ0.02; ^j0.04	<⁠0.001
Regurgitation	Present before and during and / or after TT	15	1.0 (1.0–2.0)	1.0 (1.0–2.0)	1.0 (0.5–2.0)	1.0 (1.0–2.0)	1.0 (1.0–2.0)	1.0 (0.5–2.0)	^d<⁠0.001; ⁱ0.02; ^j0.04	0.94
Aortic regurgitation (no regurgitation in 211 cases), median (IQR)
Whole group		246	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	–	<⁠0.001
Regurgitation	Present only during and / or after TT	24	0.0^d (0.0–0.0)	0.0^k (0.0–1.0)	1.0^l (0.0–1.0)	1.0^l (0.0–1.0)	1.0 (1.0–1.0)	1.0^l (0.0–1.0)	^d<⁠0.001; ^k0.002; ^l0.01	<⁠0.001
Regurgitation	Present before and during and / or after TT	11	1.0 (1.0–1.5)	1.0 (1.0–1.5)	1.0 (1.0–1.5)	1.0 (1.0–1.5)	1.0 (1.0–1.5)	1.75 (1.0–2.0)	^d<⁠0.001; ^k0.002; ^l0.01	0.22
Anthracycline	≤300 mg/m²	187	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	–	0.004
Anthracycline	>300 mg/m²	55	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	–	<⁠0.001
Valvular fibrosis	Absent	172	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	–	0.001
Valvular fibrosis	Present	69	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	–	0.004
a 0 for absence of regurgitation, 1 for mild (degree I), 1.5 for mild / moderate (degree I/II), 2 for moderate (degree II); 2.5 for moderate / severe (degree II/III); 3 for severe (degree III) b Difference between the 2 groups (the Mann–Whitney test for differences between groups at the same time point) c Difference between subsequent measurements (the Friedman test) P value: d <⁠0.001; e 0.001; f 0.004; g 0.003; h 0.05; i 0.02; j 0.04; k 0.002; l 0.01 Abbreviations: IQR, interquartile range; TT, trastuzumab therapy

The degree of mitral, tricuspid, and aortic regurgitation at baseline, during, and after TT depending on the type and presence of regurgitation is presented in Table 2. During TT, the degree of mitral, tricuspid, and aortal regurgitation increased (P <⁠0.001, Table 2). Higher degrees of mitral, tricuspid, and aortic regurgitation were found in the patients with valvular insufficiency diagnosed at baseline, during, and after TT as compared with those with valvular regurgitation observed only during or after TT (Table 2).

Changes in the mean LA, LV, and RV diameters during TT according to clinical parameters are presented in Table 3. During TT, an increase in LA, LV, and RV diameters was observed (all P <⁠0.001, Table 3). At each time point, LA and LV diameters were smaller in the patients without mitral insufficiency than in those with insufficiency both at baseline and during or after TT (Figure 1A and 1B).

**Table 3**. Associations between clinical parameters and left atrial, left ventricular, and right atrial diameters measured at 6 time points during the study
Parameter		Cardiac chamber diameter, cm, mean (SD)							P value^a	P value^b	P value^c
		Patients, n	Baseline before TT	During TT				After TT
		Patients, n	Baseline before TT	3 months	6 months	9 months	12 months	After TT
Left atrial diameter, cm, mean (SD)
Whole group		243	3.2 (0.5)	3.3 (0.5)	3.3 (0.5)	3.4 (0.5)	3.4 (0.5)	3.4 (0.5)	–	<⁠0.001	–
IHD	No	221	3.2 (0.5)	3.2 (0.5)	3.3 (0.5)	3.3 (0.5)	3.4 (0.5)	3.4 (0.5)	0.003	<⁠0.001	0.27
IHD	Yes	21	3.5 (0.3)	3.6 (0.4)	3.6 (0.4)	3.6 (0.3)	3.6 (0.3)	3.7 (0.3)	0.003	<⁠0.001	0.27
Hypertension	No	167	3.1 (0.5)	3.2 (0.4)	3.2 (0.5)	3.2 (0.4)	3.3 (0.4)	3.3 (0.4)	<⁠0.001	<⁠0.001	<⁠0.001
Hypertension	Yes	74	3.4 (0.5)	3.5 (0.5)	3.5 (0.5)	3.6 (0.5)	3.7 (0.5)	3.7 (0.5)	<⁠0.001	<⁠0.001	<⁠0.001
Diabetes mellitus	No	230	3.2 (0.5)	3.3 (0.5)	3.3 (0.5)	3.3 (0.5)	3.4 (0.5)	3.4 (0.5)	0.04	<⁠0.001	0.27
Diabetes mellitus	Yes	12	3.5 (0.6)	3.4 (0.5)	3.6 (0.4)	3.7 (0.4)	3.7 (0.4)	3.6 (0.5)	0.04	<⁠0.001	0.27
Age	≤54 years	115	3.1 (0.4)	3.2 (0.5)	3.2 (0.5)	3.2 (0.4)	3.3 (0.4)	3.3 (0.4)	<⁠0.001	<⁠0.001	0.69
Age	>54 years	126	3.3 (0.5)	3.4 (0.5)	3.4 (0.5)	3.5 (0.5)	3.5 (0.5)	3.6 (0.5)	<⁠0.001	<⁠0.001	0.69
BMI	≤25 kg/m²	87	3.0 (0.5)	3.1 (0.5)	3.1 (0.5)	3.1 (0.4)	3.2 (0.4)	3.2 (0.4)	<⁠0.001	<⁠0.001	0.37
BMI	>25 kg/m²	155	3.3 (0.5)	3.4 (0.5)	3.4 (0.5)	3.5 (0.5)	3.5 (0.5)	3.6 (0.4)	<⁠0.001	<⁠0.001	0.37
Left ventricular diameter, cm, mean (SD)
Whole group		245	4.8 (0.4)	4.9 (0.5)	4.9 (0.4)	5.0 (0.5)	5.0 (0.5)	5.0 (0.5)	–	<⁠0.001	–
Hypertension	No	176	4.8 (0.4)	4.9 (0.5)	4.9 (0.4)	4.9 (0.4)	4.9 (0.4)	4.9 (0.4)	0.008	<⁠0.001	0.37
Hypertension	Yes	78	4.9 (0.4)	5.0 (0.4)	5.0 (0.4)	5.1 (0.5)	5.1 (0.5)	5.1 (0.5)	0.008	<⁠0.001	0.37
BMI	≤25 kg/m²	92	4.7 (0.4)	4.8 (0.5)	4.8 (0.4)	4.8 (0.4)	4.8 (0.4)	4.8 (0.4)	<⁠0.001	<⁠0.001	0.90
BMI	>25 kg/m²	163	4.9 (0.4)	5.0 (0.4)	5.0 (0.4)	5.0 (0.5)	5.0 (0.5)	5.1 (0.5)	<⁠0.001	<⁠0.001	0.90
Cancer progression	No	210	4.8 (0.4)	4.9 (0.5)	5.0 (0.4)	5.0 (0.4)	5.0 (0.4)	5.0 (0.5)	0.03	<⁠0.001	0.87
Cancer progression	Yes	35	4.7 (0.5)	4.8 (0.5)	4.8 (0.4)	4.8 (0.5)	4.9 (0.5)	4.9 (0.4)	0.03	<⁠0.001	0.87
Right ventricular diameter, cm, mean (SD)
Whole group		240	2.6 (0.5)	2.6 (0.6)	2.7 (0.5)	2.7 (0.5)	2.7 (0.6)	2.7 (0.5)	–	<⁠0.001	–
IHD	No	228	2.5 (0.6)	2.6 (0.6)	2.6 (0.5)	2.7 (0.5)	2.7 (0.6)	2.7 (0.5)	0.02	<⁠0.001	0.83
IHD	Yes	22	2.8 (0.5)	2.8 (0.5)	2.9 (0.5)	2.9 (0.5)	3.0 (0.6)	2.9 (0.5)	0.02	<⁠0.001	0.83
Anthracycline	≤300 mg/m²	180	2.5 (0.6)	2.5 (0.6)	2.6 (0.5)	2.6 (0.5)	2.6 (0.6)	2.7 (0.5)	<⁠0.001	<⁠0.001	0.82
Anthracycline	>300 mg/m²	55	2.8 (0.5)	2.8 (0.5)	2.9 (0.5)	3.0 (0.5)	3.0 (0.5)	3.0 (0.5)	<⁠0.001	<⁠0.001	0.82
BMI	≤25 kg/m²	92	2.5 (0.6)	2.5 (0.5)	2.6 (0.5)	2.6 (0.5)	2.6 (0.5)	2.6 (0.6)	0.02	<⁠0.001	0.88
BMI	>25 kg/m²	158	2.6 (0.6)	2.6 (0.6)	2.7 (0.5)	2.7 (0.5)	2.8 (0.6)	2.8 (0.5)	0.02	<⁠0.001	0.88
An increase in heart chamber diameters during TT was calculated as a sum of correlation coefficients (R of a series of 6 measurements done for each patient before, during [4 measurements], and after TT) and 3 heart chambers (R of the left ventricle + R of the left atrium + R of the right atrium – calculated for each patient). The cutoff point for this variable was set at 1.9 (the upper quartile). P values were calculated using repeated measure analysis of variance. a Difference between the 2 groups b Difference between subsequent measurements c Difference in the slope of the plots representing the 2 groups Abbreviations: IHD, ischemic heart disease; others, see Tables 1 and 2

**Figure 1**. Repeated measures analysis of variance: changes in left atrial (A) and left ventricular diameter (B) during TT depending on the presence of mitral regurgitation; changes in left ventricular ejection fraction during TT depending on the presence of mitral (C), tricuspid (D), and aortic (E) regurgitation
P1, difference between groups
P2, difference between subsequent measurements
P3, difference in the slope of the plots representing the groups
Whiskers represent the 95% CI.
Abbreviations: see Table 2

Changes in the mean LVEF during the study depending on the use of radiotherapy and chemotherapy regimen are shown in Table 4. During TT, a significant decrease in LVEF was observed in the whole group (Table 4). Moreover, the women receiving radiotherapy (202 patients [81%]) showed a significantly lower mean LVEF and a greater difference in LVEF between the subsequent measurements than those who did not receive the radiotherapy (Table 4). Lower LVEF at each time point during TT was found in the patients who received anthracyclines and taxanes in the adjuvant setting (as compared with those who received only anthracyclines) (P <⁠0.001, Table 4), the patients with mitral or tricuspid regurgitation both at baseline and during or after TT (as compared with those with no regurgitation or regurgitation only during or after TT) (Figure 1C and 1D), and the patients with no aortic regurgitation or with regurgitation only during or after TT (as compared with those with aortic regurgitation both at baseline and during or after TT) (Figure 1E).

**Table 4**. Differences in the mean left ventricular ejection fraction at 6 time points during the study in the whole study group and according to radiotherapy and anthracycline use
Parameter	Left ventricular ejection fraction, %, mean (SD)							P value^a	P value^b	P value^c
	Patients, n	Baseline before TT	During TT				After TT
	Patients, n	Baseline before TT	3 months	6 months	9 months	12 months	After TT
Whole group	249	68.1 (4.9)	67.2 (4.9)	66.6 (5.0)	66.6 (4.8)	66.0 (5.4)	66.1 (5.3)	–	0.004	–
Use of radiotherapy
Whole group	249	68.1 (4.9)	67.2 (4.9)	66.6 (5.0)	66.6 (4.8)	66.0 (5.4)	66.1 (5.3)	–	–	–
No radiotherapy	47	68.4 (4.7)	67.5 (4.7)	68.0 (4.4)	67.8 (3.6)	67.9 (4.0)	67.6 (4.3)	0.06	<⁠0.001	0.003
Radiotherapy	202	68.0 (5.0)	67.1 (4.9)	66.3 (5.1)	66.3 (5.1)	65.5 (5.7)	65.8 (5.5)	0.06	<⁠0.001	0.003
Use of anthracyclines
Whole group	242	68.0 (5.0)	67.1 (4.9)	66.5 (5.0)	66.5 (4.9)	65.9 (5.5)	66.1 (5.4)	–	–	–
Anthracyclines	141	68.6 (4.8)	68.0 (4.7)	67.4 (4.9)	67.2 (4.7)	66.8 (5.3)	66.7 (5.2)	0.002	<⁠0.001	0.43
Anthracyclines + taxanes	101	67.3 (5.1)	66.0 (5.0)	65.3 (4.8)	65.6 (4.9)	64.6 (5.5)	65.1 (5.5)	0.002	<⁠0.001	0.43
Abbreviations: see Table 2

Finally, we assessed the associations between cardiovascular risk factors and the degree of valvular regurgitation and cardiac diameters. Older age was related to the presence of valvular fibrosis (59.8 [7.8] years vs 52.2 [10.1] years, P <⁠0.001; Table 1), a higher degree of mitral regurgitation (P <⁠0.001, Table 2), and a larger LA diameter (P <⁠0.001, Table 3). HA was related to valvular fibrosis (P = 0.01, Table 1), a higher degree of mitral regurgitation (Table 2), a larger LA diameter at each time point during TT (P <⁠0.001, Table 3), a higher increase in LA diameter (a greater difference between subsequent measurements) (P <⁠0.001, Table 3), and a larger LV diameter at each time point during TT (P = 0.01, Table 3). IHD was related to a larger LA diameter during TT (P = 0.003, Table 3) and a larger RV diameter (P = 0.02, Table 3) at each time point. DM was related to a larger LA diameter at each time point during TT (P = 0.04, Table 3). Finally, high BMI was related to larger LA, LV, and RV diameters at each time point during TT (P <⁠0.001, P <⁠0.001, and P = 0.02, respectively, Table 3).

The patients who received high doses of anthracyclines showed a higher mean degree of aortic regurgitation during TT and a larger RV diameter during TT (P <⁠0.001, Table 3).

No relationship between the valvular fibrosis and chemotherapy regimen or the use of radiotherapy and hormone replacement therapy was found.

Discussion

Myocardial and valvular fibrosis is the major process that contributes to impaired mechanical function of cardiomyocytes. Moreover, it affects heart muscle contraction and relaxation, influences the conduction system, and induces arrhythmia.^10-14 It was postulated that cardiac fibrosis may be caused by the use of certain drugs or by some conditions such as HA, myocardial infarction, inflammation, or aging.^15-17 In our study, valvular fibrosis was diagnosed during or after TT in 28.4% of patients with HER2-positive BC who received trastuzumab as well as chemotherapy and radiotherapy in the adjuvant setting. In 15.6% of the women, fibrosis was found only after TT, while in 32 individuals (12.8%), it was diagnosed during and after TT. Valvular fibrosis did not resolve in any of the patients after completion of TT. However, the limitation of our study is the lack of data on cardiac fibrosis before the administration of the adjuvant chemotherapy. We noted no relationship between valvular fibrosis and chemotherapy regimen or the use of radiotherapy and hormone replacement therapy. Therefore, valvular fibrosis in our patients was most probably caused by degenerative processes related to aging and comorbidities rather than by the therapy itself. Nevertheless, fibrotic processes may be aggravated by the therapy, because 15.6% of the patients in our study developed fibrosis after TT. This hypothesis is also corroborated by a higher frequency of valvular fibrosis in older patients and individuals with HA. However, the lack of a clear relationship between the therapies used and valvular fibrosis diagnosed during or after TT does not exclude the possibility of late fibrotic complications or other damage to chest structures that may occur many years after anticancer treatment irrespective of the presence of early valvular fibrosis. Therefore, asymptomatic patients who receive chemotherapy, immunotherapy (trastuzumab in the adjuvant setting), or radiotherapy require close monitoring for possible cardiac complications.^18-21

Another important issue in patients with HER2-positive BC is the search for predictors of late cardiotoxicity. Among the studied treatment modalities, radiotherapy was identified as a significant risk factor for heart, valvular, pericardial, endocardial, and lung damage. Moreover, it was reported that patients who receive anthracyclines and irradiation of the mediastinum and heart are at high risk of valvular heart disease.^22-26 However, progress in radiotherapy techniques allowed clinicians to use this modality with high accuracy, to protect the heart and lungs, as well as to lower the risk of cardiotoxicity. Importantly, in our study, the dosimetric parameter V30 did not exceed the safety level.

We observed that the patients who received a high dose of anthracyclines (>300 mg/m²) showed a larger RV diameter. This is in line with the findings of other authors,^27,28 who reported anthracyclines to be associated with increased LV diastolic size and reduced wall thickness but not with aortic stenosis. Accordingly, it was hypothesized that myocardial toxicity of anthracyclines leads to ventricular dysfunction and secondary or functional valvular regurgitation. This is in agreement with our study, as we noted an increase in all cardiac chamber diameters (LV, LA, and RV) during TT. Moreover, LA and LV diameters were larger in the patients with mitral regurgitation, which is due to a change in LV geometry (LV dilatation), possibly with a concomitant increase in LV end-diastolic pressure. Thus, in line with the hypothesis proposed by Aleman et al²⁷ and Lund et al,²⁸ it can be assumed that valvular insufficiency results from the valve annular dilatation, which is secondary to the dilatation of cardiac chambers and may by caused by cardiac edema. Moreover, in our study, the women with valvular fibrosis showed statistically higher degree of mitral regurgitation during TT. This is supported by Dickstein et al,¹² who reported fibrosis to be related to asymptomatic followed by symptomatic heart failure. In our study, during TT (and at the same time after radiotherapy), we observed enlargement of all cardiac chambers (ie, an increase in LA, LV, and RV diameters), a decrease in LVEF, as well as a more prominent increase in the degree of valvular regurgitation (only in patients with regurgitation diagnosed during TT). Moreover, the presence of valvular insufficiency before, during, or after TT was associated with a larger LA and LV diameter during TT, as well as lower LVEF. Importantly, a decrease in LVEF during TT was also reported by other investigators.^29,30

Some authors described subclinical changes after 3 months of TT, including deterioration of LV diastolic function and a small decrease in LVEF (with no overt symptoms).^31,32 Furthermore, according to the literature, asymptomatic diastolic dysfunction may develop before the onset of LV contraction disorders.³³ Increased heart chamber diameters, a reduction in LVEF, and an increase in the degree of valvular regurgitation observed during TT in our study might be due to radiotherapy- and chemotherapy-induced cardiac damage. Early effects of both these treatments (applied before TT in our study group) include generation of reactive oxygen species leading to oxidative stress, followed by apoptosis, necrosis, cardiovascular damage, increased vascular permeability, and ultimately connective tissue edema.^34-36 On the other hand, stromal edema might cause an increase in the diameter of all heart chambers. The edema of the cardiac wall (and an increase in its diameter) might be also due to increased transforming growth factor-β1 levels following radiotherapy or chemotherapy. This factor induces the synthesis of enzymes responsible for degradation of collagen, elastin, and other extracellular matrix components as well as deposition of large amounts of proteoglycan and glycosaminoglycan. These changes impair the homeostasis of the entire extracellular matrix that forms the connective tissue of the heart, ultimately leading to connective tissue edema. Fibrosis might constitute the late complication of the above process.^37,38 In summary, stromal edema, as an early effect of radiotherapy and chemotherapy, might be responsible for an increase in heart chamber diameters and the resultant weakness of the heart muscle leading to a decrease in LVEF, as observed in our study. Cardiac dysfunction might be enhanced by the administration of trastuzumab, which blocks the HER2-dependent cardioprotective pathway, thus leading to a further increase in heart chamber dimensions and a reduction in LVEF in the course of treatment, as confirmed by our study.^5,39-41

The above mechanisms underlying therapy-induced alterations in the heart are further confirmed by our finding that LVEF was lower both in the women receiving radiotherapy and in those receiving anthracyclines and taxanes (as compared with anthracyclines alone). According to the literature, taxanes increase the cardiotoxicity of anthracyclines, which is consistent with our results.⁴² Another finding that supports these observations is the fact that a larger RV diameter was related to the administration of high-dose anthracyclines. Interestingly, in the patients with mitral, aortic, and tricuspid regurgitation diagnosed before TT, the degree of regurgitation remained stable during TT despite the fact that the baseline degree was higher than in the patients without valvular regurgitation at baseline. Consequently, in patients with regurgitation diagnosed during TT, a more prominent increase in the degree of valvular regurgitation was observed. Valvular regurgitation remained stable during TT in patients with regurgitation at baseline, which can be explained by the fact that they received cardioprotective drugs before and during TT. The patients diagnosed with HA usually received β-blockers and ACEIs. The remaining patients received low-dose ACEIs as cardioprotection, and in selected patients (about 30%), low-dose β-blockers were additionally used. It was reported that a therapy with ACEIs, β-blockers, and aldosterone receptor inhibitors as well as supervised physical training of moderate intensity during TT reduces heart remodeling and therefore the risk of death from heart failure.^43,44 Thus, based on our findings and those of other authors, we may conclude that cardiac surveillance in patients with BC along with early pharmacological intervention is beneficial. The need for close monitoring of cancer patients after radiotherapy and chemotherapy was supported by Aleman et al,²⁷ who studied patients with Hodgkin lymphoma treated with a combination therapy (mediastinal radiotherapy and anthracycline-containing chemotherapy). After a median follow-up of 18.7 years, the incidence of myocardial infarction and heart failure was significantly increased (standardized incidence ratios of 3.6 and 4.9, respectively) as compared with the general population. Concomitant administration of anthracycline chemotherapy increased the incidence of heart failure by 29%. In a Norwegian study of patients with Hodgkin lymphoma treated with radiotherapy and anthracyclines, 31% of participants had moderate valvular insufficiency at 10 years, and after a mean follow-up of 22 years, progressive valvular disease was revealed.^28,45 Of patients with moderate regurgitation at first assessment, 33% developed severe regurgitation or required valve replacement. In addition, 39% of these patients had aortic stenosis (severe in some cases).

In our study, older age (>54 years) was associated with a significantly higher degree of mitral regurgitation and more dynamic changes in regurgitation, as well as a significantly larger LA diameter. Moreover, the patients with valvular fibrosis were significantly older than those without it. Our results suggest that women older than 50 years are at the highest risk of severe valvular disease during cancer treatment. Therefore, they require careful and regular monitoring as part of a long-term care. This conclusion is also supported by other researchers.⁴⁶

In our study, a slight but significant increase in the RV diameter was observed during TT. It was previously reported that 40% of patients treated with TT (with or without anthracyclines) who developed cardiotoxicity (diagnosed based on LVEF reduction) had RV dysfunction. The coexistence of LV and RV dysfunction was associated with a greater difficulty to restore ventricular function.⁴⁷ This suggests that the adverse effects of cancer treatment influence the entire myocardium. Therefore, the assessment of cardiac mechanical function on the basis of LVEF alone (regardless of the diagnostic tools used, such as echocardiography, perfusion scintigraphy, and others) is not sufficient to identify subtle subclinical changes in the whole myocardium, as suggested by previous research.⁴⁸ This is confirmed by our study, as we observed numerous such changes in cardiac structure and function.

We identified the following risk factors for the development of early asymptomatic cardiac dysfunction during cancer therapy: age, HA, IHD, DM, high BMI, and valvular insufficiency. Moreover, older age (defined as a higher mean age of patients) and HA were related to valvular fibrosis, a significantly higher degree of mitral insufficiency during TT, and larger LA and LV diameters during TT. Finally, the patients with IHD, DM, and high BMI had a significantly larger diameter of all heart chambers during TT. These findings are in line with a previously described profile of high-cardiovascular-risk women aged over 50 years with comorbidities who received an aggressive treatment (radiotherapy with irradiation of the heart, chemotherapy with anthracyclines), resulting in a high risk of cardiac complications.⁴⁶

In conclusion, this study identified subclinical cardiac changes in patients with HER2-positive BC during and after TT. Although asymptomatic, these changes may predict significant late cardiac complications. Early identification of cardiotoxicity can improve the patient prognosis by a proper therapeutic decision-making in terms of subsequent chemotherapy as well as adequate pharmacological and nonpharmacological interventions aimed at preventing cardiac complications. Multidisciplinary teams including cardiologists, physical therapists, and oncologists are needed to provide optimal care to individuals with BC at risk of cardiotoxicity. Finally, successful treatment of HER2-positive BC requires careful cardiac monitoring both during and after the therapy.^47,49,50

Correspondence to

Aleksandra Grela-Wojewoda, MD, PhD, Department of Clinical Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków Branch, ul. Garncarska 11, 31-115 Kraków, Poland, phone: +48 12 634 83 50, email: aleksandra.grela-wojewoda@onkologia.krakow.pl

Received

October 26, 2021.

Revision accepted

January 21, 2022.

Published online

January 28, 2022.

Acknowledgments

None.

Funding

None.

Contribution statement

AGW conceived the concept for the study. AGW and JN contributed to the design of the research. All authors were involved in data collection. JN, AGW, BSK, AA and EK analyzed the data. AGW, JN, and EK coordinated funding for the project. All authors edited and approved the final version of the manuscript.

Conflict of interest

None declared.

How to cite

Grela-Wojewoda A, Niemiec J, Sas-Korczyńska B, et al. Adjuvant combined therapy with trastuzumab in patients with HER2-positive breast cancer and cardiac alterations: implications for optimal cardio-oncology care. Pol Arch Intern Med. 2022; 132: 16204. doi:10.20452/pamw.16204

1.: Denduluri N, Chavez-MacGregor M, Telli ML, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2018; 36: 2433-2443.Crossref
2.: Slamon D, Eiermann W. Robert N, et al; Breast Cancer Inernational Reaserch Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365: 1273-1283.Crossref
3.: Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014; 32: 3744-3752.Crossref
4.: Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012; 2012: CD006243.Crossref
5.: Martín M, Esteva FJ, Alba E, et al. Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review and expert recommendations. Oncologist. 2009; 14: 1-11.Crossref
6.: Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology / College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018; 36: 2105-2122.Crossref
7.: Alawadi F, Abusnana S, Afandi B, et al. Emirates Diabetes Society consensus guidelines for the management of type 2 diabetes mellitus - 2020. Dubai Diabetes Endocrinol J. 2020; 26: 1-20.Crossref
8.: Lang RM, Badano LP, Victor MA, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015; 28: 1-39.e14.Crossref
9.: Lancellotti P, Tribouilloy C, Hagendorff A, et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2013; 14: 611-644.Crossref
10.: Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-β signaling in cardiac remodeling Introduction: the biology of TGF-β. J Mol Cell Cardiol. 2011; 51: 600-606.Crossref
11.: López B, González A, Ravassa S, et al. Circulating biomarkers of myocardial fibrosis: the need for a reappraisal. J Am Coll Cardiol. 2015; 65: 2449-2456.Crossref
12.: Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart. Eur J Heart Fail. 2008; 10: 933-989.
13.: Passino C, Barison A, Vergaro G, et al. Markers of fibrosis, inflammation, and remodeling pathways in heart failure. Clin Chim Acta. 2015; 443: 29-38.Crossref
14.: Tajstra M, Blamek S, Niedziela JT, et al. Patients with cardiac implantable electronic devices undergoing radiotherapy in Poland Expert opinion of the Heart Rhythm Section of the Polish Cardiac Society and the Polish Society of Radiation Oncology. Kardiol Pol. 2019; 77: 1106-1112.Crossref
15.: Caputo C, Prior D, Inder WJ. The need for annual echocardiography to detect cabergoline-associated valvulopathy in patients with prolactinoma: a systematic review and additional clinical data. Lancet Diabetes Endocrinol. 2015; 3: 906-913.Crossref
16.: Budayr A, Tan TC, Lo JC, et al. Cardiac valvular abnormalities associated with use and cumulative exposure of cabergoline for hyperprolactinemia: the CATCH study. BMC Endocr Disord. 2020; 20: 1-9.Crossref
17.: Fortier J, Pizzarotti B, Shaw R, et al. Drug-associated valvular heart diseases and serotonin-related pathways: a meta-analysis. Heart. 2019; 105: 1140-1148.Crossref
18.: Heidenreich PA, Hancock SL, Lee BK, et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003; 42: 743-749.Crossref
19.: Yamanishi H, Watanabe T, Nishinaka T, et al. Aortic regurgitation developed seven years after mediastinal radiation therapy: report of a case [in Japanese]. Kyobu Geka. 1993; 46: 610-613.
20.: Gujral DM, Lloyd G, Bhattacharyya S. Radiation-induced valvular heart disease. Heart. 2016; 102: 269-276.Crossref
21.: Styczkiewicz K, Styczkiewicz M, Mędrek S, et al. Tele-cardio-onco AID: a new concept for a coordinated care program in breast cancer (BREAST-AID): rationale and study protocol. Pol Arch Intern Med. 2019; 129: 295-298.Crossref
22.: Ong S, Aertker R, Clark A, et al. Radiation-associated valvular heart disease. J Heart Valve Dis. 2013; 22: 883-892.
23.: Filopei J, Frishman W. Radiation-induced heart disease. Cardiol Rev. 2012; 20: 184-188.Crossref
24.: Marlière S, Vautrin E, Saunier C, et al. Radiation-related heart toxicity: update in women. Ann Cardiol Angeiol (Paris). 2016; 65: 411-419.Crossref
25.: Poltavskaya MG, Emelina EI, Avdeev YV, et al. Heart valve injury due to radiation therapy. Kardiologiya. 2019; 59: 56-68.Crossref
26.: Brożek B, Damps-Konstańska I, Pierzchała W, et al. End-of-life care for patients with advanced lung cancer and chronic obstructive pulmonary disease: survey among Polish pulmonologists. Pol Arch Intern Med. 2019; 129: 242-252.Crossref
27.: Aleman BMP, Van Den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007; 109: 1878-1886.Crossref
28.: Lund MB, Ihlen H, Voss BMR, et al. Increased risk of heart valve regurgitation after mediastinal radiation for Hodgkin’s disease: an echocardiographic study. Heart. 1996; 75: 591-595.Crossref
29.: 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.Crossref
30.: Tan TC, Bouras S, Sawaya H, et al. Time trends of left ventricular ejection fraction and myocardial deformation indices in a cohort of women with breast cancer treated with anthracyclines, taxanes, and trastuzumab. J Am Soc Echocardiogr. 2015; 28: 509-514.Crossref
31.: Dores H, Abecasis J, Correia MJ, et al. Detection of early sub-clinical trastuzumab-induced cardiotoxicity in breast cancer patients. Arq Bras Cardiol. 2013; 100: 328-332.Crossref
32.: Słowik AJ, Jagielski P, Potocki P, et al. Anthracycline-induced cardiotoxicity prevention with angiotensin-converting enzyme inhibitor ramipril in women with low-risk breast cancer: results of a prospective randomized study. Kardiol Pol. 2020; 78: 131-137.Crossref
33.: Edvardsen T. Can modern echocardiographic techniques predict drug-induced cardiotoxicity? J Am Coll Cardiol. 2011; 57: 2271-2272.Crossref
34.: Santoro F, Tarantino N, Pellegrino PL, et al. Cardiovascular sequelae of radiation therapy. Clin Res Cardiol. 2014; 103: 955-967.Crossref
35.: Chargari C, Riet F, Mazevet M, et al. Complications of thoracic radiotherapy. Press Medicale. 2013; 42: e342-e351.Crossref
36.: Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys. 2010; 76: 77-85.Crossref
37.: Rübe CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforming growth factor β (TGF-β) in the lung tissue of fibrosis-prone mice after thoracic irradiation. Int J Radiat Oncol Biol Phys. 2000; 47: 1033-1042.Crossref
38.: Preidl RHM, Möbius P, Weber M, et al. Expression of transforming growth factor beta 1-related signaling proteins in irradiated vessels. Strahlenther Onkol. 2015; 191: 518-524.Crossref
39.: Agunbiade TA, Zaghlol RY, Barac A. Heart failure in relation to tumor-targeted therapies and immunotherapies. Methodist Debakey Cardiovasc J. 2019; 15: 250-257.Crossref
40.: Mohan N, Jiang J, Dokmanovic M, et al. Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers. Antib Ther. 2018; 1: 13-17.
41.: Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002; 20: 1215-1221.Crossref
42.: Salvatorelli E, Menna P, Cascegna S, et al. Paclitaxel and docetaxel stimulation of doxorubicinol formation in the human heart: implications for cardiotoxicity of doxorubicin-taxane chemotherapies. J Pharmacol Exp Ther. 2006; 318: 424-343.Crossref
43.: Oliva S, Cioffi G, Frattini S, et al. Administration of angiotensin‐converting enzyme inhibitors and β‐blockers during adjuvant trastuzumab chemotherapy for nonmetastatic breast cancer: marker of risk or cardioprotection in the real world? Oncologist. 2012; 17: 917-924.Crossref
44.: Hojan K, Procyk D, Horyńska-Kęstowicz D, et al. The preventive role of regular physical training in ventricular remodeling, serum cardiac markers, and exercise performance changes in breast cancer in women undergoing trastuzumab therapy—an REH-HER Study. J Clin Med. 2020; 9: 1379.Crossref
45.: Wethal T, Lund MB, Edvardsen T, et al. Valvular dysfunction and left ventricular changes in Hodgkin’s lymphoma survivors. A longitudinal study. Br J Cancer. 2009; 101: 575-581.Crossref
46.: Murbraech K, Wethal T, Smeland KB, et al. Valvular dysfunction in lymphoma survivors treated with autologous stem cell transplantation a national cross-sectional study. JACC Cardiovasc Imaging. 2016; 9: 230-239.Crossref
47.: Calleja A, Poulin F, Khorolsky C, et al. Right ventricular dysfunction in patients experiencing cardiotoxicity during breast cancer therapy. J Oncol. 2015; 2 015: 609194.Crossref
48.: Barthur A, Brezden-Masley C, Connelly KA, et al. Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study. J Cardiovasc Magn Reson. 2017; 19: 1-9.Crossref
49.: Tradecki M, Ziółkowska J, Roemer-Ślimak R, et al. Inability to live independently in the course of breast cancer: main risk factors. Pol Arch Intern Med. 2021; 131: 16118.Crossref
50.: Tajstra M, Blamek S, Skoczylas I, et al. Two professions against two killer diseases: the rationale, organization, and initial experience of a cardio-oncology service. Kardiol Pol. 2021; 79: 139-146.Crossref