Subclinical Myocardial Damage after Anthracycline Chemotherapy in Patients with Breast Cancer

doi:10.21203/rs.3.rs-1423714/v1

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Subclinical Myocardial Damage after Anthracycline Chemotherapy in Patients with Breast Cancer

https://doi.org/10.21203/rs.3.rs-1423714/v1

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Purpose: Data on the incidence, timing, and prediction of myocardial damage after anthracycline-based chemotherapy (AC) in patients with breast cancer are limited. We assessed myocardial damage in these patients following AC, using the high-sensitivity troponin I (TnI) assay.

Methods: We prospectively assessed TnI levels in women with breast cancer (n=51) at baseline (before the first AC), 1 week, and 1, 2, 3, 6, 9,12, and 15 months after low-to-moderate doses of AC. Subclinical myocardial damage was diagnosed when TnI levels exceeded the 99th percentile (26 pg/mL). Echocardiograms were obtained at baseline and 3, 6, 9, 12, and 15 months post-AC.

Results: Subclinical myocardial damage was detected in 43% of the patients: in 0%, 3.9%, 7.8%, 33%, 29%, 6.7%, 2.3%, and 2.3% of patients at 1 week and 1, 2, 3, 6, 9, 12, and 15 months after starting AC, respectively. From baseline to 1 week post-AC, median absolute change in TnI levels was 1.6 (interquartile range: 0.1–3.5) pg/mL. Absolute change in TnI levels ≥1.6 pg/mL at 1 week was associated with a higher peak TnI level during follow-up (p=0.042).

Conclusions: Approximately half of the patients had subclinical myocardial damage, frequently observed at 3 or 6 months post-AC. TnI level changes at 1 week after the first AC may predict subsequent myocardial damage.

breast cancer

anthracycline

biomarkers

Breast cancer is the leading cancer in women worldwide [1]. The Centers for Disease Control and Prevention (CDC) reported that 1 in 8 women will develop breast cancer during their lives [2]. Anthracycline-based chemotherapy (AC) is widely used for treating breast cancer, but its use is limited due to dose-related irreversible cardiotoxicity. The risk of cardiotoxicity increases significantly as the cumulative doxorubicin or epirubicin dose rises above 400 mg/m² or 900 mg/m², respectively [3–7]. Therefore, dose reduction of AC and early detection of cardiotoxicity before the onset of overt heart failure and/or a significant reduction in the left ventricular ejection fraction (LVEF) are recommended [3, 8, 9].

Limited data is available on the incidence, timing, and prediction of cardiotoxicity following low-to-moderate doses of AC in patients with breast cancer. The development of the high-sensitivity troponin assay has improved the detection of small-scale myocardial damage before the onset of overt heart failure [10]. In the present study, we prospectively assessed the incidence and timing of subclinical cardiotoxicity using a high-sensitivity troponin I (TnI) assay. Furthermore, we evaluated whether the changes in TnI levels at baseline (before the start of AC) and 1 week after starting AC can predict future myocardial damage.

Study Design and Study Population

The DETOX (DEtection of chemotherapy-induced cardiac TOXicity in breast cancer) study is a physician-initiated registry that prospectively enrolled all consecutive patients with breast cancer who were initially treated by AC between September 2014 and March 2016 at the Kyoto University Hospital. The relevant Review Boards and Ethics Committees at the Kyoto University Hospital approved the study protocol (R0050-1) and the study protocol was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000014741). Written informed consent from the patients was obtained before starting the study. However, we excluded patients who refused to participate in the study when contacted at follow-up, were < 18 years of age, or already had an LVEF of < 55% at the time of enrollment. For the patients who withdrew before 15 months follow-up, the evaluation at the last follow-up was considered the final measurement. The TnI and B-type natriuretic peptide (BNP) assay kits were donated by Abbott Diagnostics, which had no role in the study design, data analysis, decision to submit the manuscript for publication, and manuscript preparation.

Treatment Protocol

AC was conducted according to the Japanese guideline for diagnosis and treatment for breast cancer [11]. Patients positive for human epidermal growth factor receptor 2 (HER-2) (based on pathological findings) were administered trastuzumab concomitantly. After 3 months of AC, radiation or adjuvant chemotherapy was added if it was considered necessary (Fig. 1).

Biomarkers

Measurements of biomarkers were obtained at baseline, 1 week, and 3, 6, 9, 12, and 15 months after AC was started (Fig. 1). TnI levels were measured using the ARCHITECT STAT high-sensitivity troponin I immunoassay (Abbott Diagnostics, USA, ARCHITECT i2000SR) [12, 13]. The limit of detection for the assay was 1.1 pg/mL (range, 0–50,000 pg/mL), and the coefficients of variation at concentrations of 4.7 and 1.3 pg/mL were 10% and 20%, respectively. BNP levels were measured in EDTA plasma using a chemiluminescent microparticle immunoassay provided by Abbott Diagnostics.

Echocardiography

Echocardiograms were performed at baseline and 3, 6, 9, 12, and 15 months after AC was started (Fig. 1). Transthoracic echocardiograms were acquired by a dedicated sonographer (Y.T.) using a specific protocol at baseline and standardized time intervals. Two-dimensional images were acquired using Vivid 7 machines (GE Healthcare, Milwaukee, Wisconsin) in the parasternal short-axis view at the midpapillary level and in the apical views at 60–80 frames per second and digitally archived at the acquisition frame rate. Apical 2-chamber and 4-chamber left ventricular end-diastolic volume and end-systolic volume were calculated using the Simpson’s method of discs, as recommended by the American Society of Echocardiography [14] with papillary muscles and trabecular structures defined as being intracavitary. These volumes were used to calculate the LVEF. In all echocardiograms, LVEF (biplane method), global longitudinal strain, E/e’, and S’ were measured by cardiologists who were blinded to the biomarkers evaluated.

Definitions and endpoints

TnI level exceeding the 99th percentile (26 pg/mL) indicated myocardial damage [12]. Peak TnI was defined as the peak value during the follow-up period. Based on the Cardiac Review and Evaluation Committee classification, cardiotoxicity was defined as a reduction in LVEF of at least 5% to < 55% with symptoms of heart failure, or a reduction in LVEF of at least 10% to < 55% without symptoms of heart failure [15]. The onset of heart failure was determined as worsening dyspnea on effort, the onset of paroxysmal nocturnal dyspnea, orthopnea, leg edema, a decline in physical functioning, and/or heart failure requiring hospitalization.

Statistical analysis

The continuous variables have been presented as mean ± standard deviation or median with interquartile range [IQR], while categorical variables are presented as numbers and percentages. We compared the continuous variables using the Student’s t-test or Wilcoxon rank-sum test based on the distributions. The categorical variables were compared using the χ² or Fisher’s exact test, as was appropriate. Based on the median changes in TnI levels from baseline to 1 week after AC, the patients were divided into two groups. We compared the peak TnI levels during the follow-up period between the two groups. All statistical analyses were two-tailed and were conducted using JMP 10.0 (SAS Institute Inc., Cary, North Carolina). Results with p values < 0.05 were considered statistically significant.

Baseline characteristics

Out of 54 patients, 51 were enrolled in the registry, and 3 who refused to participate in the study were excluded. Of the 51 enrolled patients, 44 were followed for 15 months after starting AC. Of the total, 7 (13.7%) dropped out; 5 completed the follow-up after 6 months, 1 after 9 months, and the rest after 12 months. The average age of the patients was 51 ± 11 years, and they each received 232–243 mg/m² of doxorubicin-equivalent (N = 49) and 180–403 mg/m² of epirubicin-equivalent (N = 2) chemotherapies (Table 1). While a fifth of the patients (N = 10) received trastuzumab with AC, most patients underwent radiation therapy (N = 46). The median absolute change in TnI levels from baseline to 1 week after AC was 1.6 (IQR: 0.1–3.5) pg/mL (Fig. 2). When patients with changes in TnI levels ≥ 1.6 pg/mL and < 1.6 pg/mL were categorized into two groups, no significant differences were seen in the baseline characteristics, baseline echocardiographic variables, TnI levels, and BNP levels between the two groups.

Table 1

Baseline clinical characteristics and medications
	Overall	TnI changes (pg/mL)		p
	(n = 51)	≥ 1.6 (n = 26)	< 1.6 (n = 25)	value
Age, years	51 ± 11	52 ± 11	49 ± 11	0.32
BMI, kg/m²	23 ± 3.5	23 ± 4.3	22 ± 2.4	0.3
BSA, m²	1.5 ± 0.1	1.5 ± 0.1	1.5 ± 0.1	0.66
Side of breast cancer
Left	28 (54)	15 (58)	13 (52)	0.8
Right	20 (39)	9 (35)	11 (44)
Bilateral	3 (5.9)	2 (7.7)	1 (4)
Cardiovascular risk factors
Hypertension	9 (18)	2 (7.7)	7 (28)	0.08
Diabetes mellitus	2 (3.9)	2 (7.7)	0 (0)	0.49
Dyslipidemia	9 (18)	7 (27)	2 (8)	0.14
Current/past smoker	7 (14)	2 (7.7)	5 (20)	0.25
Early-stage cancer (1 or 2A)	31 (61)	13 (49)	18 (72)	0.44
ER positive	30 (59)	15 (58)	15 (60)	0.87
PR positive	18 (35)	9 (35)	9 (36)	0.92
HER-2 positive	15 (29)	9 (35)	6 (24)	0.41
Ki-67, %	33 (22–60)	28 (11–53)	35 (25–70)	0.14
Type of AC therapy
Doxorubicin	49 (96)	26 (100)	23 (92)	0.14
Epirubicin	6 (12)	2 (7.7)	4 (16)	0.42
Doxorubicin and epirubicin	4 (7.8)	2 (7.7)	2 (8.0)	0.97
Total dose of doxorubicin, mg/m²	237 (232–243)	236 (233–243)	237 (232–242)	0.77
Total dose of epirubicin, mg/m²	359 (180–403)	29, 88	226, 403	0.31
Other antineoplastic treatments
Trastuzumab	10 (20)	7 (27)	3 (12)	0.29
Pertuzumab	4 (7.8)	2 (7.7)	2 (8.0)	1
Paclitaxel	19 (37)	9 (35)	10 (40)	0.78
Docetaxel	29 (57)	16 (62)	13 (52)	0.58
Cisplatin	14 (27)	9 (35)	5 (20)	0.35
Cyclophosphamide	51 (100)	26 (100)	26 (100)
Fluorouracil	9 (18)	3 (12)	6 (24)	0.29
Hormonal therapy	24 (47)	11 (42)	13 (52)	0.58
Previous chemotherapy	23 (45)	11 (42)	12 (48)	0.78
Radiation therapy	46 (90)	23 (88)	23 (92)	1
Other baseline medications
ACE-I/ARB	6 (12)	2 (7.7)	4 (16)	0.42
β-Blocker	5 (10)	1 (3.9)	4 (16)	0.19
Statins	4 (7.8)	4 (15)	0 (0)	0.11
Echocardiography
Baseline
EF, %	64 ± 4	64 ± 3	64 ± 4	0.79
E/A	1.1 (0.9–1.5)	1.2 (0.9–1.6)	1.1 (0.8–1.7)	0.57
E/E'	8.7 (7.4–10.2)	8.7 (7.3–11)	8.7 (7.4–10)	0.51
S' (septal)	7.4 (6.5–8.8)	7.5 (6.5–8.5)	7.4 (6.4–8.8)	0.92
S' (lateral)	8.8 (7.3–10)	8.8 (7.1–10)	8.9 (7.6–11)	0.53
S' (right ventricular)	11 (9.8–13)	12 (11–13)	12 (11–14)	0.61
GLS	-20 (-21–17)	-20 (-21–16)	-20 (-22–17)	0.39
Biomarker (baseline)
Serum TnI, pg/mL	1.1 (0-2.4)	0 (0-2.1)	1.4 (0-2.6)	0.08
Plasma BNP, pg/mL	12 (5.8–20)	13 (6.3–18)	9.1 (5.4–21)	0.5
Categorical variables are presented as number (%), and continuous variables as the mean ± SD or median with interquartile range.
AC = anthracycline-based chemotherapy, ACE-I/ARB = angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, BMI = body mass index, BNP = B-type natriuretic peptide, BSA = body surface area, EF = ejection fraction, ER = estrogen receptor, GLS = global longitudinal strain, HER-2 = human epidermal growth factor receptor 2, TnI = troponin I, and PR = progesterone receptor.

Incidence and timing of myocardial damage

At 1 week and 1, 2, 3, 6, 9, 12, and 15 months after starting the AC, myocardial damage (TnI level > 26 pg/mL) was observed in 0%, 3.9%, 7.8%, 33%, 29%, 6.7%, 2.3%, and 2.3% of the patients, respectively. The TnI levels peaked at 3 or 6 months after starting the AC except in 1 patient, and the peak TnI level ranged from 3.6 to 447 pg/mL. During the study period, no patient developed heart failure. Myocardial damage was seen in 43% of the patients. However, a significant reduction in LVEF (< 55% and > 10% compared to baseline without heart failure) was observed in only 2 out of 51 patients (3.9%) (Fig. 3A). None of the patients had BNP ≥ 100 pg/mL during the study period (Fig. 3B). Unlike TnI, which peaked at 3 or 6 months after AC, BNP levels peaked at various time points.

Associations between changes in TnI levels at 1 week after the first AC and peak TnI levels

A ≥ 1.6 pg/mL change in the absolute level of TnI from baseline to 1 week after AC was significantly associated with a higher peak TnI level (median: 28 [18–48] vs. 19 [6.9–37] pg/mL, p = 0.042) (Fig. 4A). However, the two groups showed no significant differences in the LVEF (60% ± 3% vs. 60% ± 4%, p = 0.76) (Fig. 4B) .

The main finding in the current study was that approximately half of the patients had subclinical myocardial damage after low-to-moderate doses of AC, which was mostly observed at 3 or 6 months after the first AC. While changes in the TnI levels from baseline to 1 week after AC predict subclinical myocardial damage, BNP levels remained within the normal range during the 15-month follow-up and no patient developed heart failure. A significant reduction in the ejection fraction (< 55% >10% compared with baseline) without overt heart failure was observed in 2 (3.9%) of the patients during the follow-up.

Previous studies have reported the incidence and timing of cardiotoxicity after low-to-moderate AC. Gulati et al. reported subclinical myocardial damage in 4% of patients with breast cancer at the 3-month follow-up after initiation of epirubicin, and the TnI levels peaked at 80 days after initial AC [16]. On the contrary, Meessen et al. reported subclinical myocardial damage after low-to-moderate doses of AC in 24% of the observed patients at the 36-month follow-up, and the TnI levels peaked at 1 month after the final AC in patients with breast cancer, leukemia, lymphoma, and sarcoma [17]. Potential explanations for this discrepancy in the incidence and the timing of the peak of TnI may be explained by the different types and doses of AC and the heterogeneity of the study populations, including risk factors, cardiovascular comorbidities, and follow-up period.

To the best of our knowledge, this is the first study to demonstrate that absolute changes in TnI levels from baseline to 1 week after starting AC are a prognostic indicator of subsequent myocardial damage. Cardiac troponin is a sensitive and specific marker of myocardial damage, and the TnI assay identifies small-scale myocardial injuries. This cardiac biomarker can detect acute cardiomyocyte injury in acute myocardial infarction and many other clinical conditions [18, 19]. Cardinale et al. [20, 21] and Ky et al. [22] have reported that the elevation of TnI levels up to 3 months after high-dose AC predicts the development of future myocardial injury. Consistent with previous studies, we observed that early changes in TnI levels can predict future myocardial damage in patients with breast cancer after starting low-to-moderate dose AC. According to our results, low-to-moderate doses of AC for breast cancer may be clinically safe, but it is also important to note that subclinical myocardial damage was frequently observed. A previous study reported a strong association between TnI concentrations and higher cardiovascular risk in the general population [23]. Our study reveals that 3 and 6 months after starting low-to-moderate dose AC may be the best time to detect subclinical myocardial damage. Furthermore, assessing the absolute change in TnI levels from baseline to 1 week after starting AC is recommended to detect future myocardial damage.

Study limitations

The current study has several limitations. First, the number of patients was relatively small in this single-center study. Therefore, it should be considered a pilot study, and larger multicenter studies are needed to validate the findings. Second, because this study was limited to breast cancer, we cannot extrapolate the findings to other cancers treated with AC [17]. Third, it has been reported that angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACE-I/ARB) and β-blockers may effectively prevent and treat AC cardiotoxicity [8, 24]. The lower cardiotoxicity than previously reported in this study may be explained by the use of these drugs; 12% and 10% of the study patients took ACE-I/ARB and β-blockers, respectively, for hypertension and other conditions before AC. Finally, the long-term outcome over 15 months after starting AC was not available. Symptomatic heart failure due to AC has also been reported after 2 years of AC initiation and may vary with additional AC and concomitant therapy [6]. Future studies with long-term follow-up are needed to determine if the subclinical myocardial damage within 15 months after AC is associated with future cardiac events.

Approximately half of the patients with breast cancer had subclinical myocardial damage after low-to-moderate doses of AC, most frequently observed at 3 or 6 months after the AC. Changes in TnI levels from baseline to 1 week after AC may be a prognostic indicator of subsequent myocardial damage.

anthracycline-based chemotherapy

BNP

B-type natriuretic peptide

HER-2

Human epidermal growth factor receptor 2

TnI

troponin I

LVEF

left ventricular ejection fraction

Acknowledgments: We wish to specially acknowledge Mr. Tomoya Yoneda for his help in echocardiographic assessments and Ms. K. Shimada and Ms. M. Sato for their secretarial assistance.

Funding: The study was supported by Abbott Japan (Tokyo, Japan).

Competing interest: The authors have no conflicts of interest to disclose regarding this study.

Author contributions:: All authors developed the study design. Kenji Nakatsuma did the data analysis. Kenji Nakatsuma and Neiko Ozasa drafted the manuscript. All authors have approved the final article.

Data availability statement: The data that support the findings of this study are available from the corresponding author, NO, upon reasonable request.

Ethics approval:

The relevant Review Boards and Ethics Committees at the Kyoto University Hospital approved the study protocol (R0050-1) and the study protocol was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000014741). Consent to participate:

Written informed consent from the patients was obtained before starting the study.

Consent to publish:

The authors affirm that human research participants provided informed consent for publication of the images in Figure(s) 1a, 1b and 1c.

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Subclinical Myocardial Damage after Anthracycline Chemotherapy in Patients with Breast Cancer

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Version 1

Abstract

Figures

Introduction

Methods

Study Design and Study Population

Treatment Protocol

Biomarkers

Echocardiography

Definitions and endpoints

Statistical analysis

Results

Baseline characteristics

Incidence and timing of myocardial damage

Discussion

Study limitations

Conclusions

Abbreviations

Declarations

References

Status:

Version 1