Risk Factors Associated with Trastuzumab-induced Cardiotoxicity in Patients with Human Epidermal Growth Factor Receptor 2-positive Breast Cancer.

CONTEXT: Although trastuzumab is a highly effective and selective targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the drug-induced cardiotoxicity may confine its usefulness in patients. AIM: To explore risk factors associated with the development of cardiotoxicity in patients with HER2-positive breast cancer. SETTINGS AND
DESIGN: A retrospective review of medical records and chart review for all patients with breast cancer treated with trastuzumab was conducted at King Abdulaziz Medical City and King Abdullah Specialized Children Hospital in Riyadh, Kingdom of Saudi Arabia, between October 2015 and February 2018. Patients with declined left ventricular ejection fraction, either with or without cardiac symptoms, were recognized as those with cardiotoxicity due to trastuzumab administration.
RESULTS: A total of 146 patients were included in the study with an average age of 52.7 (standard deviation = 12.2) years. Thirty-two (21.9%) patients developed cardiotoxicity. However, only 24 (16.4%) were symptomatic with an apparent heart failure but it did not necessitate interruption of trastuzumab therapy. The majority of patients had prior underlying cardiovascular diseases. This study identified unilateral tumor site (62.5%), breast surgery (37.5%), and concomitant taxane chemotherapy (62.5%) as the main risk factors associated with significant increase in cardiotoxicity in patients with breast cancer (with P values of 0.0269, 0.0482, and 0.0225, respectively).
CONCLUSION: The majority of patients (more than 90%) developed cardiotoxicity after completion of chemotherapy. However, recruiting a larger sample size should be warranted to confirm or negate these findings. Copyright:

Introduction

Breast cancer is a heterogeneous type of cancer with diverse histological and clinical features among patients.[1] Breast cancers are usually classified based on their heterogeneity, which helps in selecting the appropriate therapies for optimal treatment outcome. Hormonal interventions are best used in case of luminal tumors that are positive for estrogen and progesterone receptors. Breast cancers having amplified human epidermal growth factor receptor 2 (HER2), which is usually overexpressed in 20%–30% of all patients with breast cancer, respond well to trastuzumab that targets HER2.[2] However, HER2 amplification in breast cells is an indicator of poor prognosis in patients as a result of highly aggressive activities of cancer cells that result in more metastasized tumors.[3]

Trastuzumab is an effective and a well-tolerated drug used mainly for the treatment of patients with HER2-positive metastatic breast cancer. It is commonly used as a monotherapy or in combination with other chemotherapies. Compared to the use of chemotherapy alone, trastuzumab plus chemotherapy has shown significant clinical benefits in patients by improving the disease-free survival and the overall survival rates by 33%–52% and 34%–41%, respectively.[4]

On the contrary, many studies have reported several serious and common adverse effects associated with the use of trastuzumab such as diarrhea, rash, erythema, hepatic injury, neutropenia, and cardiac dysfunction.[5] Trastuzumab-induced cardiotoxicity (TIC) occurs as a result of blockage of the HER2 signaling in cardiac myocytes.[6] Quite a few studies have investigated risk factors and the time for TIC and those studies showed diverse findings. For example, history of hypertension, smoking, familial history of coronary artery diseases, and low baseline left ventricular ejection fraction (LVEF) were considered as major predicting factors for developing TIC.[78] However, a more recent retrospective study has presented inconsistent results, where the cumulative doses of anthracyclines (e.g., doxorubicin or epirubicin) were suggested to increase the risk of TIC rather than cardiac factors or concomitant cardiovascular medications.[9] Therefore, recognizing these factors and identifying patients at high risk for developing cardiotoxicity are crucial for health-care providers to take necessary precautions and to provide appropriate treatments for better therapeutic outcomes. The aim of this study was to assess risk factors associated with the occurrence of TIC in patients with breast cancer, which could eventually help in managing this potential adverse event.

Subjects and Methods

A retrospective study of medical records and chart review was conducted for all patients with breast cancer, 18 years old or above, who had been treated with trastuzumab at the oncology outpatient clinic at King Abdulaziz Medical City (KAMC) and King Abdullah Specialized Children Hospital (KASCH) in Riyadh, Kingdom of Saudi Arabia, between October 2015 and February 2018. All patients with breast cancer who had tested for LVEF before and after trastuzumab therapy were included. Patients who had no LVEF test results before or after trastuzumab administration and elderly patients with advanced or terminal disease were excluded. LVEF assessments were usually performed at baseline and at 3 and 6 months after starting trastuzumab. Cardiotoxicity was defined according to Guglin et al.[10] (2009) as an LVEF value less than 50% or a decrease in LVEF from baseline level by more than or equal to 10% or as a symptomatic heart failure even without decline in LVEF. This study was reviewed and approved by the Institutional Review Board at King Abdullah International Medical Research Centre (KAIMRC), Riyadh, Kingdom of Saudi Arabia (Reference no. IRBC/0859/18).

Data from eligible patients with breast cancer electronic records and/or medical charts were collected using a structured data collection format. These included, but not limited to, demographic information at the start of trastuzumab administration; menopausal status; allergies; underlying cardiac diseases; histological cancer type (ductal, lobular, and others); tumor node metastasis (TNM) stage (I–IV); tumor site (unilateral and bilateral); hormone and HER2 expression status; the concomitant use of cancer chemotherapy, radiotherapy, or endocrine therapy; and the pre- and post-trastuzumab LVEF.

Descriptive and statistical analyses of data were carried out using the Statistical Package of the Social Sciences (SPSS) software package, version 21.0 (Release 21.0.0.0, IBM, Armonk, NY, USA). Continuous variables were summarized as percentages or mean values with standard deviation (SD). Categorical variables were presented as proportions with interquartile range. Statistical analyses of the data were performed using Student’s t-test, one-way analysis of variance (ANOVA), Pearson’s chi-squared test (χ2), or Fisher’s exact test with 95% confidence interval (CI). Multivariate logistic regression analysis was also performed to identify factors associated with the risk of cardiotoxicity. Statistical significance was considered at P values less than 0.05.

Results

A total of 163 patients were identified as being treated with trastuzumab (Herceptin® from F. Hoffmann-La Roche Ltd, Basel, Switzerland). Seventeen patients were excluded from the study sample, three patients had previous history of cardiomyopathies and 14 patients had no LVEF assessment either before or after trastuzumab administration. The average age of the eligible patients was 52.7 ± 12.2 years. The majority of patients were either overweight or obese (37.0% and 45.9%, respectively). All patients received trastuzumab treatment for invasive ductal carcinoma. Most patients (91.1%) had unilateral tumor situated and had undergone either complete mastectomy (51.4%) or lumpectomy (17.8%). Table 1 presents the general profile of patients with breast cancer treated with trastuzumab included in this study.

Table 1

Profile of patients with breast cancer treated with trastuzumab, n = 146

Variable	Value
Age in years
Mean ± SD	52.7 ± 12.2
Median (range)	52 (24–89)
Gender, n (%)
Male	0 (0.0%)
Female	146 (100.0%)
BMI, n (%)
<18.5 (underweight)	1 (0.7%)
18.5–24.9 (healthy weight)	24 (16.4%)
25–29.9 (overweight)	54 (37.0%)
>30 (obesity)	67 (45.9%)
Nationality, n (%)
Saudi	138 (94.5%)
Non-Saudi	8 (5.5%)
Menopausal status, n (%)
Premenopausal	65 (44.5%)
Postmenopausal	81 (55.5%)
Allergies, n (%)
No	133 (91.1%)
Yes	13 (8.9%)
Hypertension, n (%)
No	97 (66.4%)
Yes	49 (33.6%)
Hyperlipidemia, n (%)
No	116 (79.5%)
Yes	30 (20.5%)
Diabetes, n (%)
No	105 (71.9%)
Yes	41 (28.1%)
Thyroid dysfunction, n (%)
Normal	128 (87.7%)
Hypothyroidism	9 (6.2%)
Hyperthyroidism	9 (6.2%)
Histological cancer type, n (%)
Ductal	146 (100.0%)
Lobular	0 (0.0%)
TNM stage, n (%)
I	8 (5.5%)
II	52 (35.6%)
III	45 (30.8%)
IV	41 (28.1%)
Tumor site, n (%)
Unilateral	133 (91.1%)
Bilateral	13 (8.9%)
Surgery, n (%)
No	45 (30.8%)
Yes: Mastectomy	75 (51.4%)
Lumpectomy	26 (17.8%)
Estrogen receptor, n (%)
Positive	82 (56.2%)
Negative	64 (43.8%)
Progesterone receptor, n (%)
Positive	69 (47.3%)
Negative	77 (52.7%)
HER2 expression, n (%)
2+	20 (13.7%)
3+	126 (86.3%)
Trastuzumab, n (%)
Adjuvant/neoadjuvant	103 (70.5%)
Palliative	43 (29.5%)
Radiotherapy, n (%)
No	80 (54.8%)
Yes	66 (45.2%)
Endocrine therapy, n (%)
No	73 (50.0%)
Yes: Tamoxifen	36 (24.7%)
Anastrozole/letrozole	46 (31.5%)
Both	9 (%)
Anthracycline, n (%)
No	98 (67.1%)
Yes: Doxorubicin	15 (10.3%)
Epirubicin	33 (22.6%)
Taxane, n (%)
No	60 (41.1%)
Yes: Docetaxel	52 (35.6%)
Paclitaxel	34 (23.3%)
Both anthracycline and taxane
No	102 (69.9%)
Yes	44 (30.1%)

Numerous patients had underlying cardiovascular risk factors, including 49 (33.6%) with hypertension, 30 (20.5%) with hyperlipidemia, 41 (27.1%) with diabetes mellitus, and 18 (12.4%) with thyroid disease. A total of 37 (25.3%) patients were being treated with antihypertensive and/or statin before the initiation of trastuzumab treatment. No patient had a history of heart failure before cancer therapy.

Of 146 patients, 32 (21.9%) patients developed cardiotoxicity with noteworthy decline in LVEF values; with median LVEF decrease of 30% (range, 18%–55%) from baseline levels at the time of diagnosis. However, only 24 (16.4%) were having symptomatic heart failure but did not necessitate trastuzumab interruption. Only three patients (9.4%) developed cardiotoxicity during the 1st-year treatment period, the remaining 29 patients (90.6%) developed cardiotoxicity after completion of anthracycline and/or taxane chemotherapy.

A significant increase in the cardiotoxicity was revealed in patients who had unilateral tumor (81.3%) versus patients with bilateral tumor (18.8%), P = 0.0269. Patients with either partial or complete surgical resection of breast tissues also showed a significant increase in cardiotoxicity (62.5%) in comparison with patients who did not undergo any surgery (37.5%), P = 0.0482. Moreover, patients given taxane chemotherapy had significant higher rate of cardiotoxicity (62.5%) compared with patients who did not use taxane (37.5%), P = 0.0225. In other patients, disease or intervention-related factors did not show any significant influence on the frequency of cardiotoxicity.

Table 2 shows the distribution of cardiotoxicity according to the different factors assessed in patients with breast cancer and the multivariate logistic regression analysis of these factors associated with TIC in patients with breast cancer. None of the evaluated factors showed any significant difference between the two patient groups. However, tumor site and previous treatment with taxane were nearly significant (OR = 3.68; 95% CI: 0.90–15.03; P = 0.0700 and OR = 1.72; 95% CI: 0.93–3.21; P = 0.0863, respectively).

Table 2

Multivariate logistic regression analysis of TIC in patients with breast cancer

Variable	Cardiotoxicity
	Positive		Negative		OR	P value
	n = 32		n = 114		(95% CI)
	n	%	n	%
Age in years						0.4478
<50	13	40.6	49	43.0	0.98
>50	19	59.4	65	57.0	(0.92–1.04)
BMI, n (%)						0.3260
Underweight/normal weight	7	21.9	18	15.8	0.73
Overweight/obesity	25	78.1	96	84.2	(0.39–1.37)
Menopausal status, n (%)						0.7729
Premenopausal	14	43.8	51	44.7	1.23
Postmenopausal	18	56.3	63	55.3	(0.30–4.98)
Hypertension, n (%)						0.5013
No	19	59.4	78	68.4	1.49
Yes	13	40.6	36	31.6	(0.47–4.78)
Hyperlipidemia, n (%)						0.2836
No	25	78.1	91	79.8	0.450
Yes	7	21.9	23	20.2	(0.11–1.93)
Diabetes, n (%)						0.0551
No	19	59.4	86	75.4	3.98
Yes	13	40.6	28	24.6	(0.97–16.29)
Thyroid dysfunction, n (%)						0.3340
Normal	28	87.5	10	87.7	0.63
Abnormal	4	12.5	14	12.3	(0.25–1.61)
TNM stage, n (%)						0.3768
I/II	8	25.0	52	45.6	1.45
III/IV	24	75.0	62	54.4	(0.64–3.27)
Tumor site, n (%)						0.0700
Unilateral	26	81.3	107	93.9	3.68
Bilateral	6	18.8	7	6.1	(0.90–15.03)
Surgery, n (%)						0.1288
No	12	37.5	33	28.9	0.54
Yes	20	62.5	81	71.1	(0.25–1.19)
Estrogen receptor, n (%)						0.7280
Positive	16	50.0	66	57.9	1.36
Negative	16	50.0	48	42.1	(0.24–7.71)
Progesterone receptor, n (%)						0.7643
Positive	13	40.6	56	49.1	1.26
Negative	19	59.4	58	50.9	(0.28–5.58)
HER2 expression, n (%)						0.5976
2+	5	15.6	15	13.2	0.68
3+	27	84.4	99	86.8	(0.17–2.79)
Trastuzumab, n (%)						0.5011
Adjuvant/neoadjuvant	19	59.4	84	73.7	0.62
Palliative	13	40.6	30	26.3	(0.16–2.47)
Radiotherapy, n (%)						0.8669
No	17	53.1	63	55.3	1.09
Yes	15	46.9	51	44.7	(0.40–2.93)
Endocrine therapy, n (%)						0.7914
No	15	46.9	49	43.0	1.18
Yes	17	53.1	65	57.0	(0.35–4.01)
Anthracycline, n (%)						0.4249
No	22	68.8	76	66.7	0.77
Yes	10	31.2	38	33.3	(0.41–1.45)
Taxane, n (%)						0.0863
No	12	37.5	48	42.1	1.72
Yes	20	62.5	66	57.9	(0.93–3.21)

Discussion

The cardiotoxicity is a well-known adverse effect associated with a number of anticancer therapies including anthracycline,[11] doxorubicin,[12] epirubicin,[13] trastuzumab,[14] and others. This study explores the risk factors associated with TIC in patients with HER2-positive breast cancer. The overall incidence of TIC was 21.9%. However, most of the patients did not develop a significant decline in LVEF values or overt heart failure symptoms. The incidence of TIC in patients with breast cancer varies in the published literature, yet it was reported in 2%–7% when trastuzumab is used as monotherapy and up to 28% when combined with other chemotherapies, especially anthracyclines and taxanes.[151617] TIC usually occurs as an asymptomatic reduction of LVEF without serious heart failure complications.[1819] Nevertheless, TIC is a reversible event in the majority of patients with breast cancer after trastuzumab withdrawal and initiation of heart failure therapy.[20]

Several studies have attempted to investigate the risk factors associated with TIC in patients with HER2-positive breast cancer. This study has recognized a number of factors associated with significant increases in TIC, including tumor site (unilateral vs. bilateral), breast surgery, and concomitant taxane chemotherapy. Other studies have reported a diverse number of risk factors that include elderly age,[21] African ethnicity,[22] overweight,[23] mastectomy surgery,[24] concurrent anthracyclines,[25] baseline LVEF value,[26] underlying cardiac conditions,[27] and diabetes.[28]

On the contrary, studies have also explored the time for development of TIC. The majority of TIC in patients with breast cancer in this study (more than 90%) had developed cardiotoxicity after completion of chemotherapy. Barely 10% of TIC occurred during the 1st year of treatment. This finding is consistent with a recent randomized controlled trial, which reported a significant increase in the cardiotoxicity frequency in patients in the 2-year treatment group rather than that in the 1-year group.[29] Similarly, Tang et al.,[24] in 2017, identified a median time of TIC development to be approximately 28 weeks after initiation of trastuzumab treatment. However, Moilanen et al.,[30] in 2018, reported that most of the noteworthy declines in LVEF (≥10%), which required trastuzumab interruption occurred within 6 months of treatment.

Furthermore, a number of studies have reported no significant efficacy or benefits for adjuvant trastuzumab treatments for more than 12 months.[293132] Longer trastuzumab treatment periods do neither increase disease-free survival nor the overall survival rate of patients with HER2-positive breast cancer. Therefore, maintaining the optimum trastuzumab administration within the current standard therapy of 12 months is pivotal for avoiding the considerable increase in the incidence of TIC associated with longer treatments.

In addition to the prominent importance of risk–benefit assessment regarding the inclusion of trastuzumab to the conventional cancer chemotherapy, a quite few approaches were proposed to prevent or at least to minimize the potential risk for cardiotoxicity in patients with breast cancer during trastuzumab treatment. These include regular cardiac imaging and LVEF monitoring for early detection of TIC, and avoiding, if possible, the concomitant administration of anthracyclines with trastuzumab.[33] Recently, identification of the beneficial effects of cardiac progenitor cell–derived exosomes in ischemic heart disease has opened the door for using such innovative method to attenuate drug-induced oxidative stress in cardiac myocytes, thus protecting against chemotherapy-induced cardiotoxicity.[3435]

Conclusion

TIC is a rather fairly common adverse event in the majority of HER2-positive breast cancer receiving trastuzumab therapy even after withdrawal of treatment. This study has ascertained the importance of continuous screening for any imminent cardiotoxicity in patients with breast cancer during the treatment period and even after completion of chemotherapy. Identification of cardiotoxicity-associated factors and early recognition of patients with breast cancer at high risk for TIC are essential for evading such deleterious adverse effects and initiating heart failure therapy if needed. Therefore, continuous monitoring of cardiac function is highly recommended to manage any emerging cardiac events and to improve the adjuvant treatment outcomes in these patients. Further studies should carefully focus on including other elements, besides LVEF, such as cardiac enzymes and myocytes oxidative stress, which are indispensable to understand the mechanism of trastuzumab-associated cardiotoxicity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.