Cardiotoxicity in breast cancer patients receiving trastuzumab with or without prior anthracycline-based chemotherapy: A prospective study from a tertiary cancer institute at Guwahati, India

Arpita Ray; Naba Kumar Kalita; Neelakshi Mahanta; Alfarid Shahid Ali; Madhav Kashyap

doi:10.4103/oji.oji_31_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 6 | Issue : 3 | Page : 66-71

Cardiotoxicity in breast cancer patients receiving trastuzumab with or without prior anthracycline-based chemotherapy: A prospective study from a tertiary cancer institute at Guwahati, India

Arpita Ray, Naba Kumar Kalita, Neelakshi Mahanta, Alfarid Shahid Ali, Madhav Kashyap
Department of Medical Oncology, SCI, Guwahati, Assam, India

Date of Submission	06-Aug-2022
Date of Decision	10-Nov-2022
Date of Acceptance	14-Nov-2022
Date of Web Publication	21-Dec-2022

Correspondence Address:
Arpita Ray
Assistant Professor of Medicine, Fellow of Medical Oncology, SCI, Guwahati, Assam
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/oji.oji_31_22

Abstract

Background: Trastuzumab (Herceptin) is used in human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients either alone or in combination with various chemotherapeutic agents in the neoadjuvant, adjuvant as well as palliative settings. Cardiotoxicity remains an issue of concern with the use of trastuzumab which may be enhanced with the prior use of anthracycline-based chemotherapeutic agents. Aim: This prospective study was conducted with the aim of identifying the occurrence of cardiotoxicity in patients receiving trastuzumab with or without a history of prior use of anthracycline-based chemotherapy. Materials and Methods: The study was conducted over a period of 1½ years. All the HER2-positive breast cancer patients who received trastuzumab-based therapy in adjuvant as well as maintenance settings and the cardiotoxicity in terms of drop in left ventricular ejection fraction (LVEF) from the lower limit of normal range were evaluated. A significant drop is defined when LVEF drop is >10%. Cardiotoxicity was compared between those who received prior anthracycline-based chemotherapy versus nonanthracycline-based chemotherapy. Results: A total of 62 HER2-positive breast cancer patients who fulfilled the inclusion and exclusion criteria were enrolled for analysis. Thirty-two patients received prior anthracycline-based chemotherapy and 30 patients received nonanthracycline-based chemotherapy. A significant drop in LVEF of >10% was found in 20 out of 62 patients (32.3%). This significant drop in LVEF was found more in those patients who received prior anthracycline-based chemotherapy (n = 15) versus who did not receive prior anthracycline-based chemotherapy (n = 5) (46.9% vs. 16.7%; P = 0.0109). Conclusion: Trastuzumab-induced cardiotoxicity (LVEF drop >10%) is higher among breast cancer patients who received prior anthracycline-based chemotherapy as compared to those who did not receive prior anthracycline. This clinically significant drop in LVEF warranted an interruption in the treatment till stabilization and improvement of the cardiac function.

Keywords: Breast cancer, cardiotoxicity, echocardiography, prior anthracycline-based chemotherapy, trastuzumab

How to cite this article:
Ray A, Kalita NK, Mahanta N, Ali AS, Kashyap M. Cardiotoxicity in breast cancer patients receiving trastuzumab with or without prior anthracycline-based chemotherapy: A prospective study from a tertiary cancer institute at Guwahati, India. Oncol J India 2022;6:66-71

How to cite this URL:
Ray A, Kalita NK, Mahanta N, Ali AS, Kashyap M. Cardiotoxicity in breast cancer patients receiving trastuzumab with or without prior anthracycline-based chemotherapy: A prospective study from a tertiary cancer institute at Guwahati, India. Oncol J India [serial online] 2022 [cited 2023 Jun 4];6:66-71. Available from: https://www.ojionline.org/text.asp?2022/6/3/66/364563

Introduction

Breast cancer is the most common cancer among women worldwide and >1 million new cases are diagnosed yearly.^[1] The overexpression of human epidermal growth factor receptor-2 (HER2) is seen in 20%–25% of breast cancers. HER2 overexpression has been found to be associated with aggressive growth and poor prognosis.^[2] Trastuzumab is a humanized monoclonal antibody which acts against the extracellular domain of HER2, targeting HER2 overexpressing tumors.

Trastuzumab-based therapy has dramatically improved the treatment outcome in HER2-positive breast cancer patients. Two decades of clinical experience have shown that treatment with trastuzumab has been effective in inhibiting the proliferation of HER2-expressing breast cancer cells.^[3],[4] Several initial Phase II trials^[5],[6] indicated high efficacy and favorable safety profile of trastuzumab. However, Slamon et al. 2001,^[7] in a Phase III trial, reported an unexpectedly high rate of adverse cardiac events. Seidman et al. in a retrospective review stated that trastuzumab-based therapy increases the risk of cardiac dysfunction and such risk is greatest among patients receiving concurrent anthracyclines.^[8],[9]

Cardiac dysfunction with trastuzumab is often asymptomatic but can be symptomatic as well and the cardiotoxicity has been found to be aggravated with the prior use of chemotherapeutic agents such as anthracyclines. Previously published literatures showed that cancer therapy-related cardiac dysfunctions range from 9% to 26% after treatment with doxorubicin, 13%–17% with trastuzumab, and 27%–34% with combination therapies.^{[8],[10],[11],[12],[13]} The concurrent use of doxorubicin (anthracycline based) chemotherapy causes increased oxidative stress via mitochondrial and iron-dependent generation of superoxide which is then transformed into hydrogen peroxide and peroxynitrite. These reactive oxygen and nitrogen species aggravate the imbalance between pro-survival and pro-apoptotic signaling leading to cardiac cell death.^[14]

Several studies have been carried out worldwide to assess the cardiotoxicity of trastuzumab-based therapies. However, data from Indian studies, especially in Northeast India, are lacking. Hence, we attempt to assess the cardiotoxicity profile of our patients receiving trastuzumab in adjuvant and maintenance settings in breast cancer patients.

Materials and Methods

The present study was a prospective, nonrandomized one conducted in a tertiary care cancer center in Guwahati, Northeast India, over a period of 1½ years from February 2021 to July 2022.

The HER2-positive breast cancer patients who were planned to receive trastuzumab along with chemotherapy in adjuvant setting followed by trastuzumab alone in maintenance setting were included in the study analysis. The study evaluates the trastuzumab-induced decline in cardiac function. The patients with Eastern Cooperative Oncology Group Performance Status (PS) >2, those with baseline left ventricular ejection fraction (LVEF) <55% on echocardiography or on previous cardiac medications, those having metastatic disease, and other patients who received prior trastuzumab-based therapy were excluded from the study enrollment.

The details of patient characteristics including demographic, pathological, and clinical profiles and imaging findings were recorded. Immunohistochemi stry (IHC) finding of 3+ was considered HER2 positive. In case of equivocal findings on IHC, fluorescence in situ hybridization analysis was done for confirmation of HER2 positivity. A proper clinical staging was done for all the patients as per the AJCC manual 8^th Edition.

Trastuzumab was given at a dose of 8 mg/kg body weight as a loading dose in the first cycle followed by 6 mg/kg body weight in the subsequent cycles at every 3 weekly intervals.

The various chemotherapy regimens that were followed, both in the adjuvant setting were:

AC regimen consisted of Adriamycin 60 mg/m² plus cyclophosphamide 600 mg/m²
2. EC regimen consisted of epirubicin 90–100 mg/m² plus cyclophosphamide 600 mg/m²
3. D+T regimen consisted of docetaxel at 100 mg/m² plus trastuzumab
4. P+T regimen consisted of paclitaxel 175 mg/m² plus trastuzumab
5. TCH regimen consisted of docetaxel 75 mg/m² plus carboplatin area under curve 5 plus trastuzumab.

All the regimens were given intravenously on a day 1 basis at 3 weekly intervals and they were followed with maintenance trastuzumab at 6 mg/kg body weight 3 weekly up to 16 cycles (1 year).

Patients were evaluated for cardiotoxicity by history and clinical examination (looking for overt signs of heart failure [HF]) and echocardiography imaging evaluation. Echocardiography was done at the baseline, prior to initiation of trastuzumab therapy and at regular intervals of every 3 cycles after the start of trastuzumab uptill the completion of one year of treatment i.e. 16 cycles of Trastuzumab based treatment.

LVEF value was determined on echocardiography, and the lower limit of normal value was 55%. A significant fall of ejection fraction was defined as a fall of LVEF >10% from the lower limit of normal range.^[8] The treatment was interrupted for such patients when the drop in LVEF was found to be >10% and was resumed on correction of the same. The drop in LVEF was determined for all the patients. Subgroup analysis for drop in LVEF was done for those patients who received prior anthracycline-based chemotherapy and for those who did not receive prior anthracycline.

Statistical analysis

The data collected were entered into Microsoft Excel sheet and analyzed using SPSS statistics software for Windows, version 23 (IBM Corp., Armonk, New York, USA). Categorical data were represented in the form of frequencies and proportions. The difference in drop in LVEF between the two groups was analyzed using Chi-square test. P < 0.05 was considered statistically significant.

The study was approved by the Institutional Ethics Committee vide number SCI/ECR/2020/19.

Results

Ninety-six HER2-positive breast cancer patients were screened for eligibility, of which 23 patients presented with metastatic disease and hence excluded from the study. From 73 remaining cases, 3 patients had cardiac dysfunction at baseline, 5 had received trastuzumab within 6 months, and 3 patients defaulted treatment, and hence, these 11 cases were excluded. Therefore, a total of 62 HER2-positive breast cancer patients fulfilled the inclusion and exclusion criteria and enrolled in the study for analysis.

The basic characteristics of the patient profile are depicted in [Table 1]. The median age of presentation was 44 years (range: 26 to71 years). All patients were of the female sex. Majority of the patients (54.8%) belonged to the age group of 41–50 years. Majority of the patients (n = 48) had no known comorbidities such as hypertension (HTN) or diabetes mellitus (DM). Out of 62 HER2 neu-positive patients, 25 cases (40.3%) were triple positive, 36 (58.1%) were hormone receptor (HR) negative, while 1 (1.6%) were estrogen receptor (ER) positive but progesterone receptor (PR) negative. All patients had a PS 0–1, and baseline LVEF >55%. According to the stage-wise distribution, majority of patients (n = 36; 58.1%) presented at Stage IIB followed by Stage IIA (n = 22; 35.5%).

Table 1: Basic characteristics of the patient profile

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In the present study, 32 patients received prior anthracycline-based chemotherapy while 30 patients received nonanthracycline-based chemotherapy. All patients received treatment in the adjuvant setting.

Among the anthracycline-based chemotherapy regimens (n = 32), majority (n = 31: 96.9%) of patients received 4 cycles of AC followed by 4 cycles of P + T. Among the nonanthracycline-based chemotherapy regimens (n = 30), majority (n = 24: 80%) of patients received TCH up to 6 cycles. All the patients received maintenance trastuzumab after completion of chemotherapy up to 1 year to complete total 16 cycles of trastuzumab. All the regimens were given at 3-weekly intervals.

The drop in LVEF on echocardiography was recorded after every 3 cycles up to 1 year (16 cycles of trastuzumab) during trastuzumab therapy and is depicted in [Table 2]. During treatment, a drop of >10% was considered a clinically significant drop and treatment was temporarily halted till the cardiac function was restored. Adequate cardiology consultation and intervention was done. Over 1-year period of trastuzumab therapy, all the patients experienced some kind of drop in LVEF and a significant drop in LVEF (>10%) was observed in 20 (32.3%) out of 62 patients.

Table 2: Left ventricular ejection fraction drop after every 3 cycles of trastuzumab

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During subgroup analysis, when a drop in LVEF was evaluated between types of chemotherapy, it was found that 46.9% of patients (15 out of 32) who received prior anthracycline-based chemotherapy and 16.7% of patients (5 out of 30) who did not receive prior anthracycline experienced >10% drop in LVEF. The Chi-square test was applied to compare the difference between these two groups and found to be statistically significant [P = 0.0109, [Table 3]].

Table 3: Comparison of drop in left ventricular ejection fraction between prior anthracycline versus no prior anthracycline groups

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For comparison of LVEF drops among different ages, we divided the age groups into ≤50 years and >50 years. Irrespective of prior anthracycline used, we found that a significant LVEF drop of >10 was observed more in older age group (>50 years) than ≤50 years (63.6% vs. 25.5%: P = 0.0141). However, we found that 6 out of 7 older age group patients with LVEF drop >10% had prior anthracycline-based chemotherapy treatment. In our study, the age range of 41–50 years was the most common age group (n = 34). Twelve out of these 34 cases had LVEF drop >10% and 9 out of these 12 cases had prior treatment with anthracycline-based chemotherapy.

When the drop in LVEF was evaluated in relation to comorbidities in the form of HTN/DM (n = 14), irrespective of prior anthracycline, we found a significant drop >10% in a higher trend in cases with comorbidities (42.9%: 6/14) than cases with no comorbidities (29.2%: 14/48) (P = 0.33).

Discussion

Due to poor prognosis of HER2-positive breast cancer patients, the trastuzumab-induced cardiotoxicity should be weighed against its potential clinical benefit. Although there are improved outcomes with the use of trastuzumab, cardiac toxicity is an important concern for medical oncologists, cardiologists and patients. The present study has been conducted to evaluate cardiac changes among HER2-expressed breast cancer patients receiving trastuzumab-based therapy in adjuvant and maintenance settings. The drop in LVEF on echocardiography has been noted and compared between those who received prior anthracycline-based chemotherapy versus who did not receive prior anthracycline. We find a significant drop in LVEF (>10%) is seen more in those who received prior anthracycline-based chemotherapy.

Trastuzumab-induced cardiotoxicity (TIC) has been evaluated in several studies with the help of echocardiography.^[15],[16] We also evaluated the cardiac function at baseline and after every 3^rd cycle with the help of echocardiography. Till now, there is no definitive recommendation for routine use of biomarkers in predilection of TIC. Cardinale et al.^[15] evaluated the TIC by using echocardiography, and they also evaluated the importance of troponin I in the identification of patients who are at risk for development of TIC and who are unlikely to recover from cardiac dysfunction despite HF therapy. Onitilo et al.^[17] in a pilot study evaluated the role of serum biomarkers such as B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein, and cardiac troponin I for early detection of TIC.

In the present study, we included 62 HER2-positive breast cancer patients who fulfilled the eligibility criteria and the median age of presentation was 44 years. Most patients (52%) were in the age group of 41–50 years. Cardinale et al.^[15] in their study on HER2-positive breast cancer patients found the mean of presentation of 50 ± 10 years. In our study, 58% of patients were HR (ER, PR) negative, while 40% were triple positive and the rest 2% were ER positive but PR negative.

In the present study, we evaluated cardiotoxicity in patients who received trastuzumab in adjuvant and maintenance settings. We excluded those patients treated in metastatic settings to negate the bias of interval chemotherapy or additional hormonal therapy on the cardiovascular outcome. Cardinale et al.^[15] in their study evaluated cardiotoxicity among patients who received trastuzumab in both adjuvant (49%) and metastatic (51%) settings.

In the present study, all patients attained some kind of drop in LVEF during the course of treatment. For analysis, we divided the drop in LVEF into two groups such as ≤10% drop in LVEF and >10% decline in LVEF. A significant drop of >10% was found in 32.3% of patients. Several pivotal adjuvant clinical trials have been reported symptomatic congestive HF rates which range from 0.8% to 5.1% and decreased LVEF (>10%) rates which range from 3.5% to 19%.^{[18],[19],[20],[21],[22],[23],[24],[25],[26],[27]} Aggarwal et al.,^[16] in a study, reported >10% drop in LVEF in 4.6% of patients.

Cardiac dysfunction is the most troubling adverse effect of trastuzumab. A randomized trial revealed a significant increase in risk of cardiac dysfunction for concurrent treatment with anthracycline, cyclophosphamide, and trastuzumab as compared to treatment only with anthracycline and cyclophosphamide.^[7] We found that a significant drop in LVEF >10% was seen more among those who received prior anthracycline than who received no prior anthracycline (46.9% vs. 16.7%; P = 0.0109). Other trials including our data show that trastuzumab increases the probability of anthracycline-associated cardiac toxicity.^[19] Slamon et al.^[19] in an adjuvant trial on HER2-positive breast cancers found a higher subclinical loss of mean LVEF (defined as >10% relative loss) among patients who received AC followed by docetaxel plus trastuzumab as compared to those who received nonanthracycline TCH chemotherapy (18.6% vs. 9.4%, P < 0.001). In their study, the risk–benefit ratio favored TCH regimen over AC followed by docetaxel plus trastuzumab.

Identification of risk factors for TIC is also important to derive which group of patients are more likely to develop TIC. Till now, risk factor for TIC has not been clearly determined. Trastuzumab is not always rechallenged among patients suffering from TIC, particularly in adjuvant settings. Hence, early identification of risk factors for TIC and group of patients who may recover from cardiac dysfunction is crucial. This may guide us to avoid indiscriminate discontinuation of trastuzumab in all patients who developed TIC. Moreover, a prophylactic therapy can be initiated in selected high-risk patients.^[11] The older age group of patients and those with cardiac comorbidities are the high-risk factors for TIC.^[7] In our study, LVEF drop >10% is seen more in older age group (>50 years) than ≤50 years (63.6% vs. 25.5%; P = 0.0141). Slamon et al.^[7] in a study reported older age as the only significant risk factor for TIC. We also find that LVEF drop >10% is seen more among the patients with comorbidities such as HTN/DM as compared to those with no comorbidities (42.9% vs. 29.2%; P = 0.33). While, Aggarwal et al.^[16] in a study reported a drop in LVEF profile of 0%–5% group among 80.6% of patients with comorbidities (HTN/DM/coronary artery disease). Hence, it is important to keep a vigilance on the cardiac function as the age increases with regular monitoring of the cardiac function in elderly comorbid patients on trastuzumab, especially in those who have a history of prior treatment with anthracycline-based chemotherapy.

When we further subcategorized the patients according to their visits, we found that patients, who received trastuzumab with a prior history of anthracycline-based chemotherapy, had a significant drop in LVEF of >10% started as early as the 6^th cycle. Whereas, patients who received trastuzumab along with other nonanthracycline-based chemotherapy had a significant drop in LVEF of >10% started after the 9^th cycle. Aggarwal et al.^[16] similarly demonstrated a mean drop of >10% in LVEF profiles in 4.6% of patients which developed over after a mean of 6 months after starting therapy with trastuzumab.

A higher percentage of drop of LVEF among our patients may be due to inapparent underlying cardiac dysfunction (for example due to anemia, or various other causes of cardiomyopathies) that may need a further detailed evaluation and assessment prior to therapy with trastuzumab, and especially in the background of treatment with anthracycline-based chemotherapy. There may also perhaps be a role of studying the cardiac biomarkers such as pro-BNP and troponin levels prior to the start of therapy with trastuzumab, especially in the background of previous treatment with anthracyclines to rule out any incipient cardiac ischemia or ventricular dysfunction.

Understanding of long-term and life-altering toxic effects due to adjuvant anthracyclines provides a support for use of nonanthracycline regimens. Anthracycline-induced long-term cardiac and hematological side effects have been underestimated. The possible reason is as majority of adjuvant studies have been designed to evaluate efficacy and safety with a follow-up period of 7–10 years and more longer-term safety data on cardiac outcomes missing due to loss of later follow-up.^{[28],[29],[30]}

Limitation

The sample size is less to present concrete data and survival was not evaluated due to no or only short-term follow-up period. Hence, we are unable to evaluate risk–benefit ratio between prior anthracycline versus no prior anthracycline. Hence, larger data with longer follow-up period are necessary for better evaluation.

Conclusion

The discovery of trastuzumab has changed the paradigm of treatment for the HER2-expressed breast cancer patients who otherwise have an aggressive tumor biology. Concerns regarding the trastuzumab-induced cardiotoxicity have risen over the years, and the potential for cardiotoxicity may increase with the previous use of anthracycline-based chemotherapy. Clinical deterioration of the cardiac function or a drop in LVEF by >10% may lead to interruption in the treatment till stabilization and improvement of the cardiac function. This warrants regular and strict surveillance of patients receiving trastuzumab, especially during treatment.

It is hence very important to keep a keen eye and look for clinical as well as laboratory parameters to determine any deterioration in cardiac functioning of patients on trastuzumab, especially in those who have a prior history of anthracycline-based chemotherapy. In patients who are of advanced age or with comorbidities or those who have borderline cardiac function, it may be thus better to avoid anthracycline-based chemotherapy when trastuzumab is advocated and alternate chemotherapeutic agents may be preferred with trastuzumab to avoid treatment interruption.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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