Cardiotoxicity among Patients Using Pertuzumab, Trastuzumab and Taxane with HER2-Positive Early- Stage Breast Cancer: A Single-Centre Experience

Aim: In this study, we aimed to investigate the incidence rate, risk factors, and mortality rates in patients with early-stage breast cancer using anti-HER2 (Human epidermal growth factor receptor2) treatment. Patients and Methods: A total of 106 patients diagnosed with human epidermal growth factor 2 (HER2)-positive early-stage breast cancer and receiving anti-HER2 treatment at King Abdulaziz Medical City (KAMC) from 2015 to 2019 were included in the analysis to assess the incidence of Original Research Article Algarni et al.; JPRI, 33(59B): 465-474, 2021; Article no.JPRI.79539 466 cardiotoxicity was collected as a retrospective study. Univariate and multivariate analyses as well as multiple exact logistic regression analysis were conducted to understand the relationships between the left ventricular ejection fraction (LVEF) and treatment combinations and comorbidities Results: The LVEF measurements using an echocardiography method at the baseline (before any treatment) and during the anti-HER2 therapy were assessed. The results suggest that the higher the drug combination, the higher the odds ratio for the declined ejection fraction (EF) patient group. Further, patients treated with the pertuzumab and trastuzumab combination were four times more likely to have a decline in their EF than those who did not use the pertuzumab and trastuzumab drug combination (OR 4.28, 95% CI [1.68–10.91]). Conclusion: This study demonstrated that the drug combination considered here is associated with reduced LVEF and, similarly, comorbidities were also related to EF. However, a larger study in a global patient population will confirm the present observations.


INTRODUCTION
Cancer is the most prevalent cause of death globally among non-communicable diseases. Breast cancer is the second most common form of cancer [1,2] and is categorised based on its aetiology, molecular features, clinical conditions and other factors. For clinical diagnosis and treatment, breast cancer is largely classified according to the receptors, such as estrogen receptor, progesterone receptor and human epidermal growth factor 2 (HER2) receptors. The prevalence of specific hormone receptor-based breast cancer varies globally. Reports suggest that such variation of the receptor (estrogen/progesterone), positive or negative, varies depending on the geographical region and ethnic group [3,4]. Breast cancer is the most diagnosed cancer in women in Saudi Arabia, with a prevalence of 21.8% [2]. The mortality rate due to breast cancer is high and is experiencing an increasing trend [5]. In 2020, diagnosed breast cancer patients were an estimated 2.3 million, with a global death toll of 6,85,000. The scenario is not different in Saudi Arabia. The most recent study of cancer-related mortality among Saudi women has found that breast cancer is the ninth leading cause of death [6][7][8]. According to the Saudi Cancer Registry of the King Faisal Specialist Hospital and Research Centre, around 930 new cases of breast cancer are diagnosed each year in Saudi Arabia. In 2010, of 5,378 cancer diagnoses in Saudi Arabia, 1,473 (27.4%) were for breast cancer, making it the most common newly diagnosed cancer among women [9].
Clinical trials demonstrated that combining taxanes with trastuzumab and pertuzumab as targeted therapy for HER2 significantly improves the overall response rates and survival as a first-line therapy, followed by pertuzumab and trastuzumab as maintenance therapy. Although many clinical studies have reported that cardiac adverse events, such as decreased ejection fraction (EF) and heart failure (HF), are associated with using this combination, the huge benefit of this targeted therapy warrants its use in most breast cancer cases, with close monitoring of cardiac functions.
Trastuzumab as monotherapy is associated with cardiotoxicity, but the exact mechanism of toxicity remains unknown. In patients with normal left ventricular function before starting trastuzumab therapy, the risk of HF is low.
Cardiac adverse events, such as decreased EF and HF, have been of specific concern in patients with HER2-positive breast cancer. Further studies that focus on evaluating and monitoring the incidence of cardiotoxicity are required to guide early management and/or improve outcomes.
Studies of patients treated for the active disease with reduced cardiac function at baseline have reported serious adverse events attributable to HER2-directed therapy. Thus, we have estimated the incidence and associated risk factors of cardiotoxicity effects from anti-HER2 treatment among all patients treated for HER2-positive early-stage breast cancer at a single centre.

Study Design
This single-site retrospective study was designed to understand and evaluate the incidence of cardiotoxicity in early-stage breast cancer patients who were receiving anti-HER2 medications, such as pertuzumab, trastuzumab and taxane. An extensive assessment was done for possible risk factors associated with earlystage breast cancer patients who underwent anti-HER2 treatment (Fig. 1).

Study Location and Duration
The study was conducted at King Abdulaziz Medical City (KAMC), Jeddah, Saudi Arabia. The data was considered for patients with breast cancer for five years in this treatment centre, and information related to the patients was collected from January 2015 to December 2019. Patient selection was done strictly following the approved eligibility criteria according to the study design and protocol.

Patient Inclusion Criteria
The study design contains precise inclusion and exclusion criteria for patient selection. During patient selection, each prospective patient's report was carefully reviewed by the study investigator. Every patient in this study underwent a left ventricular ejection fraction (LVEF) measurement using an echocardiography method at the baseline (before any treatment) and during anti-HER2 therapy. According to the instruction of the International Agency for Research on Cancer (IARC), Saudi Arabia, the estimated age-standardised incidence rate (ASIR) for breast cancer was 22.4 per 100,000 women in 2008 [10]. In this study, the patients' ages were considered following the IARC recommendations.
Only adult female patients, aged ≥ 22.4 years, were considered eligible for this study. Furthermore, histologically confirmed diagnosis of HER2-positive early-stage breast cancer for the study population was obtained from medical reports.
Only patients who were undergoing anti-HER2 treatment between 2015 and 2019 and had the required medical records were eligible for this study. It was carefully observed during the medical record assessment that patients were being treated with specific therapeutic agents, including pertuzumab, trastuzumab and taxane.

Fig. 1. Patient enrolment, screening, inclusion and exclusion in the study
During the screening, patients with HER2negative reports were excluded from the study. Additionally, patients who did not meet the inclusion criteria mentioned in (Fig. 1), such as patients having metastatic breast cancer, male cancer patients and patients undergoing other radiation and chemotherapeutic treatments, were excluded from the study.

Cardiotoxicity Consideration and Evaluation
Besides the mentioned criteria, each report was keenly investigated for cardiotoxicity during patient selection. Cardiotoxicity was considered as (1) a reduction of LVEF, either globally or specifically in the interventricular septum; (2) symptoms or signs associated with HF; and (3) a reduction in LVEF baseline values from 5%-< 55% in the presence of signs or symptoms of HF and a reduction in LVEF ≥ 10%-< 55% without signs or symptoms of HF. Specifically, a 1% decline in the EF basal reading was considered an indicator of cardiotoxicity incidence.

Other Parameters
The parameters considered for this study included the LVEF percentage at pre-and posttreatment stages, menopausal state, BMI, hormone receptor status and stage of the disease. Additionally, associated comorbidities were also considered, such as cardiovascular risk factors, hypertension, coronary artery disease, congestive HF, kidney disease, diabetes mellitus and any other comorbidities.

Statistical Analysis
A detailed descriptive analysis was conducted for the obtained patient data. All categorical data were expressed as percentages and numerical data were presented as mean (±SD). We conducted chi-square (χ2) tests and Fisher exact tests for less frequent (˂ 5) samples to compare between the patients with and without declined EF. Multiple exact logistic regression with a standard maximum-likelihood-based estimator was applied to examine the association between the declined EF and applied medications. All statistical tests were conducted two-tailed, and findings were considered statistically significant at P < 0.05. All analyses were conducted using SAS statistical software (version 9.4, SAS Institute Inc. Cary, NC).

Analysis
The initial patient enrolment comprised 674 patients. However, due to the strict inclusion and exclusion criteria, the final dataset contained 106 patients (Fig. 1). The median age of the patients was 50 years. The age range of the patients was between 27 and 89 years (Table 1).

Menopausal Stage
It was observed that almost half of the selected study participants (42.45%, n = 45) were at the postmenopausal stage. Conversely, 33.96% (n = 36) and 23.58% (n = 25) of the patients were at the premenopausal and perimenopausal stages, respectively (Table 1).
Our observation suggested a significant (P < 0.0001) presence of comorbidities among the declined EF (35.42%) patient group compared to the non-declined EF patient population (25.86%).

Hormonal status
All the patients were examined for the presence of specific hormonal receptors. Progesterone and estrogen receptor presence was investigated. Most of the patients (66.05%, n = 70) had estrogen-positive reports, followed by progesterone-positive (50%, n = 53), progesterone-negative (49.06%, n = 52) and estrogen-negative (33.02%, n = 35) results. Only two patients did not show any positive or negative results for progesterone or estrogen receptor presence.

Medication after Diagnosis
Most of the patients (97.17%, n = 103) were receiving a combination of trastuzumab and taxol as treatment for HER-positive early-stage breast cancer, followed by taxol (92.45%, n = 98) and pertuzumab (53.77%, n = 57) (Table 1). In univariate analysis, a statistically significant difference was observed in the declined and non-declined EF patient groups between the patients treated with pertuzumab (P = 0.001), the patients treated with a combination of pertuzumab and trastuzumab (P = 0.001) and the patients treated with a combination of pertuzumab, trastuzumab and taxol (P = 0.0008) (Table 1, Fig. 2 Table 2).
The pre-and post-comorbidity (risk factors and association with a decline in ejection fraction (EF) comparisons of number of the patients (Fig.  3) suggested that there was a significant difference in the EFs for hypertension, dyslipidemia, diabetes mellitus and cardiovascular disease.

DISCUSSION
Cancer has emerged as a curse to human society in this century, taking a toll on millions of lives irrespective of geographical region, gender and age. Breast cancer's global prevalence is rising and, presently, breast cancer is the second most common cancer in the world [1]. Several factors are found to be responsible for inducing or promoting breast cancer, categorised as hereditary, demographic, reproductive, hormonal, breast-associated and lifestyle-associated factors [1]. However, there has been no established linear association or relationship of these factors in inducing or aiding the progression of breast cancer. Although the relationship or influence of individual factors is known in many cases, their collective impact has not been discovered.
The advancement of medical science saved millions of lives this century by applying some wonder life-saving drugs. For HER2-positive breast cancer, trastuzumab, pertuzumab and taxol have been used for decades worldwide [11]. As a first-line treatment, these drugs were successful in improving the time required for disease progression, response time, specific targeting to solid tumours, and the time required for treatment failure [12].
These drugs are used in different combinations as part of chemotherapy, depending on the diagnosis [13]. Such combination therapy has also demonstrated improvement in the overall survival of the patient [12]. Over the decades, the usage of pertuzumab, trastuzumab and taxol as potentially reliable therapeutic agents for breast cancer treatment has increased, and they are being used differently on a case-by-case basis [14,15]. Using pertuzumab, trastuzumab and taxol as part of the first-line chemotherapeutic treatment for HER2-positive early-stage breast cancer has helped many patients to survive longer and combat the disease. Trastuzumab, a monoclonal antibody used for HER2-positive breast cancer, remains the gold standard of treatment so far [16].
However, side effect prevention has been a concern in the application of these chemotherapeutic agents [17]. Most of the reported side effects are infusion-related, such as fever and chills. Apart from these, there is a range of recorded mild-to-moderate adverse responses that include myalgia, diarrhoea, haematotoxicity, infections, rash, arthralgia and others [18][19][20].
Cardiotoxicity has been a serious concern in using these drugs. A serious adverse event, symptomatic HF, is reported in 1-4% of patients and LVEF association was also noted. In most cases, the cardiological events were reversible and temporary and discontinuation of the therapeutic agent improved the condition [21]. Ewer and Ewer [22] argued that the cardiotoxicity-related alteration due to trastuzumab use may have microscopic ultrastructural changes in the heart muscles, which are partially reversible after the discontinuation of the medication. However, in most of the reports related to cardiotoxicityrelated issues due to using trastuzumab, it has been suggested that it was mainly anthracyclineinduced, and the trastuzumab-induced cardiac changes are reversible [23]. Several recent reports have suggested multiple ways of tackling such cardiotoxicity [24,25].
In this study, we have witnessed the induction of cardiotoxicity in early-stage breast cancer patients who are being treated with various combinations of pertuzumab, trastuzumab and taxol. Our results are statistically significant and are, as per the reports, related to cardiotoxicity associated with these drugs. Another report had also earlier suggested cardiotoxicity association due to treatment with the trastuzumab and pertuzumab combination [26]. Recently, Abdel-Razaq et al. [27] reported that 90% of HER2positive breast cancer patients showed trastuzumab-induced cardiotoxicity in Saudi Arabia. Similar to our observations, Abulkhair et al. [28] reported trastuzumab-associated cardiotoxicity in HER2-positive breast cancer patients in a single institution-based retrospective study. Another single-centre study in the Saudi Arabia region reported persistently low LVEF during follow-up in most of the patients due to drug-induced cardiomyopathy [29]. It was observed in this study that LVEF reduction is associated with the increasing combination of pertuzumab, trastuzumab and taxol. Moreover, associations with comorbidities were also observed in the present study population. Caron and Nohria [30] recommended categorising high-risk HER2-positive breast cancer patients who may show association with cardiotoxicity due to therapeutic effects and considering modified treatment regimens, such as using anthracycline-free treatment regimen, dose reduction and other possibilities to avoid cardiotoxicity.

CONCLUSION
In this study, we observed a statistically significant association between reduced LVEF and various combinations of pertuzumab, trastuzumab and taxol. An association between comorbidities and LVEF reduction was also found in the present HER2-positive early-stage breast cancer patient population.

RECOMMENDATIONS
Additional larger multicentre-based studies are essential to understand and establish the cardiotoxicity effects of trastuzumab, pertuzumab and taxol. A diverse patient population, increased number of drug combinations, longer study durations and attention to individual comorbidities may help in understanding the relation of cardiotoxicity during the use of these chemotherapeutic agents.

DISCLAIMER
The products used for this research are commonly and predominantly used products in our country and area of research. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Furthermore, the research was not funded by the producing company but by the authors' personal efforts.

ETHICAL APPROVAL
Appropriate ethical approval was obtained from the Institutional Review Board (No: SP21J/048/03).