You are viewing the site in preview mode

Skip to main content
Download PDF

Predictors of trastuzumab-induced cardiotoxicity among racially and ethnically diverse patients with HER2-positive breast cancer

Cardio-Oncology volume 10, Article number: 68 (2024) Cite this article

Abstract

Background

While trastuzumab has been shown to improve disease-free and overall survival in patients with HER2-positive breast cancer, it may also cause trastuzumab-induced cardiotoxicity (TIC). Although racial and ethnic minorities are at higher risk for cardiovascular disease (CVD) compared to non-Hispanic Whites (NHW), limited data exists on TIC incidence in diverse multi-ethnic populations. Our objective was to assess racial and ethnic differences in TIC and left ventricular ejection fraction (LVEF) recovery among patients with HER2-positive breast cancer.

Methods

We conducted a retrospective cohort study including patients diagnosed with stage I-III HER2-positive breast cancer between 2007 and 2022 who had received adjuvant trastuzumab. We analyzed associations between sociodemographic factors, tumor characteristics, treatment regimens, and CVD risk factors with the primary outcomes of TIC and LVEF recovery, using multivariable logistic regression models. TIC was defined as > 10% decrease in LVEF to an overall LVEF < 50%; LVEF recovery as a return to a LVEF > 50%.

Results

Among 496 evaluable patients, median age was 53 years (IQR: 45.0–62.0) with 36.6% NHW, 15.8% non-Hispanic Black (NHB), 27.8% Hispanic, and 19.8% Other. Fifty-three (10.6%) patients developed TIC, half of whom experienced LVEF recovery. Compared to NHW, NHB had a higher rate of TIC (9.3% vs. 17.7%, respectively) and lower rate of LVEF recovery (70.6% vs. 21.4%, respectively), however, race/ethnicity was not a significant predictor of TIC after adjusting for confounders. Increasing age, lower baseline LVEF, anthracycline use, and presence of hypertension or coronary artery disease were significantly associated with TIC in multivariable analysis.

Conclusions

TIC was more common among NHB compared to NHW, however, Black race was not consistently associated with TIC after adjustment for CVD risk factors. This suggests that CVD comorbidities (e.g., hypertension) that more frequently affect racial and ethnic minorities and are modifiable may explain differences in TIC incidence and recovery.

Background

HER2 (Human Epidermal growth factor Receptor 2), a marker that is over-expressed in up to 25% of breast cancers, has historically been associated with poor prognosis and aggressive tumor biology [1]. The introduction of trastuzumab (TZB)—a monoclonal antibody that selectively targets HER2 and elicits macrophage-mediated phagocytosis of HER2 + tumor cells—has dramatically improved disease free and overall survival rates (with a relative risk reduction of 35–60% and 23–33%, respectively) [2,3]. However, TZB therapy continues to pose significant risk of adverse cardiac events, including both asymptomatic left ventricular ejection fraction (LVEF) decline and symptomatic heart failure [4,5,6]. Trastuzumab-induced cardiotoxicity (TIC) may be quantitatively defined as an absolute decrease in LVEF of > 10% to an LVEF < 50%.7 Clinical trials have identified TIC rates spanning 4-15%, reaching up to 27% in those with concomitant anthracycline use [7,8,9,10,11]. Of note, TIC rates as high as 27% have not been otherwise reported. There has been a general temporal trend towards decreased TIC incidence accompanying the reduction of anthracycline use, with earlier anthracycline-based trials demonstrating higher TIC incidence [7,8]. Newer forms of HER-2 targeted therapies, such as pertuzumab and ado-trastuzumab emantansine (T-DM1; a HER-2 targeted antibody-drug conjugate) have been administered in the adjuvant and neoadjuvant settings with suggestion of lower risk of cardiac events with T-DM1 [12].

Asymptomatic decrease in LVEF generally resolves with discontinuation of the therapy, with rates of full LVEF recovery reaching up to 40% in patients who had also previously received anthracyclines [2,13]. Smaller studies have also reported recovery rates up to 60% (total n = 250), however, the notion of reversibility is still contested as many patients remain on cardiac medications and maintain LVEFs lower than their initial baseline [14,15]. Additionally, current thought posits that at least a component of these presumed recoveries reflects a percentage of initial false positive diagnoses of TIC [16]. The mechanism underlying TIC is thought to involve trastuzumab-mediated interference of downstream HER-2 survival signaling and neuregulin activity, leading to increased cardiomyocyte susceptibility to oxidative stress-induced cell death [7,17]. On the physiological and histological levels, TIC has been characterized by reversible vascular and cardiomyocyte congestion and coronary artery microthrombus formation [18].

Previous studies have identified various risk factors for the development of TIC, including: prior anthracycline exposure, smoking, obesity, hypertension (HTN), diabetes mellitus (DM), hyperlipidemia (HLD), coronary artery disease (CAD), and increasing age [19]. The interplay between HTN and breast cancer is often bi-directional and complex: both entities can exacerbate risk for the other through mediation of common inflammatory pathways. Beta blockers, ACE-inhibitors, and statins (albeit with weaker data for statins specifically) have been identified as potential mediators of TIC incidence and recovery [18,19]. However, there are limited data from racially or ethnically diverse populations on the role of antihypertensive regimens before and after TZB initiation and efficacy of blood pressure control over time among patients of varying levels of cardiovascular disease (CVD) risk.

While the association between TZB and cardiotoxicity is well-established, there are limited data on racial and ethnic differences in TIC incidence or LVEF recovery [1]. In a prior study with a sample size of 216 women (consisting of 27% non-Hispanic Black [NHB] women and 63% non-Hispanic White [NHW] women), NHB women were found to have up to three times higher risk (adjusting for cardiovascular risk factors) of developing TIC and increased likelihood of premature cessation of TZB therapy compared to NHW women [2]. Significant racial and ethnic disparities are known to exist regarding CVD risk factors, as 41.8% and 34.2% of Black Americans are diagnosed with HTN and DM compared to 34.2% and 7.4% of White Americans, respectively. This increased risk further translates to disproportionate morbidity, as Black adults have more than two times the risk of death secondary to CVD relative to White adults [19,20,21].

Despite these disparities in CVD risk and outcomes, ethnic and racial minority groups tend to be underrepresented in clinical trials and observational studies. Most published literature on TIC either fail to report on the differential incidence of their primary outcomes by race and ethnicity or include a small percentage of minority groups [2,4,8,19,22,23]. Our study objective is to assess factors associated with TIC incidence and recovery in a multi-ethnic cohort of breast cancer patients treated with adjuvant TZB. We evaluated the relationship between demographic factors, tumor characteristics, HTN management, and CVD risk factors and TIC incidence, LVEF recovery, and TZB resumption.

Methods

Study population

We conducted a retrospective cohort study of patients diagnosed with operable breast cancer in 2007–2022 at Columbia University Irving Medical Center (CUIMC) in New York, NY to determine predictors of trastuzumab (TZB)-induced cardiotoxicity (TIC), evaluate racial and ethnic differences in TIC, and explore the cardiotoxic side effects of newer HER2-targeted therapies, such as pertuzumab and the antibody-drug conjugate, ado-trastuzumab emtansine (T-DM1). Participants were included if they met the following eligibility criteria: (1) diagnosed with histologically-confirmed stage I-III HER2 + breast cancer, (2) receipt of at least one dose of adjuvant or neoadjuvant TZB, and (3) receipt of at least 2 echocardiograms or multigated acquisition (MUGA) scans before and after starting TZB-based therapy to determine left ventricular ejection fraction (LVEF) at baseline and during TZB therapy. Exclusion criteria included metastatic breast cancer at diagnosis and less than two echocardiograms. This study was approved by the Institutional Review Board at CUIMC.

Data collection

Data on patient demographics, cardiovascular disease (CVD) risk factors, and breast tumor characteristics were extracted from the electronic health record (EHR) and the New York-Presbyterian (NYP) Tumor Registry. Patients with stage I-III breast cancer were identified by analysis of breast tumor characteristics from the NYP Tumor Registry and pathology reports from the EHR.

Outcomes

The primary outcome was TIC, defined as a > 10% absolute decline in LVEF to a fraction < 50% at any time during or after TZB therapy [7]. For patients receiving TZB, routine serial cardiac monitoring is typically performed at baseline, before starting TZB, and subsequently every three months during maintenance TZB therapy for a year. The mean LVEF estimate was used if a range was provided on the echocardiogram or MUGA scan reports. LVEF values were extracted from outpatient clinic notes if echocardiography reports or MUGA scans were unavailable. General clinical practice used to dictate that TZB be discontinued if an asymptomatic LVEF decline to < 50% is detected during routine cardiac monitoring but may be resumed with evidence of LVEF recovery, though as of late most cardio-oncologists will continue therapy up to an LVEF of 40% in the setting of permissive cardiotoxicity in asymptomatic patients. LVEF recovery was primarily defined as a return of LVEF to greater than or equal to 50% on echocardiography. A supplementary definition of recovery entailing a return of LVEF to within 5% points of baseline was also utilized to corroborate the trends observed with the primary definition and account for any clinically insignificant changes captured by the primary definition. Intervals of treatment administration and discontinuation were ascertained from clinical notes and infusion records from the EHR.

Covariates

Demographic data on race/ethnicity were obtained from the EHR and NYP Tumor Registry. Race/ethnicity consisted of four categories: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic/Latinx, and Asian/Pacific Islander/Other. We also categorized race as Black vs. non-Black in our multivariable models. Baseline demographic and tumor characteristics included: age at diagnosis, sex, marital status (married/unmarried), breast cancer stage (I, II, or III), estrogen receptor (ER) status (positive/negative/unknown), and progesterone receptor (PR) status (positive/negative/unknown) from the NYP Tumor Registry. Data on treatment history included: type of breast surgery (lumpectomy/mastectomy), radiation therapy (yes/no), hormonal therapy (yes/no), anthracycline-based chemotherapy, taxane-based chemotherapy, pertuzumab, T-DM1, and anti-hypertensive regimens before and after TZB therapy from the EHR, using pharmacy records from the NYP infusion center for intravenous medications and outpatient medication lists for oral medications. Data were collected on CVD risk factors including hypertension (HTN), diabetes mellitus (DM), hyperlipidemia (HLD), coronary artery disease (CAD), body mass index (BMI) at diagnosis (defined as BMI < 25 kg/m2 as underweight and normal, BMI 25-29.9 as overweight, or BMI\(\:\ge\:\)30 as obese), and smoking status (current/former/never smoker). Diagnoses of HTN (401.9/I10), DM (250.0/E11.10), HLD (242.2 or 272.9/E78.5 or E78.0), and CAD (414.01/I25.10) were identified in the EHR using ICD-9/10 diagnostic codes.

Data on blood pressure management were collected from the EHR. Baseline anti-hypertensive medications were ascertained from the last clinical encounter immediately prior to TZB initiation. Medication lists from the most recent clinical encounter informed the HTN regimens documented for patients after TZB. Baseline blood pressure was extracted from flowsheets and clinical notes in the three visits immediately prior to TZB initiation up to 2 months prior to treatment initiation. Follow-up blood pressure values were collected from clinical notes input at three time points over the course of TZB administration or following completion of treatment. Averages of three blood pressure measurements before and three measurements after initiating TZB were used to determine hypertensive status. A patient was considered to have poorly-controlled hypertension if the mean of three systolic blood pressure readings was greater than 140 mmHg.

Statistical analysis

We generated frequency tables of baseline characteristics stratified by racial and ethnic groups and incidence of TIC. Chi-square test, or Fisher’s exact test for expected cell ranges below 5, was applied to compare frequency distributions of categorical variables and Analysis of Variance (ANOVA) was used to compare frequency distributions of continuous variables between race and ethnicity groups. Chi-square test or Fisher’s exact test for expected cell ranges below 5 and two-sample t-test were used to compare categorical and continuous variables, respectively, between those who did and did not experience TIC. The association between race and ethnicity and TIC was assessed while controlling for covariates using a multivariable logistic regression model. Covariates found to be significant on univariable analysis and those deemed clinically relevant to the outcome were included in the multivariable models. ER and PR status were excluded from the final model due to their correlation with hormonal therapy use. Sex was excluded due to low numbers of male patients with breast cancer. In the multivariable regression model, age at diagnosis was analyzed as a continuous variable.

Overall survival from time of diagnosis was analyzed according to the method of Kaplan and Meier and compared between groups stratified by TIC incidence and race (Black vs. non-Black). Cox regression analysis was carried out to identify factors associated with all-cause mortality when adjusting for known prognostic factors. Specifically, three Cox regression models were constructed: Model 1 incorporated known breast cancer prognostic factors, Model 2 additionally included CVD risk factors, and Model 3 included TIC in addition to the risk factors input into Model 1. All statistical analysis was conducted using RStudio (2022.07.1). A p-value of < 0.05 was considered statistically significant.

Results

Of the 722 patients diagnosed with operable HER2 + breast cancer and treated with trastuzumab (TZB) between January 2007 to December 2022 at Columbia University Irving Medical Center (CUIMC), 496 (68.7%) met inclusion criteria and were included in the analysis (Fig. 1). The main reasons for exclusion included the presence of metastatic disease at diagnosis (n = 114) and lack of at least two available echocardiograms (n = 108). The median number of echocardiograms per patient with TIC after treatment initiation was 6, with a range of 1–20. Duplicated data in the initial data set further reduced the cohort by four patients. Among evaluable patients, median age at diagnosis was 53.0 years (interquartile range [IQR]: 45.0, 62.0) and the cohort was racially/ethnically diverse, with: 36.6% non-Hispanic White (NHW), 27.8% Hispanic, 15.8% non-Hispanic Black (NHB), and 19.8% identifying as Asian/Pacific Islander or Other (Table 1). Over 99% were female, most patients were diagnosed with either stage 1 or 2 disease (n = 421, 84.9%) and 30.2% (n = 150) of the total cohort were treated with anthracyclines. Comparison of baseline characteristics stratified by race and ethnicity is provided in Table 1. The proportion of patients with a diagnosis of HTN at baseline was higher among Hispanic and NHB patients (54.7% and 50.0%, respectively) compared to NHW (27.6%). In addition, anthracycline use was higher among Hispanic and NHB patients (36.0% and 41.0%, respectively) compared to NHW (29.8%).

Fig. 1
figure 1

Study Population Flow Diagram

Full size image
Table 1 Baseline characteristics of breast cancer patients treated with adjuvant trastuzumab stratified by racial and ethnic groups
Full size table

Table 2 compares baseline characteristics between patients who did and did not develop TIC. Overall, 53 (10.7%) of patients experienced trastuzumab-induced cardiotoxicity (TIC). Patients who developed TIC were older at the time of diagnosis (median 57.0 years vs. 52.0 years, p = 0.051) and more often had a history of anthracycline exposure (50.9% vs. 27.8%, p = 0.001), HTN (60.4% vs. 37.0%, p = 0.002), coronary artery disease [CAD] (11.3% vs. 2.5%, p = 0.003), and lower median baseline left ventricular ejection fraction [LVEF] (57.5% vs. 62.5%, p < 0.001). Additionally, patients with TIC more often saw an increase in quantity of anti-hypertensives prescribed following TZB (45.3% vs. 23.7%, p = 0.047).

Table 2 Baseline demographic and clinical characteristics of breast cancer patients stratified by trastuzumab-induced cardiotoxicity (TIC)
Full size table

Three multivariable models were constructed using factors relevant to TIC incidence and those found to be significant in univariable analysis (Table 3). The first model included age at diagnosis, NHB race, year of diagnosis, history of anthracycline use, smoking history, history of HTN, DM, HLD, and CAD, and baseline LVEF. Model 2 included age at diagnosis, NHB race, anthracycline exposure, prior diagnosis of HTN and CAD, baseline LVEF, and a NHB*CAD interaction term. Model 3 was comprised of age at diagnosis, NHB race, anthracycline use, prior diagnosis of HTN and CAD, baseline LVEF, and a NHB*HTN interaction term. Across all models, older age, anthracycline exposure, HTN, CAD, and lower baseline LVEF were significantly associated with TIC while Black race was variably significant. The interaction term consisting of NHB race and HTN was found to be borderline significant (p = 0.074), while the NHB*CAD term was not significant (p = 0.627) (Table 3).

Table 3 Univariable and multivariable analysis of baseline characteristics with the outcome of TIC
Full size table

Among patients who developed TIC during TZB treatment, NHB individuals had the lowest rate of LVEF recovery while NHW patients had the highest recovery rates (3.85% vs. 6.63%, respectively; p = 0.036). This trend was maintained when defining recovery as a return to LVEF within 5% points of baseline (Supplementary Fig. 1, Additional File 1). Figure 2 directly compares relative rates of TIC and LVEF recovery across racial and ethnic groups. Patients who did not recover tended to be older than those who did achieve recovery (60.0 vs. 53.5 years, p = 0.087; Supplementary Table 1, Additional File 2). Except for race and ethnicity, there were no significant differences in baseline characteristics between those who did and did not recover (Supplementary Table 2, Additional File 2). There were no baseline demographic differences between those who did and did not recover according to the secondary definition of recovery. Per this definition, patients who did not recover again tended to be older (median age at diagnosis of 57.0 [IQR: 48.0, 73.0] vs. 56.0 [IQR: 45.0, 66.0]), albeit not at statistically significant level. Additionally, based on available data, no differences in baseline characteristics or rates of recovery were found between TIC patients who eventually resumed TZB (N = 29, 59.2%) vs. those who permanently discontinued TZB treatment (N = 20, 40.8%) (Supplementary Table 2, Additional File 3). Given that only 53 patients out of the total cohort experienced TIC, the sample size was too small to carry out multivariable analysis of predictors of LVEF recovery. Rates of follow up with a cardiologist were similar between those who did and did not recover (n = 18 [75.0%] vs. n = 17 [68.0%], p = 0.188). Additionally, there were no significant differences in rates of overall or class-specific anti-hypertensive use between those who did and did not recover.

Fig. 2
figure 2

Trastuzumab-induced cardiotoxicity (TIC) incidence and recovery across race and ethnicity. Data presented for cohort consisting of patients diagnosed with stage I-III HER2-positive breast cancer and treated with adjuvant trastuzumab at Columbia University Irving Medical Center, New York, NY (2007–2022). TIC; trastuzumab-induced cardiotoxicity; NHW: non-Hispanic White; NHB: Non-Hispanic Black

Full size image

In this study population, the proportion of HER2 + breast cancer patients who were treated with TZB and anthracyclines peaked in 2007–2009 at 68.8% and gradually declined to 4.6% as of 2022, with a corresponding increase in pertuzumab use (Fig. 3). Ado-trastuzumab emtansine (T-DM1) use has gradually begun to increase since 2019. TIC incidence has declined over time alongside these temporal changes in the treatment of HER2 + breast cancer.

Those who developed TIC had lower overall survival than those who did not (p < 0.001) (Fig. 4a). There was no significant difference in survival when comparing NHB patients to all other races (Fig. 4b). Moreover, survival was not associated with level of hypertension control as determined by the mean of three blood pressure readings after treatment initiation (p = 0.79) (Supplementary Fig. 2A, Additional File 4). Increase in quantity of anti-hypertensive medications following treatment initiation also did not correlate with improved survival outcomes (Supplementary Fig. 2B, Additional File 4). TIC was associated with a nearly three-fold increased risk of all-cause mortality (hazard ratio = 2.94 95% CI = 1.38–6.30,p = 0.005). Cox regression analysis further revealed that increased age, advanced breast cancer stage, and diagnosis of CAD, were associated with increased risk of mortality when adjusting for other known prognostic factors (Table 4).

Fig. 3
figure 3

Trends in trastuzumab-induced cardiotoxicity (TIC) and use of anthracyclines and HER2-directed therapies over time. Data presented for cohort consisting of patients diagnosed with stage I-III HER2-positive breast cancer and treated with adjuvant trastuzumab at Columbia University Irving Medical Center, New York, NY (2007–2022). The accompanying table displays frequencies and incidence rates for each group

Full size image
Fig. 4
figure 4

Kaplan-Meier analysis of overall survival since date of breast cancer diagnosis. (A) Survival of patients who incurred TIC vs. those who did not experience TIC; (B) Survival of NHB patients vs. all others. Data presented for cohort consisting of patients diagnosed with stage I-III HER2-positive breast cancer and treated with adjuvant trastuzumab at Columbia University Irving Medical Center, New York, NY (2007–2022)

Full size image
Table 4 Cox multivariable regression model of factors associated with mortality
Full size table

Discussion

In this retrospective study of 496 patients with HER2 + breast cancer treated with adjuvant trastuzumab (TZB), we evaluated racial and ethnic differences in trastuzumab-induced cardiotoxicity (TIC) and left ventricular ejection fraction (LVEF) recovery in a diverse, multi-ethnic cohort. Compared to racial and ethnic demographics of the U.S. population [24], our study was enriched for Hispanic and non-Hispanic Black (NHB) patients, which allowed us to assess racial disparities in TIC incidence. To the best of our knowledge, this study was the first of its kind to concurrently analyze TIC incidence, recovery, and the role of hypertension in a diverse multi-ethnic cohort. We found higher rates of TIC and lower rates of TIC recovery among NHB compared to non-Hispanic White (NHW) patients. On multivariable analysis, NHB race did not consistently predict TIC incidence when controlling for cardiovascular disease (CVD) risk factors. The interaction terms for CAD*NHB race and HTN*NHB race were not significant on multivariable regression. These results suggest that CAD and hypertension do not mediate the higher incidence of TIC among NHB individuals. Moreover, NHB race in itself does not increase risk of TIC when taking into account concurrent diagnoses of CAD and HTN, age of diagnosis, and prior anthracycline use.

We observed a TIC rate of about 11%, with a gradual decrease over time as frequency of anthracycline use decreased and other HER2-directed therapies became more commonly administered. In observational studies where the majority of patients with HER2 + breast cancer had received anthracyclines, TIC rates ranged from 3.6–22%[4, 22. We found anthracycline exposure to be consistently associated with TIC, in line with prior studies that have reported increased odds of TIC incidence by 2-5.5-fold in those who had been treated with anthracyclines [8,25]. In our study, anthracycline use was more common among racial and ethnic minorities relative to their White counterparts and may be a contributory factor to the differential rates of TIC. Since the BCIRG006 trial [26] demonstrated similar disease-free survival benefit with anthracycline and non-anthracycline based chemotherapy for the treatment of HER2 + breast cancer, there has been a steady decline in the use of anthracyclines and the emerging use of other HER2-directed therapies [27,28]. These changes in treatment patterns have likely made the greatest impact on reducing TIC incidence over time.

It has been reported that Black women with invasive breast cancer have 72–173% increased hazard of CVD-related death relative to their White counterparts [29]. Indeed, we found that the incidence of CVD risk factors was significantly higher among NHB patients compared to other racial and ethnic groups. Socioeconomic disparities such as healthcare access, insurance coverage, and quality of care may influence early detection rates and subsequent management of both the primary disease process and cardiotoxic sequelae. Additionally, geographic distribution of accessible facilities and resources required for adequate cardiac monitoring may also widen these disparities [2,30]. Lifestyle factors that play a significant role in cardiovascular health, such as diet, exercise, and smoking, may also vary considerably across cultures and socioeconomic strata [2,19,30]. These environmental factors may therefore differentially affect cardiotoxicity risk by race and ethnicity.

In our study, NHB race remained a significant predictor of TIC after controlling for cardiovascular risk factors including baseline LVEF, CAD, and HTN. We decided to model race as NHB vs. “all else” in our multivariable approach given the higher prevalence of cardiovascular comorbidities among NHB patients at baseline. This framework is also reflected in the nationally utilized American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk calculator, that inputs Black race as a risk factor [31]. A recent study of 1,399 HER2-positive breast cancer patients similarly found that the racial and ethnic disparity in cardiotoxicity risk persisted after controlling for cardiovascular comorbidities as well as social determinants of health (SDoH; e.g., income, education, and insurance) on multivariable analysis [32]. These results imply the role of an additional set of confounders other than cardiovascular risk factors and SDoH that predispose NHB patients to increased TIC risk. In contrast to our study, the racial distribution of this study cohort was relatively limited and consisted of 69 (12%) Black, 1,064 (76%) White, and 166 (12%) “Other” (120 Asian, 1 American Indian/Alaska Native, 1 Native Hawaiian/Pacific Islander, and 44 other or refused to answer). While certain genetic polymorphisms have been found to confer increased susceptibility to cardiotoxicity, the existing data do not suggest a differential frequency of these genetic variants among racial and ethnic minorities [2,7]. Finally, and perhaps most saliently, it is crucial to address that the validity of our current understanding of TIC is limited by the size and diversity of study cohorts to date [2,29].

While certain CVD risk factors, such as coronary artery disease (CAD) and baseline LVEF, were correlated with TIC on multivariable regression, other metabolic and cardiovascular risk factors such as smoking history, diabetes mellitus (DM), hyperlipidemia (HLD), and body mass index (BMI) were not predictive of TIC when controlling for age, race, and anthracycline use (among other covariates). This suggests that not all cardiovascular risk factors or comorbidities are necessarily implicated in the mechanisms underlying development of TIC. Given that TIC is in part defined by LVEF, it follows that baseline LVEF was directly associated with TIC incidence.

The significance of HTN on regression analysis may reflect: (1) the co-incidence of cancer and HTN in a reciprocally causative fashion; and (2) a specific inflammatory process mediated by TZB that precipitates both HTN and TIC. Indeed, inhibition of HER2-mediated molecular pathways with anthracyclines has been shown to increase arterial wall stiffness potentially by way of exacerbation of reactive oxygen species (ROS) accumulation—a potential mechanism that could increase TIC risk for those with elevated vascular stiffness at baseline [7,33,34]. We found a borderline significant association between HTN and TIC, consistent with previous reports [4,8,35].

In terms of medical management of CVD risk factors such as HTN, the current body of literature suggests that extent of blood pressure control has a less explicit role in mitigating cardiotoxicity following TZB treatment. While the predictive role of blood pressure in itself has not been extensively reported on, the utility of anti-hypertensives (in part due to their prevention of cardiac remodeling) has been found to attenuate risk of TIC and promote recovery [36,37]. Namely, several randomized controlled trials found that ACE-inhibitors and beta blockers mitigated LVEF decline, predicted LVEF recovery 3–12 months after treatment initiation (when taken in conjunction), and were generally well-tolerated; however, they did not significantly contribute to reversal of TZB-induced LV remodeling [36,38,39]. In 2019, a multicenter randomized, double-blind, placebo-control trial (RCT) including 468 women found that the ACE-inhibitor Lisinopril and beta blocker Carvedilol were found to confer a protective effect in patients with anthracycline exposure history [38]. Specifically, cardiotoxicity-free survival was extended in patients treated with carvedilol and lisinopril (p = 0.009 and p = 0.015, respectively) compared to placebo. Patients receiving ACE-inhibitors or beta-blockers in both the anthracycline and non-anthracycline groups saw less interruptions in trastuzumab treatment compared to placebo groups [38].

Additionally, prior observational studies have shown that concomitant statin use has been found to reduce cardiotoxicity risk and limit LVEF decline in patients with and without anthracycline exposure treated with TZB [40]. In this study, we did not identify a correlation between TIC incidence or recovery and any individual class of anti-hypertensive agent, perhaps due to insufficient sample size. Additionally, there was no survival difference between patients with sufficient blood pressure control and those who retained high blood pressure following treatment initiation, nor was there any correlation of survival with an increase in quantity of anti-hypertensives prescribed (Supplementary Fig. 2, Additional File 4).

Among patients who developed TIC, we observed slightly lower rates of LVEF recovery of 52.8% compared to 60-62.5% reported in prior literature [14,41]. This discrepancy could likely be due to our inclusion of more racially and ethnically diverse patients and a higher-risk cohort with more baseline CVD risk factors. There were no associations between recovery and TZB resumption, corroborating that appropriate resumption of TZB after initial occurrence of TIC does not compromise cardiovascular outcomes. SCHOLAR and SAFE-HeaRT are two modern phase I trials following permissive cardiotoxicity in breast cancer patients receiving trastuzumab that suggested that trastuzumab continuation, even with associated LV systolic dysfunction, may be safe (about 10% of patients in both studies discontinued TZB due to cardiac-dose limiting toxicity) [42]. While a preventative anti-hypertensive regimen may further ameliorate outcomes, the sample sizes of patients with TIC and TZB resumption were too small in this study to extrapolate any clinically meaningful conclusions regarding the role of specific anti-hypertensives.

Limitations

Our study had several limitations. Clinical records including medication regimens and blood pressure readings across time points was not consistently available for all patients, thus limiting the scope of data that could be collected. Additionally, partitioning the cohort across strata such as TIC recovery or race and ethnicity inevitably created subgroups that consisted of smaller numbers of individuals, further limiting statistical power. Moreover, this was a single institution study in an urban academic center, which limited the generalizability of our findings to other geographic and clinical settings. Furthermore, the exact parameters used to define TIC vary across the literature, and while using quantitative measurements facilitates internal validity and objectivity, this definition fails to capture patients who experienced chemotherapy-induced heart failure without LVEF decline. We were also missing data on socioeconomic status and other SDoH. Moreover, our study did not include an analysis of competing risk of TIC and overall survival, in large part due to the robust survival rate of this cohort. However, without this analysis it remains possible that we did not observe TIC in some patients due to death prior to sufficient exposure to acquire TIC (albeit we would expect this effect to be minimal). Additionally, given that the echocardiograms were performed across a wide range of years, the consistency of measurement is limited by interobserver variability as not all echocardiograms were interpreted by the same reader.

Strengths of our study include a relatively large sample size of 496 patients with diverse racial and ethnic backgrounds and limited missing data regarding demographics, tumor characteristics, breast cancer treatments, and comorbidities. Additionally, we were also able to access more granular data including anti-hypertensive regimens and blood pressure values across several time points to further supplement our analysis of factors underlying trends in TIC incidence. Access to the electronic health record (EHR) also facilitated < 5% missing data for all covariates included in the study. Furthermore, we were able to specifically focus on the incidence of TIC in the adjuvant setting rather than the broader categorization of chemotherapy-induced cardiotoxicity frequently seen in the published literature.

Conclusion

In our racially and ethnically diverse cohort of breast cancer patients, NHB and Hispanic patients had a higher prevalence of cardiovascular risk factors including obesity, HTN, and DM compared to NHW. Moreover, NHB had the highest incidence of TIC coupled with the lowest rates of recovery, underscoring both the disparity in risk and in effective treatment affecting this group. Given the observed racial disparities in TIC and LVEF recovery in the setting of higher baseline prevalence of HTN and DM, adequate medical management of these cardiovascular comorbidities, closer cardiac monitoring, and restricted use of anthracyclines may be appropriate interventions to reduce the health disparities in TIC incidence and recovery rates.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CVD:

Cardiovascular disease

LVEF:

Left ventricular ejection fraction

HER2:

Human Epidermal growth factor Receptor 2

HTN:

Hypertension

NHB:

Non-Hispanic Black

NHW:

Non-Hispanic White

TIC:

Trastuzumab induced cardiotoxicity

TZB:

Trastuzumab

References

  1. Barish R, Gates E, Barac A. Trastuzumab-Induced Cardiomyopathy. Cardiol Clin. 2019;37(4):407–18.

    Article  PubMed  Google Scholar 

  2. Litvak A, Batukbhai B, Russell SD, Tsai HL, Rosner GL, Jeter SC, et al. Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer. Cancer. 2018;124(9):1904–11.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  4. Costa RB, Kurra G, Greenberg L, Geyer CE. Efficacy and cardiac safety of adjuvant trastuzumab-based chemotherapy regimens for HER2-positive early breast cancer. Ann Oncol. 2010;21(11):2153–60.

    Article  PubMed  Google Scholar 

  5. Rugo HS, Brufsky AM, Ulcickas Yood M, Tripathy D, Kaufman PA, Mayer M, et al. Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2013;141(3):461–70.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mantarro S, Rossi M, Bonifazi M, D’Amico R, Blandizzi C, La Vecchia C, et al. Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer. Intern Emerg Med. 2016;11(1):123–40.

    Article  PubMed  Google Scholar 

  7. Dempsey N, Rosenthal A, Dabas N, Kropotova Y, Lippman M, Bishopric NH. Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies. Breast Cancer Res Treat. 2021;188(1):21–36.

    Article  PubMed  Google Scholar 

  8. Onitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors. Ther Adv Drug Saf. 2014;5(4):154–66.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Perez EA. Safety of aromatase inhibitors in the adjuvant setting. Breast Cancer Res Treat. 2007;105(1):75–89.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tan TC, Scherrer-Crosbie M. Assessing the Cardiac toxicity of Chemotherapeutic agents: Role of Echocardiography. Curr Cardiovasc Imaging Rep. 2012;5(6):403–9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001;104(4):557–67.

    Article  PubMed  Google Scholar 

  12. Ponde N, Ameye L, Lambertini M, Paesmans M, Piccart M, de Azambuja E. Trastuzumab emtansine (T-DM1)-associated cardiotoxicity: pooled analysis in advanced HER2-positive breast cancer. Eur J Cancer. 2020;126:65–73.

    Article  PubMed  Google Scholar 

  13. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–801.

    Article  PubMed  Google Scholar 

  14. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28(25):3910–6.

    Article  PubMed  Google Scholar 

  15. Telli ML, Hunt SA, Carlson RW, Guardino AE. Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol. 2007;25(23):3525–33.

    Article  PubMed  Google Scholar 

  16. Collier P, Hussain M, Popovic ZB, Griffin BP. Cardiac surveillance for anti-HER2 chemotherapy. Cleve Clin J Med. 2021;88(2):110–6.

    Article  PubMed  Google Scholar 

  17. Grazette LP, Boecker W, Matsui T, Semigran M, Force TL, Hajjar RJ, et al. Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol. 2004;44(11):2231–8.

    Article  PubMed  Google Scholar 

  18. Olorundare OE, Adeneye AA, Akinsola AO, Ajayi AM, Agede OA, Soyemi SS, et al. Therapeutic potentials of selected Antihypertensive agents and their fixed-dose combinations against Trastuzumab-Mediated Cardiotoxicity. Front Pharmacol. 2020;11:610331.

    Article  PubMed  Google Scholar 

  19. Javed Z, Haisum Maqsood M, Yahya T, Amin Z, Acquah I, Valero-Elizondo J, et al. Race, racism, and Cardiovascular Health: applying a Social Determinants of Health Framework to Racial/Ethnic disparities in Cardiovascular Disease. Circ Cardiovasc Qual Outcomes. 2022;15(1):e007917.

    Article  PubMed  Google Scholar 

  20. Aggarwal R, Chiu N, Wadhera RK, Moran AE, Raber I, Shen C, et al. Racial/Ethnic disparities in hypertension prevalence, awareness, treatment, and control in the United States, 2013 to 2018. Hypertension. 2021;78(6):1719–26.

    Article  PubMed  Google Scholar 

  21. Parker ED, Lin J, Mahoney T, Ume N, Yang G, Gabbay RA, et al. Economic costs of diabetes in the U.S. in 2022. Diabetes Care. 2024;47(1):26–43.

    Article  PubMed  Google Scholar 

  22. Grela-Wojewoda A, Puskulluoglu M, Sas-Korczynska B, Zemelka T, Pacholczak-Madej R, Wysocki WM et al. Biomarkers of Trastuzumab-Induced Cardiac Toxicity in HER2- positive breast Cancer Patient Population. Cancers (Basel). 2022;14(14).

  23. Advani PP, Ballman KV, Dockter TJ, Colon-Otero G, Perez EA. Long-term Cardiac Safety Analysis of NCCTG N9831 (Alliance) Adjuvant Trastuzumab Trial. J Clin Oncol. 2016;34(6):581–7.

    Article  PubMed  Google Scholar 

  24. U.S. Census Bureau QuickFacts: United States www.census.gov [ https://www.census.gov/quickfacts/fact/table/US/RHI125222#RHI125222

  25. Al-Saleh K, Abdel-Warith A, Alghamdi M, Aldiab A, Ali A, Alsaeed EF, et al. Incidence of trastuzumab-induced cardiotoxicity and impact of body mass index in patients with breast cancer: results from a Saudi tertiary cancer center. Mol Clin Oncol. 2022;16(4):78.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.

    Article  PubMed  PubMed Central  Google Scholar 

  27. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab Emtansine for residual invasive HER2-Positive breast Cancer. N Engl J Med. 2019;380(7):617–28.

    Article  Google Scholar 

  28. Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, et al. Adjuvant pertuzumab and trastuzumab in early HER2-Positive breast Cancer in the APHINITY Trial: 6 years’ Follow-Up. J Clin Oncol. 2021;39(13):1448–57.

    Article  PubMed  Google Scholar 

  29. Troeschel AN, Liu Y, Collin LJ, Bradshaw PT, Ward KC, Gogineni K, et al. Race differences in cardiovascular disease and breast cancer mortality among US women diagnosed with invasive breast cancer. Int J Epidemiol. 2019;48(6):1897–905.

    Article  PubMed  Google Scholar 

  30. Tarantini L, Cioffi G, Gori S, Tuccia F, Boccardi L, Bovelli D, et al. Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world women with breast cancer. J Card Fail. 2012;18(2):113–9.

    Article  PubMed  Google Scholar 

  31. Khatib R, Glowacki N, Lauffenburger J, Siddiqi A. Race/Ethnic differences in atherosclerotic Cardiovascular Disease Risk factors among patients with hypertension: analysis from 143 primary care clinics. Am J Hypertens. 2021;34(9):948–55.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Al-Sadawi M, Hussain Y, Copeland-Halperin RS, Tobin JN, Moskowitz CS, Dang CT, et al. Racial and socioeconomic disparities in Cardiotoxicity among Women with HER2-Positive breast Cancer. Am J Cardiol. 2021;147:116–21.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Anjos M, Fontes-Oliveira M, Costa VM, Santos M, Ferreira R. An update of the molecular mechanisms underlying doxorubicin plus trastuzumab induced cardiotoxicity. Life Sci. 2021;280:119760.

    Article  PubMed  Google Scholar 

  34. Leung HW, Chan AL. Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data. Expert Opin Drug Saf. 2015;14(11):1661–71.

    Article  PubMed  Google Scholar 

  35. Jawa Z, Perez RM, Garlie L, Singh M, Qamar R, Khandheria BK, et al. Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: a meta-analysis. Med (Baltim). 2016;95(44):e5195.

    Article  Google Scholar 

  36. Pituskin E, Mackey JR, Koshman S, Jassal D, Pitz M, Haykowsky MJ, et al. Multidisciplinary Approach to Novel therapies in Cardio-Oncology Research (MANTICORE 101-Breast): a Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity. J Clin Oncol. 2017;35(8):870–7.

    Article  PubMed  Google Scholar 

  37. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32.

    Article  PubMed  Google Scholar 

  38. Guglin M, Krischer J, Tamura R, Fink A, Bello-Matricaria L, McCaskill-Stevens W, et al. Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in patients with breast Cancer. J Am Coll Cardiol. 2019;73(22):2859–68.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lin M, Xiong W, Wang S, Li Y, Hou C, Li C, et al. The Research Progress of Trastuzumab-Induced Cardiotoxicity in HER-2-Positive breast Cancer Treatment. Front Cardiovasc Med. 2021;8:821663.

    Article  PubMed  Google Scholar 

  40. Calvillo-Arguelles O, Abdel-Qadir H, Michalowska M, Billia F, Suntheralingam S, Amir E, et al. Cardioprotective effect of statins in patients with HER2-Positive breast Cancer receiving Trastuzumab Therapy. Can J Cardiol. 2019;35(2):153–9.

    Article  PubMed  Google Scholar 

  41. Moilanen T, Jokimaki A, Tenhunen O, Koivunen JP. Trastuzumab-induced cardiotoxicity and its risk factors in real-world setting of breast cancer patients. J Cancer Res Clin Oncol. 2018;144(8):1613–21.

    Article  PubMed  Google Scholar 

  42. Zhou S, Cirne F, Chow J, Zereshkian A, Bordeleau L, Dhesy-Thind S, et al. Three-year outcomes following permissive cardiotoxicity in patients on Trastuzumab. Oncologist. 2023;28(9):e712–22.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the National Institutes of Health, National Cancer Institute R01CA226060, P30 CA013696. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Medicine, Vagelos College of Physicians & Surgeons, New York, NY, USA

    Anna Vaynrub & Katherine D. Crew

  2. Department of Epidemiology, Mailman School of Public Health, New York, NY, USA

    Leila Mishalani & Katherine D. Crew

  3. Section of Cardiology, Columbia University Medical Center, New York, NY, USA

    Jayant Raikhelkar

  4. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, 161 Fort Washington Avenue, 10-1069, New York, NY, 10032, USA

    Katherine D. Crew

Authors
  1. Anna Vaynrub
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Leila Mishalani
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Jayant Raikhelkar
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Katherine D. Crew
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

AV analyzed and interpreted demographic, clinical, and survival data, produced the corresponding tables and figures, and drafted and revised the manuscript. LM majorly contributed to data collection, table/figure formatting, and the manuscript revision process. JR reviewed and provided revisions for the manuscript. KC oversaw and guided conceptual design and data analysis and provided critical revisions for the manuscript.

Corresponding author

Correspondence to Katherine D. Crew.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board at CUIMC and need for consent was waived.

Consent for publication

Not applicable.

Disclosures

The authors have no disclosures to report.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vaynrub, A., Mishalani, L., Raikhelkar, J. et al. Predictors of trastuzumab-induced cardiotoxicity among racially and ethnically diverse patients with HER2-positive breast cancer. Cardio-Oncology 10, 68 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40959-024-00272-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40959-024-00272-8

Keywords

Cardio-Oncology

ISSN: 2057-3804

Contact us