Abstract

Background: Elderly breast cancer patients are usually excluded from clinical trials. Nevertheless, with the increasing use of trastuzumab, there is a need to address trastuzumab-related cardiotoxicity in this population.

Patients and methods: Records for patients ≥70 years treated with trastuzumab since 2005 were reviewed. New York Heart Association classification was used to document symptomatic cardiotoxicity. Asymptomatic cardiotoxicity was defined as an absolute drop ≥10% with a final left ventricular ejection fraction <50% or an absolute drop >20%.

Results: Forty-five patients, median age 75.9 years (range 70–92), were identified. Three of 24 (12.5%) early breast cancer patients and 5 of 21 (23.8%) with advanced disease experienced asymptomatic cardiotoxicity. Four of 45 patients (8.9%), all with advanced breast cancer, developed symptomatic congestive heart failure. All but one of them recovered in a median time of 5 weeks (range 3–21). Patients with trastuzumab-related cardiotoxicity presented more often with cardiovascular risk factors, such as history of cardiac disease (33% versus 9.1%, P = 0.017) and diabetes (33.3% versus 6.1%, P = 0.010), compared with those without.

Conclusions: Elderly breast cancer patients with a history of cardiac disease and/or diabetes treated with trastuzumab have an increased incidence of cardiotoxicity. Continuous cardiac monitoring is especially advised in this population.

introduction

Human epidermal growth factor receptor-2 (HER-2) is a member of the epidermal growth factor receptor family that functions as a transmembrane receptor tyrosine kinase and plays a critical role in cell growth and proliferation [1]. HER-2 protein is overexpressed in up to 20% of breast cancers and is associated with poor prognosis and response to treatment [2, 3].

Trastuzumab (Herceptin®; F.Hoffmann-La Roche Ltd., Basel, Switzerland) is a humanized mAb directed against the extracellular domain of the HER-2 receptor [4]. In randomized multicenter trials with HER-2-overexpressing metastatic breast cancer patients, the addition of trastuzumab to first-line chemotherapy improved the objective response rate, the time to disease progression and overall survival over chemotherapy alone [5, 6]. As such, trastuzumab has become a milestone in the treatment of patients with advanced-stage breast cancer. More recently, data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival as compared with chemotherapy alone [7–10]. Thus, trastuzumab is now considered a standard of care for adjuvant treatment of patients with HER-2-overexpressing early-stage breast cancer.

These benefits have none the less come with the cost of a potentially increased risk of cardiotoxicity. As cardiac events were not anticipated, monitoring of cardiac function was not mandatory in most of the initial studies with trastuzumab. In addition, studies in which cardiac function was monitored reported different types and timings of monitoring. As a consequence, it is difficult to compare results between studies and to identify predisposing risk factors for trastuzumab-related cardiotoxicity. It is also difficult to compare trastuzumab-associated cardiotoxicity with that associated with other chemotherapeutic agents because the mechanisms of trastuzumab-induced cardiotoxicity are yet to be elucidated and probably rely on the blockade of HER-2 signaling necessary for the growth, repair and survival of cardiomyocytes [11]. Trastuzumab-related cardiotoxicity differs from that of anthracyclines, as it is neither dose related nor associated with identifiable ultrastructural abnormalities and it is expressed in a broad range of severities, most of which is reversible with treatment discontinuation [12–15].

A large review including data from 1219 advanced breast cancer patients showed an increased risk for cardiac events in patients receiving concomitant trastuzumab and an anthracycline derivative plus cyclophosphamide (27%), when compared with the substantially lower risk in patients treated with paclitaxel and trastuzumab (13%) or trastuzumab alone (3%–7%) [16]. In addition to concurrent anthracycline or taxane use, other major risk factors for trastuzumab-related cardiotoxicity include age >60 years and left ventricular ejection fraction (LVEF) [5, 14, 16] at baseline and prior anthracycline exposure [17–19]. Current or previous treatment with antihypertensive medication [19] and a body mass index (BMI) >25 [18] have been shown to increase the risk of a cardiac event in some but not in all trials.

One of the major caveats of clinical trials in oncology relates to the limited information that we have in the elderly population, a particularly common group of patients with this disease. Clinical trials including patients with trastuzumab are limited to women up to 65 years old and with an optimal performance status [20]. Thus, the results only apply to a relatively young and healthy patient population. Extrapolation to the entire population requires a note of caution. Although trastuzumab-related cardiotoxicity has become better characterized as experience with this agent has increased and consequently risk factors and appropriate monitoring and treatment procedures are being identified, there is still much work to be done to accurately characterize this event in aged breast cancer patients. Given the benefit of trastuzumab [21–23] and the lack of known predictive risk factors for cardiac toxicity in such a population, we aimed to assess the cardiac safety profile of trastuzumab in elderly breast cancer patients in the setting of routine clinical practice.

patients and methods

Data from HER-2-overexpressing breast cancer patients aged ≥70 years treated since 2005 at the Breast Cancer Unit of Vall d'Hebron University Hospital were collected. Patients were considered for the study if they had received at least one dose of a trastuzumab-based regimen for the treatment of early or advanced disease and had carried out at least two LVEF assessments while on treatment. Patients who were withdrawn from trastuzumab therapy due to a cardiac event were also recorded. The LVEF was assessed either by a multiple-gated acquisition scanning or by echocardiography [24]. Symptomatic cardiotoxicity was retrospectively assessed based on clinical records, which included medical history, physical examination and diagnostic tests (chest X-ray, electrocardiogram, 2D echo, radionuclide angiography, blood tests).

Cardiac events were categorized by the New York Heart Association (NYHA) functional classification system and then used to document symptomatic cardiotoxicity [25]. Asymptomatic cardiotoxicity was defined as an absolute drop ≥10% resulting in a final LVEF <50% or any absolute drop >20%.

Trastuzumab was discontinued in patients who either developed cardiac symptoms or experienced a significant decrease in LVEF. In other cases, the decision to continue trastuzumab was considered on a case-by-case basis following strict cardiac monitoring. Re-treatment with trastuzumab in those patients who developed any cardiac event and recovered after discontinuation and appropriate cardiac therapy was evaluated carefully in each case.

The following cardiovascular risk factors (CRF) for the development of a cardiac event were retrospectively assessed: current or prior therapy for hypertension, diabetes and dyslipidemia; obesity (BMI >30 kg/m2); prior anthracycline exposure (cumulative dose, type and time between the last anthracycline administration and the first trastuzumab dose); concomitant exposure to anthracyclines or taxanes; number of previous treatments; prior left-sided radiation therapy; baseline LVEF; smoking history and history of previous episodes of heart failure, cardiac arrhythmia, ischemia or valvular heart disease.

statistical analysis

Descriptive analysis of data was carried out according to standard methodology. Factors included in the univariate logistic regression model were history of cardiac toxicity, obesity, smoking history, hypertension, diabetes, dyslipidemia, cumulative dose of previous anthracyclines and age. Confounding and effect-modification variables were studied by multivariate analysis. SPSS v.15 for Windows (SPSS Inc., Chicago, IL) was used for the statistical analysis.

results

Data from 45 patients ≥70 years old were collected. Patient demographics and baseline characteristics are detailed in Table 1. Median age at the time of initiation of trastuzumab-based treatment was 75.9 years (range 70–92 years). Eleven patients (24.4%) were over the age of 80. Eastern Cooperative Oncology Group performance status at the beginning of the treatment was zero, one and two in 31.1%, 57.8% and 11.1% of patients, respectively. Fifty-six percent of the patients received trastuzumab as neoadjuvant or adjuvant treatment and 44% for treatment of metastatic disease. Determination of LVEF at baseline was carried out in every case and was repeated during treatment in all patients after a median interval of 4.5 months (range 0.5–14.0). The median LVEF value at baseline was 64.0% (range 46.3–76.0). Median duration of trastuzumab-based treatment was 49 weeks (range 1–156).

Table 1.

Patient demographics and baseline disease characteristics

Characteristics No. of patients (N = 45) 
Age (years)   
    70–75 27 60.0 
    76–80 15.6 
    ≥81 11 24.4 
ECOG performance status   
    0 14 31.1 
    1 26 57.8 
    2 11.1 
Stage of disease   
    I 4.5 
    II 10 22.2 
    III 13 28.9 
    IV 20 44.4 
Histological type   
    Ductal carcinoma 39 86.7 
    Lobular carcinoma 13.3 
Baseline LVEF   
    ≤50% 4.4 
    >50% 43 95.6 
Characteristics No. of patients (N = 45) 
Age (years)   
    70–75 27 60.0 
    76–80 15.6 
    ≥81 11 24.4 
ECOG performance status   
    0 14 31.1 
    1 26 57.8 
    2 11.1 
Stage of disease   
    I 4.5 
    II 10 22.2 
    III 13 28.9 
    IV 20 44.4 
Histological type   
    Ductal carcinoma 39 86.7 
    Lobular carcinoma 13.3 
Baseline LVEF   
    ≤50% 4.4 
    >50% 43 95.6 

ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction.

A total of 12 patients of 45 (26.7%) experienced a cardiac event, as described in Table 2. Eight patients (17.8%) developed asymptomatic LVEF decline and four patients (8.9%) developed symptomatic congestive heart failure (CHF). Among the eight patients with asymptomatic cardiac events, one was receiving trastuzumab alone and two trastuzumab in combination with either letrozole or vinorelbine in the adjuvant setting. In the metastatic setting, one patient received trastuzumab alone, while in the remaining four patients trastuzumab was administered in combination with vinorelbine, letrozole, exemestane or liposomal doxorubicin plus paclitaxel. Among the four patients with CHF, one patient was receiving trastuzumab alone and three had trastuzumab in combination with gemcitabine, vinorelbine or liposomal doxorubicin plus paclitaxel for metastatic disease. The LVEF at baseline, the lowest value during trastuzumab and the LVEF after completion of therapy are reported in Table 2.

Table 2.

Symptomatic and asymptomatic cardiac events distributed by stage of disease per patient

Cardiotoxicity Disease stage No. of risk factors Baseline LVEF (%) Time to onset (weeks) Lowest LVEF value Time to recovery (weeks) Trastuzumab discontinuation LVEF after completion of therapy 
Symptomatic IV 63.8 72 NA No recovery Yes NA 
56.0 NA Yes NA 
70.0 33.0 Yes 68.0 
50.8 40.8 21 Yes 55.3 
Asymptomatic I–III 57.0 46.6 52 Yes 46.6 
62.0 42 49.0 Yes 50.0 
62.0 49.0 18 Yes 69.0 
IV 69.0 48.0 Yes 60.0 
58.0 40.0 Yes 62.0 
63.0 132 47.0 Yes 60.8 
65.6 72 48.0 No 53.0 
71.8 39 48.6 No 58.6 
Cardiotoxicity Disease stage No. of risk factors Baseline LVEF (%) Time to onset (weeks) Lowest LVEF value Time to recovery (weeks) Trastuzumab discontinuation LVEF after completion of therapy 
Symptomatic IV 63.8 72 NA No recovery Yes NA 
56.0 NA Yes NA 
70.0 33.0 Yes 68.0 
50.8 40.8 21 Yes 55.3 
Asymptomatic I–III 57.0 46.6 52 Yes 46.6 
62.0 42 49.0 Yes 50.0 
62.0 49.0 18 Yes 69.0 
IV 69.0 48.0 Yes 60.0 
58.0 40.0 Yes 62.0 
63.0 132 47.0 Yes 60.8 
65.6 72 48.0 No 53.0 
71.8 39 48.6 No 58.6 

LVEF, left ventricular ejection fraction; NA, not available.

All eight patients with asymptomatic cardiac events recovered completely after trastuzumab discontinuation. The median time to onset of an asymptomatic cardiac event was 24 weeks (range 6–132 weeks), with a median time to recovery of 6 weeks (range 2–52 weeks). After complete recovery of cardiac function, trastuzumab was reintroduced in four patients; only one patient had a repeat asymptomatic LVEF drop that completely recovered without withdrawing the treatment.

The median time to onset of cardiac heart failure was 7 weeks (range 3–72 weeks). All the patients with symptomatic cardiotoxicity presented with rapidly progressing (≤10 days) dyspnea and orthopnea. In all the four cases, physical examination revealed crepitations over the lung bases, tachypnea, mild cyanosis, jugular venous distension and bilateral lower extremity edema. Electrocardiogram, 2D echo and chest X-rays were carried out in all the patients and confirmed the diagnosis of heart failure. Common causes of acute hearth failure, including coronary artery disease, hypertension, arrhythmias, myocarditis, and valvulopathy, were ruled out. Oxygen supplementation and depletive treatment was established in all cases. Vasoactive drugs were required in only one patient that developed acute pulmonary edema. According to NYHA criteria, one patient experienced CHF class III and three patients experienced CHF class IV. Among the four patients who developed CHF, only one did not recover cardiac function despite standard cardiac therapy and discontinuation of trastuzumab. The other three patients recovered in a median time of 5 weeks (range 3–21 weeks). One patient was retreated with trastuzumab without experiencing new cardiac events.

When patients who experienced cardiac toxicity were compared with those without, no difference was found in terms of trastuzumab treatment duration, LVEF values at baseline, history of anthracycline exposure and previous left-sided radiotherapy. The distribution of CRF in the whole study population and in the patients who experienced any cardiac event is reported on Table 3. Patients experiencing asymptomatic LVEF decline or CHF during treatment with trastuzumab presented more often with CRF, as compared with patients without cardiac events. In the univariate analysis, in which the 45 patients were included, the development of trastuzumab-related cardiac toxicity was significantly associated with overweight (BMI >30) (P = 0.045), history of a previous cardiac event (P = 0.047), and diabetes mellitus (P = 0.017). After all analyzed clinical variables were controlled for confounding and effect-modification variables, elderly HER-2-overexpressing breast cancer patients were still significantly more likely to develop asymptomatic or symptomatic cardiac events during treatment with trastuzumab if presenting with diabetes (P = 0.010) and a history of previous cardiac disease (P = 0.017).

Table 3.

Univariate and multivariate analysis of cardiac Risk factors

Risk factor All patients (N = 45), n (%) Patients with cardiotoxicity (n = 12), n (%) Patients without cardiotoxicity (n = 33), n (%) P value, univariate P value, multivariate 
History of cardiac disease 7 (15.6) 4 (33) 3 (9.1) 0.047 0.017 
Obesity (BMI >30) 19 (42.2) 8 (66.6) 11 (33.3) 0.045 0.838 
Tobacco 1 (3.3) 1 (3.3) 0.542 0.785 
Hypertension 25 (55.5) 7 (58.3) 18 (54.5) 0.821 0.135 
Diabetes mellitus 6 (13.3) 4 (33.3) 2 (6.1) 0.017 0.010 
Dyslipidemia 13 (28.9) 5 (41.7) 8 (24.3) 0.254 0.761 
Anthracycline exposure      
    Prior 15 (33.3) 5 (41.7) 10 (30.3) 0.475  
    Concomitant 3 (6.7) 2 (16.7) 1 (3.3) 0.105  
    Cumulative dose (mg/m2133 (0–540) 111 (0–360) 131 (0–540) 0.893  
Prior left-sided radiotherapy 17 (37.8) 5 (41.7) 12 (36.4) 0.977  
Duration of trastuzumab (weeks) 49 49 49 0.923  
LVEF at baseline (%) 64 63 64 0.923  
Risk factor All patients (N = 45), n (%) Patients with cardiotoxicity (n = 12), n (%) Patients without cardiotoxicity (n = 33), n (%) P value, univariate P value, multivariate 
History of cardiac disease 7 (15.6) 4 (33) 3 (9.1) 0.047 0.017 
Obesity (BMI >30) 19 (42.2) 8 (66.6) 11 (33.3) 0.045 0.838 
Tobacco 1 (3.3) 1 (3.3) 0.542 0.785 
Hypertension 25 (55.5) 7 (58.3) 18 (54.5) 0.821 0.135 
Diabetes mellitus 6 (13.3) 4 (33.3) 2 (6.1) 0.017 0.010 
Dyslipidemia 13 (28.9) 5 (41.7) 8 (24.3) 0.254 0.761 
Anthracycline exposure      
    Prior 15 (33.3) 5 (41.7) 10 (30.3) 0.475  
    Concomitant 3 (6.7) 2 (16.7) 1 (3.3) 0.105  
    Cumulative dose (mg/m2133 (0–540) 111 (0–360) 131 (0–540) 0.893  
Prior left-sided radiotherapy 17 (37.8) 5 (41.7) 12 (36.4) 0.977  
Duration of trastuzumab (weeks) 49 49 49 0.923  
LVEF at baseline (%) 64 63 64 0.923  

BMI, body mass index; LVEF, left ventricular ejection fraction.

discussion

Trastuzumab is a current standard of care in HER-2-positive breast cancer patients [26, 27]. Although well tolerated, concerns about cardiotoxicity have recently led to a push to identify patients at risk of developing treatment-related cardiac events. Until now, few risk factors [5, 17–19] have been identified among patients enrolled in clinical trials, who are generally <70 years and in optimal general health.

The incidence of cancer increases greatly with age and ∼70% of all newly diagnosed cancers are in patients >65 years [28]. Given the expected increase in the absolute number of elderly cancer patients over the coming decades, information about efficacy and safety of anticancer treatments is needed in this population as to date they have been frequently excluded from pivotal studies [20, 29]. We designed this study with the aim of assessing the cardiac safety profile and potential cardiac risk factors associated with trastuzumab in breast cancer patients >70 years.

We observed an overall incidence of cardiac events of 26.7%, with 8.9% of the events being symptomatic. Of note, most cases (91.7%) were reversible. The rate of cardiac events appears to be slightly higher than that reported in the trastuzumab pivotal trials [5, 6]. Indeed, the reported overall and symptomatic cardiotoxicity were 21.8% and 10.7%, respectively, in the H0648g study [5] and 18.6% and 17%, respectively, in the M77001 study [6]. This discordance is ascribed in part to the characteristics of the patient populations—specifically age and comorbidities—and in part to the longer median follow-up and the use of continuous trastuzumab treatment after breast cancer progression. Indeed, our findings are more consistent with those from the retrospective analysis from the MD Anderson Cancer Center than those from the pivotal study. Guarneri et al. [14] reported a cardiac event rate of 28.3% in 173 patients with metastatic breast cancer with a median age of 50 years over a median of 21 months of trastuzumab administration. Similarly, an Italian multicenter retrospective study in 55 metastatic breast cancer patients with a median age of 73.8 years reported three symptomatic drops in LVEF and four symptomatic cardiac events described as hypertensive crisis in two patients and thoracic oppression and atrial fibrillation in one patient each. Also consistent with previously reported data [15, 21, 24, 30], all but one patient in our series completely recovered cardiac function.

It is worth noting that trastuzumab was prescribed in two patients with LVEF values ≤50%. One of these patients presented with a life-threatening metastatic disease, the other with a high-risk operated early breast cancer. Both patients had no CRF. Neither symptomatic heart failure nor LVEF decline was reported. However, the use of trastuzumab remains controversial in patients with LVEF ≤50%, a careful evaluation of the balance between risk and benefit of treatment in these cases is mandatory, and a close monitoring of selected cases is advised [31–33].

To our knowledge, this report is the first to address in a detailed and comprehensive manner the value of CRF and trastuzumab-related cardiac toxicity in an elderly breast cancer population. Previous studies have focused on baseline and post-anthracycline/cyclophosphamide LVEF [14,17–19], prior or concomitant use of antihypertensive medication [19], and high BMI (>25) [18] separately.

We demonstrated a significantly increased incidence of cardiac events among patients with a history of cardiac disease and diabetes according to the definitions of the Framingham Study [34, 35]. Other well-known cardiac event-related factors, such as hypertension and a smoking history, were not demonstrated to increase trastuzumab-related cardiotoxicity in this study. However, it is important to be cautious when interpreting our data given the small sample size and the very limited power to detect small differences in multivariate analysis. Of note, the risk factors associated with the cardiotoxicity of trastuzumab are similar to those of anthracyclines, polichemotherapy and irradiation [36, 37].

Data obtained in this report can serve to advise clinicians to be aware of symptomatic and asymptomatic cardiac dysfunction in elderly patients, especially in those with one or more CRF. We describe a trastuzumab safety profile among elderly breast cancer patients that is similar to that already reported in light of the greater number of cases of asymptomatic LVEF decline compared with CHF [12], the high proportion of reversibility, the relative safety on re-treatment [14, 30] and the lack of association between trastuzumab dose [14] and left-sided radiotherapy [38] and cardiotoxicity. Nevertheless, the fact that the mortality rate at 5 years after diagnosis of CHF is ∼50% in patients >65 years [39] warrants close surveillance of early symptoms and cardiac function in the elderly breast cancer population to be treated with trastuzumab. Likewise, it is reasonable to refer elderly breast cancer patients to the cardiologist if one or more CRF are present before or during treatment with trastuzumab, to prompt a multidisciplinary approach to patient care [31].

Upcoming cardiac safety data in elderly patients receiving trastuzumab-based therapy within prospective clinical trials are awaited with great expectation. Similarly, the assessment of troponin I levels might be useful to establish the diagnosis and prognosis of trastuzumab-related cardiotoxicity [40, 41]. Meanwhile, despite the limited number of patients of our series, this report may contribute to characterize those elderly women with breast cancer who are most likely to develop cardiac toxicity during treatment with trastuzumab.

disclosure

The authors declare no conflict of interest.

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