Trastuzumab-related Cardiotoxicity in the Elderly
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.
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. HER-2 protein is overexpressed in up to 20% of breast cancers and is associated with poor prognosis and response to treatment.
Trastuzumab (Herceptin®; F.Hoffmann-La Roche Ltd., Basel, Switzerland) is a humanized mAb directed against the extracellular domain of the HER-2 receptor. 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. 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. 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. 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.
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%). 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. 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. 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 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.
Abstract and Introduction
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. HER-2 protein is overexpressed in up to 20% of breast cancers and is associated with poor prognosis and response to treatment.
Trastuzumab (Herceptin®; F.Hoffmann-La Roche Ltd., Basel, Switzerland) is a humanized mAb directed against the extracellular domain of the HER-2 receptor. 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. 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. 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. 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.
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%). 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. 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. 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 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.