Trastuzumab-related Cardiotoxicity in the Elderly
Trastuzumab is a current standard of care in HER-2-positive breast cancer patients. 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 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. 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. 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. Indeed, the reported overall and symptomatic cardiotoxicity were 21.8% and 10.7%, respectively, in the H0648g study and 18.6% and 17%, respectively, in the M77001 study. 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. 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, 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.
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, prior or concomitant use of antihypertensive medication [19], and high BMI (>25) 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. 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.
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, the high proportion of reversibility, the relative safety on re-treatment and the lack of association between trastuzumab dose 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 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.
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. 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.
Discussion
Trastuzumab is a current standard of care in HER-2-positive breast cancer patients. 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 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. 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. 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. Indeed, the reported overall and symptomatic cardiotoxicity were 21.8% and 10.7%, respectively, in the H0648g study and 18.6% and 17%, respectively, in the M77001 study. 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. 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, 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.
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, prior or concomitant use of antihypertensive medication [19], and high BMI (>25) 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. 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.
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, the high proportion of reversibility, the relative safety on re-treatment and the lack of association between trastuzumab dose 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 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.
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. 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.
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