Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers

Mohan, Nishant; Jiang, Jiangsong; Dokmanovic, Milos; Wu, Wen Jin

doi:10.1093/abt/tby003

Cited by 103 publications

(98 citation statements)

References 35 publications

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“…In line with this, Zardavas et al reported an increased risk of trastuzumabrelated cardiotoxicity (TRIC) in patients with increased cTn levels after anthracycline treatment [32]. This could be explained by the increased myocardial susceptibility to damage when the combination of anthracyclines and trastuzumab is being used [45,46]. On another hand, Kitayama et al reported elevated absolute hs-cTn levels throughout the treatment in patients developing CTAC, while baseline hs-cTn levels did not seem to have a significant predictive value [35].…”

Section: Cardiac Troponins Predictors Of Ctacmentioning

confidence: 84%

Cardiac Biomarkers in Patients with Cancer: Considerations, Clinical Implications, and Future Avenues

et al. 2020

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Purpose of the Review As the number of cancer survivors increases due to early screening and modern (antineoplastic) treatments, cancer treatment associated cardiotoxicity (CTAC) is becoming an increasing health burden that affects survival and quality of life among cancer survivors. Thus, clinicians need to identify adverse events early, in an effort to take suitable measures before the occurrence of permanent or irreversible cardiac dysfunction. Recent Findings Cardiac troponin (cTn) and B-type natriuretic peptide (BNP) have been proven to detect subclinical cardiotoxicity during antineoplastic treatment. As such, these cardio-specific biomarkers could predict which patients are at risk of developing CTAC even before the start of therapy. Nevertheless, there are inconsistent data from published studies, and the recommendations regarding the use of these biomarkers and their validity are mostly based on expert consensus opinion. Summary In this review, we summarize available literature that evaluates biomarkers of CTAC, and we encourage strategies that integrate circulating biomarkers and cardiac imaging in identifying cancer patients that are at high risk.

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Section: Cardiac Troponins Predictors Of Ctacmentioning

confidence: 84%

Cardiac Biomarkers in Patients with Cancer: Considerations, Clinical Implications, and Future Avenues

et al. 2020

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“…The incidence of New York Heart Association class III and IV cardiac dysfunction was also notably higher in patients who received trastuzumab with anthracycline and cyclophosphamide (16%) compared with those who received anthracycline and cyclophosphamide (3%), trastuzumab and paclitaxel (2%), or paclitaxel alone (1%) . Following the identification of trastuzumab‐associated cardiac events, subsequent trials of trastuzumab adopted stringent criteria for patient enrollment (excluding those at increased risk for cardiac adverse events), avoided concurrent use of trastuzumab with anthracyclines, implemented rigorous protocols for monitoring of cardiac function, and recommended discontinuation of trastuzumab upon detection of cardiac symptoms . In a retrospective analysis of women treated with HER2‐targeted therapy for metastatic breast cancer, most cases of symptomatic heart failure recovered with trastuzumab discontinuation and cardiac therapy .…”

Section: Resultsmentioning

confidence: 99%

“…One such compound that has improved breast cancer care is the human epidermal growth factor receptor 2 (HER2)‐targeted agent trastuzumab. Although trastuzumab can have cardiac‐associated side effects, effective monitoring and management have contributed to the success of this agent, highlighting the importance of cardiac monitoring in the successful treatment of patients with breast cancer .…”

Section: Introductionmentioning

confidence: 99%

“…The use of stringent and appropriate monitoring helps maximize treatment benefit and supports the health and well‐being of the patient. The inclusion of cardiac monitoring in these routine assessments can enable early detection of possible CVD risks and subsequent implementation of management strategies to improve quality of life and treatment outcomes . Depending on the severity of the comorbidity, survival of patients with early breast cancer and comorbid conditions can be similar to that of patients with higher disease stages, suggesting that monitoring of comorbidities could result in longer overall breast cancer survival .…”

Section: Introductionmentioning

confidence: 99%

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Prevention, Monitoring, and Management of Cardiac Dysfunction in Patients with Metastatic Breast Cancer

et al. 2019

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Cardiac monitoring is becoming an important part of breast cancer care. Breast cancer and cardiovascular disease (CVD) share many common risk factors, and it is estimated that by the median age of diagnosis, many patients with breast cancer will have established or subclinical CVD. In addition, a number of treatments for metastatic breast cancer are known to have cardiac effects. As such, there is a clear need to prevent, identify, and effectively manage cardiovascular events in patients with breast cancer. Current clinical practice for patients with metastatic breast cancer involves a comprehensive set of assessments to ensure efficacy and safety of treatment. Adding cardiac monitoring to the assessments already required for patients with breast cancer may improve survival and quality of life. Currently, cardiac monitoring is recommended for several breast cancer treatments, and guidelines related to cardiac monitoring are available. Here, we review the risk of CVD in patients with breast cancer, providing an overview of the cardiac events associated with standard therapies for metastatic breast cancer. We also assess the current clinical recommendations relating to cardiac monitoring, and practical management strategies for oncologists. Cardio‐oncology is a growing medical subspecialty that promotes the need for effective cancer therapy while minimizing cardiac effects. Integrating cardiac monitoring into routine clinical practice may safeguard patients with metastatic breast cancer against adverse cardiac effects. Implications for Practice This review details the common risk factors associated with cardiovascular disease that are frequently observed in patients with metastatic breast cancer, as well as the adverse cardiac effects of many therapies that are commonly prescribed. The review also provides a rationale for routine and comprehensive cardiovascular assessment of all patients at baseline, and during and after therapy depending on the treatment and presence of risk factors for cardiovascular disease. The medical discipline of cardio‐oncology is increasingly being recognized as an important part of clinical practice to ensure effective cancer therapy while maintaining cardiac health.

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“…A key side effect of trastuzumab is cardiotoxicity. 93 Throughout trastuzumab treatment, individuals in the PERSEPHONE trial were monitored for signs of cardiotoxicity based on their LVEF. Data on cause of death, including death as a result of chronic heart failure, were collected on a specific CRF that was filled in when required.…”

Section: Cardiac Toxicitymentioning

confidence: 99%

Six versus 12 months’ adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT

Earl

Hiller

Vallier

et al. 2020

Health Technol Assess

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Background The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives To establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. Design This was a Phase III randomised controlled non-inferiority trial. Setting The setting was 152 NHS hospitals. Participants A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. Intervention Randomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment. Main outcomes The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. Results Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months’ trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months’ trastuzumab, and thus there is a high probability that 6 months’ trastuzumab is cost-effective compared with 12 months’ trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. Limitations The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. Conclusions PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months’ adjuvant trastuzumab is non-inferior to 12 months’. Six months’ treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. Future work Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. Trial registration Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

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Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers

Cited by 103 publications

References 35 publications

Cardiac Biomarkers in Patients with Cancer: Considerations, Clinical Implications, and Future Avenues

Cardiac Biomarkers in Patients with Cancer: Considerations, Clinical Implications, and Future Avenues

Prevention, Monitoring, and Management of Cardiac Dysfunction in Patients with Metastatic Breast Cancer

Six versus 12 months’ adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT

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