Body Surface Area and Baseline Blood Pressure Predict Subclinical Anthracycline Cardiotoxicity in Women Treated for Early Breast Cancer

Background and Aims: Anthracyclines are highly effective chemotherapeutic agents which may cause long-term cardiac damage (chronic anthracycline cardiotoxicity) and heart failure. The pathogenesis of anthracycline cardiotoxicity remains incompletely understood and individual susceptibility difficult to predict. We sought clinical features which might contribute to improved risk assessment. / Methods: Subjects were women with early breast cancer, free of pre-existing cardiac disease. Left ventricular ejection fraction was measured using cardiovascular magnetic resonance before and >12 months after anthracycline-based chemotherapy (>3 months post-Trastuzumab). Variables associated with subclinical cardiotoxicity (defined as a fall in left ventricular ejection fraction of ≥5%) were identified by logistic regression. / Results: One hundred and sixty-five women (mean age 48.3 years at enrollment) completed the study 21.7 months [IQR 18.0-26.8] after starting chemotherapy. All received anthracyclines (98.8% epirubicin, cumulative dose 400 [300-450] mg/m2); 18% Trastuzumab. Baseline blood pressure was elevated (≥140/90mmHg, mean 147.3/86.1mmHg) in 18 subjects. Thirty-four subjects (20.7%) were identified with subclinical cardiotoxicity, independent predictors of which were the number of anthracycline cycles (odds ratio, OR 1.64 [1.17-2.30] per cycle), blood pressure ≥140/90mmHg (OR 5.36 [1.73-17.61]), body surface area (OR 2.08 [1.36-3.20] per standard deviation (0.16m2) increase), and Trastuzumab therapy (OR 3.35 [1.18-9.51]). The resultant predictive-model had an area under the receiver operating characteristics curve of 0.78 [0.70-0.86]. / Conclusions: We found subclinical cardiotoxicity to be common even within this low risk cohort. Risk of cardiotoxicity was associated with modestly elevated baseline blood pressure – indicating that close attention should be paid to blood pressure in patients considered for anthracycline based chemotherapy. The association with higher body surface area suggests that indexing of anthracycline doses to surface area may not be appropriate for all, and points to the need for additional research in this area

Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast cancer.

BACKGROUND AND AIMS: Anthracyclines are highly effective chemotherapeutic agents which may cause long-term cardiac damage (chronic anthracycline cardiotoxicity) and heart failure. The pathogenesis of anthracycline cardiotoxicity remains incompletely understood and individual susceptibility difficult to predict. We sought clinical features which might contribute to improved risk assessment. METHODS: Subjects were women with early breast cancer, free of pre-existing cardiac disease. Left ventricular ejection fraction was measured using cardiovascular magnetic resonance before and >12 months after anthracycline-based chemotherapy (>3 months post-Trastuzumab). Variables associated with subclinical cardiotoxicity (defined as a fall in left ventricular ejection fraction of ≥5%) were identified by logistic regression. RESULTS: One hundred and sixty-five women (mean age 48.3 years at enrollment) completed the study 21.7 months [IQR 18.0-26.8] after starting chemotherapy. All received anthracyclines (98.8% epirubicin, cumulative dose 400 [300-450] mg/m2); 18% Trastuzumab. Baseline blood pressure was elevated (≥140/90mmHg, mean 147.3/86.1mmHg) in 18 subjects. Thirty-four subjects (20.7%) were identified with subclinical cardiotoxicity, independent predictors of which were the number of anthracycline cycles (odds ratio, OR 1.64 [1.17-2.30] per cycle), blood pressure ≥140/90mmHg (OR 5.36 [1.73-17.61]), body surface area (OR 2.08 [1.36-3.20] per standard deviation (0.16m2) increase), and Trastuzumab therapy (OR 3.35 [1.18-9.51]). The resultant predictive-model had an area under the receiver operating characteristics curve of 0.78 [0.70-0.86]. CONCLUSIONS: We found subclinical cardiotoxicity to be common even within this low risk cohort. Risk of cardiotoxicity was associated with modestly elevated baseline blood pressure-indicating that close attention should be paid to blood pressure in patients considered for anthracycline based chemotherapy. The association with higher body surface area suggests that indexing of anthracycline doses to surface area may not be appropriate for all, and points to the need for additional research in this area

The Breast Cancer, Early Disease: Toxicity from Therapy with Epirubicin Regimens – Cardiac Assessment and Risk Evaluation (BETTER-CARE) Study: Design, Set-up and Analysis of a Prospective Multicentre Collaboration to Investigate the Pharmacogenetics of Anthracycline Cardiotoxicity, using Cardiovascular Magnetic Resonance Imaging.

Anthracyclines are highly effective chemotherapy drugs. However, their use is associated with anthracycline cardiotoxicity (AC), which may result in premature heart failure. Risk of AC is related to cumulative dose, but is also highly idiosyncratic. Effective tests to predict susceptibility are lacking: serial measurement of left ventricular ejection fraction (LVEF) detects cardiotoxicity only after significant damage has occurred. I hypothesised that: (i) Genetic variation underlies susceptibility to cAC. (ii) Risk of cAC could be predicted after the 1st dose of anthracycline by measuring oxidative stress (urinary F2-Isoprostanes, uF2IP), and (iii) also by cardiovascular magnetic resonance imaging (CMR) tissue characterisation (EGRE and STIR). I tested these hypotheses in a prospective gene-environment interaction study, whereby 164 women underwent measurement of LVEF, before and >12 months after anthracyclinechemotherapy. Sixty subjects participated in the 1st dose sub-studies. The mean change in LVEF at follow-up (ĢLVEF) was -2.2%. Thirty-four subjects (20.7%) experienced a fall in LVEF .5% (the cAC group). LVEF fell by 0.8% in the remaining 130 (minimally affected controls). An a priori tiered genetic analysis was performed. High probability variants (Tier 1) were identified (i) by cross referencing human GWAS and gene-expression / proteomic data from animal models of AC (N=12) (ii) from associations with AC reported by others (N=4). Significant associations were discovered with CLCNKA rs10927887 (OR 4.7 [2.1-10.5]) and PDE4D rs1588265 (OR 3.3 [1.51-7.37]), p=0.003 and p=0.045 respectively (Bonferroni corrected). There were correlations between ĢLVEF and percentage change in uF2IP (r=0.30, p=0.04), EGRE (r=-0.35, p=0.01) and STIR (r=-0.29, p=0.03). My results support all 3 hypotheses, and suggest that it may be possible to develop tests to identify individuals at increased risk of cAC and premature heart failure before the majority of the damage is caused. Recognition of this susceptibility could inform treatment decisions and /or identify those requiring greater cardiac surveillance

BETTER-CARE_Paper1

This dataset supports the results of the BETTER-CARE study reported in Kotwinski et al, Body Surface Area and Baseline Blood Pressure Predict Subclinical Anthracycline Cardiotoxicity in Women Treated for Early Breast Cancer. PLOS One. 201