Nomogram for Predicting Risk of Cancer Therapy-Related Cardiac Dysfunction in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Abstract

Background: Cancer therapy-related cardiac dysfunction (CTRCD) is an important treatment-limiting toxicity for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that adversely affects cancer and cardiovascular outcomes. Easy-to-use tools that incorporate readily accessible clinical variables for individual estimation of CTRCD risk are needed.

Methods and results: From 2004 to 2013, 1440 patients with stage I to III HER2-positive breast cancer treated with trastuzumab-based therapy were identified. A multivariable Cox proportional hazards model was constructed to identify risk factors for CTRCD and included the 1377 patients in whom data were complete. Nine clinical variables, including age, race, body mass index, left ventricular ejection fraction, systolic blood pressure, coronary artery disease, diabetes, arrhythmia, and anthracycline exposure were built into a nomogram estimating risk of CTRCD at 1 year. The nomogram was validated for calibration and discrimination using bootstrap resampling. A total of 177 CTRCD events occurred within 1 year of HER2-targeted treatment. The nomogram for prediction of 1-year CTRCD probability demonstrated good discrimination, with a concordance index of 0.687. The predicted and observed probabilities of CTRCD were similar, demonstrating good model calibration.

Conclusions: A nomogram composed of 9 readily accessible clinical variables provides an individualized 1-year risk estimate of CTRCD among women with HER2-positive breast cancer receiving HER2-targeted therapy. This nomogram represents a simple-to-use tool for clinicians and patients that can inform clinical decision-making on breast cancer treatment options, optimal frequency of cardiac surveillance, and role of cardioprotective strategies.

Keywords: breast cancer; cardiotoxicity; cardio‐oncology.

Figure 1. Nomogram of risk model for predicting 1‐year probabilities of cancer therapy–related cardiac dysfunction (CTRCD) after human epidermal growth factor receptor 2–targeted therapy.

To estimate risk of CTRCD, an individual patient's baseline characteristics are plotted on each variable axis, and a vertical line is drawn to the points’ axis to determine the points for that variable. The points for all 9 variables are added, the sum is located on the “Total Points” axis, and a vertical line is drawn to the bottom axis to obtain the 1‐year probability of CTRCD. The total score can be calculated as follows: {1.4×[age−20]}+{19×[body mass index (BMI)≥30 kg/m²]}+{44×I[Black]}+{73×I[current/prior anthracyclines]}+{30×I[baseline systolic blood pressure (SBP) ≥130 mm Hg]}+{44×I[baseline left ventricular ejection fraction (LVEF) <60%]}+{63×I[coronary artery disease (CAD)]}+{80×I[arrhythmia]}+{13×I[diabetes]}, where I[] denotes the indicator function equal to 1 if the condition within the brackets is present, and 0 otherwise.

Figure 2. Calibration plot of 1‐year cancer therapy–related cardiac dysfunction (CTRCD) nomogram.

The x axis displays the nomogram‐predicted probability of 1‐year CTRCD‐free survival. Patients were grouped by quartiles of predicted risk (first quartile, <103 points; second quartile, 103–129 points; third quartile, 130–156 points; and fourth quartile, >156 points). The y axis represents the observed 1‐year probability of CTRCD‐free survival, as estimated by Kaplan‐Meier method. Gray line indicates ideal agreement between observed and predicted probabilities of 1‐year CTRCD. Black line denotes actual prediction from the nomogram. Dots denote apparent predictive accuracy, which was calculated by plotting the mean Kaplan‐Meier estimate for each quartile vs the mean nomogram‐predicted probabilities for patients in each quartile. X denotes the bootstrap‐corrected estimates. Vertical bars indicate 95% CI.

Figure 3. Receiver operating characteristic (ROC) curve for 1‐year cancer therapy–related cardiac dysfunction of the nomogram.

AUC indicates area under ROC curve.

Figure 4. Decision curve of the nomogram for 1‐year cancer therapy–related cardiac dysfunction (CTRCD).

Net benefit curves show the clinical usefulness of intervention guided by the CTRCD risk nomogram (blue line) relative to a strategy of intervention for all patients regardless of risk (red line) or intervention for no patients irrespective of risk (green line). The net benefit (y axis) is plotted as a function of threshold probability (x axis), defined as the probability of disease that would prompt intervention. The 1‐year CTRCD risk nomogram has positive net benefit for threshold probabilities of 5% to 30%.