Date of Award

January 2015

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Raymond Russell

Subject Area(s)

Medicine

Abstract

A major limitation of some of the most effective breast cancer (BC) therapies is the development of heart failure or left ventricular dysfunction. However, knowledge of the risk factors for development of cardiotoxicity from use of current standard BC therapies is incomplete. This study aimed to determine the incidence and predictors of cardiotoxicity associated with anthracycline and trastuzumab treatment.

We retrospectively identified patients in the Yale Nuclear Cardiology database who were diagnosed with BC between 2003 and 2013. The patients were grouped into cohorts based on whether they had received an anthracycline or trastuzumab as a part of their treatment regimen. As some patients had received both of these agents, the cohorts were not mutually exclusive. The independent variables of interest were baseline patient characteristics and comorbidities, baseline cardiac imaging parameters, and treatment factors (radiotherapy, cumulative anthracycline dose, and treatment with other agents). The endpoint was development of cardiotoxicity, as defined by a new diagnosis of congestive heart failure (CHF), admission for an acute CHF exacerbation, or a significant pre-defined decline in left ventricular ejection fraction.

We identified 571 women with BC. In the anthracycline cohort, patients were 50.84 years old on average (SD: 9.65, n = 496). The 3-year cumulative incidences of cardiotoxicity in the anthracycline and trastuzumab cohorts were 12.70 and 42.54 cardiac events per 100 people, respectively. The results of a multivariate Cox proportional-hazards regression analysis suggested that receipt of bevacizumab or trastuzumab independently increased the risk of cardiotoxicity in patients treated with an anthracycline (HR: 4.70, 95% CI for HR: 1.78-12.44, p-value: 0.002 or HR: 10.51, 95% CI for HR: 5.83-18.93, p-value: < 0.001, respectively). In the trastuzumab cohort, the mean age was 52.01 (SD: 10.66, n = 134). In a similar multivariate analysis, anthracycline was not shown to increase the incidence of cardiotoxicity in patients who received trastuzumab, regardless of the cumulative anthracycline dose level (≤ 240 mg/m2 or > 240 mg/m2). However, dyslipidemia was a significant risk factor (HR: 3.66, 95% CI for HR: 1.80-7.42, p-value: < 0.001). Interestingly, use of radiotherapy was associated with a lower incidence of developing cardiotoxicity in the anthracycline and trastuzumab cohorts, irrespective of the laterality of radiotherapy. A positive smoking history was related to a shorter time to cardiotoxicity for both the anthracycline and trastuzumab cohorts (HR: 2.82, 95% CI for HR: 1.39-5.71, p-value: 0.0039 and HR: 3.01, 95% CI for HR: 1.42-6.39, p-value: 0.0040, respectively). In the anthracycline cohort, an abnormal baseline left ventricular end-diastolic volume and an abnormal baseline peak filling rate were not significantly associated with cardiotoxicity.

In conclusion, trastuzumab and bevacizumab significantly increase risk of cardiotoxicity in patients who receive an anthracycline. Smoking and dyslipidemia are potential targets for risk reduction. The lack of a significant cardiotoxic effect associated with radiotherapy suggests that previously accepted beliefs regarding radiotherapy's harmful cardiac effects when used for BC treatment may be outdated, although further analysis in larger groups and accounting for additional confounding variables is necessary. Future studies are necessary to re-evaluate modern radiotherapy's cardiac effects.

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