Early Increases in GDF-15 Are Associated With Declines in Cardiac Function With Breast Cancer Therapy

BACKGROUND: Growth differentiation factor (GDF)-15 is a stress-responsive cytokine induced by mitochondrial dysfunction and genotoxic stress, mechanisms central to anthracycline cardiotoxicity. Whether early changes in GDF-15 following cancer therapy relate to subsequent cardiac dysfunction is not established. OBJECTIVES: We evaluated the longitudinal trajectory of GDF-15 and its associations with changes in cardiac function and structure following cardiotoxic cancer therapy in women with breast cancer. METHODS: In 366 women receiving anthracyclines and/or trastuzumab from the Penn Cardiotoxicity of Cancer Therapy prospective cohort study, associations between baseline, early-peak (maximum 0-6-month change), and longitudinal GDF-15 concentrations with quantitative echocardiographic measures of systolic, diastolic, and structural function over 36 months were evaluated using multivariable linear mixed-effects models. RESULTS: GDF-15 rose from a median baseline of 662 to an early-peak of 1,412 pg/mL, with trajectories differing across regimens (P = 0.004). Each doubling of the early-peak-to-baseline GDF-15 ratio was associated with a subsequent 1.5 percentage point decline in left ventricular ejection fraction (β -1.5%; 95% CI: -2.5 to -0.6; P = 0.002) and a 0.9-unit worsening in longitudinal strain (β 0.9; 95% CI: 0.4-1.4; P = 0.001). GDF-15 was not associated with diastolic outcomes, incident diastolic dysfunction, or incident cancer therapy-related cardiac dysfunction. CONCLUSIONS: In women receiving anthracycline- and/or trastuzumab-based breast cancer therapy, early increases in GDF-15 were associated with modest declines in left ventricular ejection fraction and worsening of longitudinal strain, without associations with diastolic measures. These findings support mechanistic investigation of GDF-15 in anthracycline-related cardiotoxicity. (Cardiotoxicity of Cancer Therapy [CCT]; NCT01173341).