Cardiovascular toxicities with pediatric tyrosine kinase inhibitor therapy: An analysis of adverse events reported to the Food and Drug Administration.

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

BRCA1/2 Mutations and Cardiovascular Function in Breast Cancer Survivors.

OBJECTIVE: Animal models suggest that BRCA1/2 mutations increase doxorubicin-induced cardiotoxicity risk but data in humans are limited. We aimed to determine whether germline BRCA1/2 mutations are associated with cardiac dysfunction in breast cancer survivors. METHODS: In a single-center cross-sectional study, stage I-III breast cancer survivors were enrolled according to three groups: (1) BRCA1/2 mutation carriers treated with doxorubicin; (2) BRCA1/2 mutation non-carriers treated with doxorubicin; and (3) BRCA1/2 mutation carriers treated with non-doxorubicin cancer therapy. In age-adjusted analysis, core-lab quantitated measures of echocardiography-derived cardiac function and cardiopulmonary exercise testing (CPET) were compared across the groups. A complementary in vitro study was performed to assess the impact of BRCA1 loss of function on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) survival following doxorubicin exposure. RESULTS: Sixty-seven women with mean (standard deviation) age of 50 (11) years were included. Age-adjusted left ventricular ejection fraction (LVEF) was lower in participants receiving doxorubicin regardless of BRCA1/2 mutation status (p = 0.03). In doxorubicin-treated BRCA1/2 mutation carriers and non-carriers, LVEF was lower by 5.4% (95% CI; -9.3, -1.5) and 4.8% (95% CI; -9.1, -0.5), respectively compared to carriers without doxorubicin exposure. No significant differences in VO2max were observed across the three groups (poverall = 0.07). Doxorubicin caused a dose-dependent reduction in viability of iPSC-CMs in vitro without differences between BRCA1 mutant and wild type controls (p > 0.05). CONCLUSIONS: BRCA1/2 mutation status was not associated with differences in measures of cardiovascular function or fitness. Our findings do not support a role for increased cardiotoxicity risk with BRCA1/2 mutations in women with breast cancer.

Changes in Cardiovascular Biomarkers With Breast Cancer Therapy and Associations With Cardiac Dysfunction.

Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort of 323 patients treated with anthracyclines and/or trastuzumab followed over a maximum of 3.7 years with serial echocardiograms. CTRCD was defined as a ≥10% decline in left ventricular ejection fraction to a value <50%. Associations between changes in biomarkers and left ventricular ejection fraction were evaluated in repeated-measures linear regression models. Cox regression models assessed the associations between biomarkers and CTRCD. Early increases in all biomarkers occurred with anthracycline-based regimens. hs-cTnT levels >14 ng/L at anthracycline completion were associated with a 2-fold increased CTRCD risk (hazard ratio, 2.01; 95% CI, 1.00-4.06). There was a modest association between changes in NT-proBNP and left ventricular ejection fraction in the overall cohort; this was most pronounced with sequential anthracycline and trastuzumab (1.1% left ventricular ejection fraction decline [95% CI, -1.8 to -0.4] with each NT-proBNP doubling). Increases in NT-proBNP were also associated with CTRCD (hazard ratio per doubling, 1.56; 95% CI, 1.32-1.84). Increases in myeloperoxidase were associated with CTRCD in patients who received sequential anthracycline and trastuzumab (hazard ratio per doubling, 1.28; 95% CI, 1.04-1.58). Conclusions Cardiovascular biomarkers may play an important role in CTRCD risk prediction in patients with breast cancer who receive cardiotoxic cancer therapy, particularly in those treated with sequential anthracycline and trastuzumab therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01173341.

Detailed phenotyping reveals distinct trajectories of cardiovascular function and symptoms with exposure to modern breast cancer therapy.

BACKGROUND: Breast cancer therapies are associated with a risk of cardiac dysfunction, most commonly defined by changes in left ventricular ejection fraction (LVEF). Recently, the authors identified 3 classes of LVEF change after exposure to anthracyclines and/or trastuzumab using latent class growth modeling. The objective of the current study was to characterize the clinical, biochemical, and functional profiles associated with LVEF trajectory class membership. METHODS: Transthoracic echocardiography and biomarker assessments were performed and questionnaires were administered at standardized intervals in a longitudinal cohort of 314 patients with breast cancer who were treated with anthracyclines and/or trastuzumab. Univariable and multivariable multinomial regression analyses evaluated associations between baseline variables and LVEF trajectory class membership. Generalized estimating equations were used to define mean changes in cardiovascular measures over time within each class. RESULTS: Among the 3 distinct subgroups of LVEF changes identified (stable [class 1]; modest, persistent decline [class 2]; and significant early decline followed by partial recovery [class 3]), higher baseline LVEF, radiotherapy, and sequential therapy with anthracyclines and/or trastuzumab were associated with class 2 or 3 membership. Sustained abnormalities in longitudinal strain and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were observed in patients in class 2, as were heart failure symptoms. Similar abnormalities were observed in patients in class 3, but there was a trend toward recovery, particularly for longitudinal strain. CONCLUSIONS: Patients with modest, persistent LVEF declines experienced sustained abnormalities in imaging and biochemical markers of cardiac function and heart failure symptoms. Further investigation is needed to characterize the long-term risk of heart failure, particularly in those with modest LVEF declines.

Early Changes in Cardiovascular Biomarkers with Contemporary Thoracic Radiation Therapy for Breast Cancer, Lung Cancer, and Lymphoma.

PURPOSE: We characterized the early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy (RT) and evaluated their associations with radiation dose-volume metrics including mean heart dose (MHD), V5, and V30. METHODS AND MATERIALS: In a prospective longitudinal study of 87 patients with breast cancer, lung cancer, or mediastinal lymphoma treated with photon or proton thoracic RT, blood samples were obtained pre-RT and after completion of RT (median, 20 days; interquartile range [IQR], 1-35). High-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, placental growth factor (PIGF), and growth differentiation factor 15 (GDF-15) were measured. Associations between MHD, V5 and V30, and biomarker levels and associations between echocardiography-derived measures of cardiac function and biomarker levels were assessed in multivariable linear regression models. Analyses were performed according to the following subgroups: (1) breast cancer alone and (2) lung cancer and lymphoma combined. RESULTS: The median (IQR) estimates of MHD ranged from 1.3 Gy (0.9-2.4) in breast cancer (n = 60) to 6.8 Gy (5.4-10.2) in mediastinal lymphoma (n = 14) and 8.4 Gy (6.7-16.1) in lung cancer (n = 13) patients (P < .001). There were no significant increases in biomarker levels from pre-RT to post-RT in breast cancer. In lung cancer/lymphoma, PIGF increased from a median (IQR) of 20 ng/L (16-26) to 22 ng/L (16-30) (P = .005), and GDF-15 increased from 1171 ng/L (755-2493) to 1887 ng/L (903-3763) (P = .006). MHD, V5, and V30 were significantly associated with post-RT PIGF and GDF-15 levels in multivariable models. Changes in biomarkers were not significantly associated with changes in echocardiography-derived measures of cardiac function. CONCLUSION: Contemporary thoracic RT induces acute abnormalities in vascular and inflammatory biomarkers that are associated with radiation dose-volume metrics, particularly in lung cancer and mediastinal lymphoma. Long-term follow-up studies are needed to determine the impact of these changes on the development of overt cardiac disease.