Herrmann, Joerg

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation. Methods Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival. Results The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7 months (interquartile range, 0.4‐7.6 months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune‐related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI‐induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6 months and 12 months. Eleven patients (65%) died over the median follow‐up period of 4.6 months (interquartile range, 1.5‐13.2 months) from the time of ICI initiation, with cancer progression being the most common cause of death. Conclusions ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further.

Abstract This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

e24103 Background: Many of the 200,000 patients diagnosed with breast cancer (BC) annually in the United States receive anthracycline-based therapy, increasing their risk of future congestive heart failure. N-terminal brain natriuretic peptide (NT-proBNP) has been used as a biomarker of asymptomatic cardiac dysfunction in the general population and is of interest to identify patients who might benefit from echocardiography during survivorship. This study aimed to assess how age, baseline comorbidities, and time since BC diagnosis impact NT-proBNP levels after anthracycline-based chemotherapy. Methods: This retrospective study, using samples collected in our ongoing prospective Mayo Clinic Breast Disease Registry, included 20 survivors of non-metastatic BC patients per year for each of the first 5 years after anthracycline-based chemotherapy (n=100 total). NT-pro-BNP levels were assessed using a Roche immunoassay. Cardiac risk factors were obtained by chart review. Multivariable linear regression models assessed associations between NT-proBNP values and these independent variables: baseline cardiac risk factors (including hypertension, hyperlipidemia, obesity, diabetes mellitus, and smoking), tumor ER status (surrogate for possible endocrine therapy), time between diagnosis and serum collection, T and N status, use of trastuzumab, and age. Results: The mean age at the time of BC diagnosis was 52.2 (SD 9.8). 13% of tumors were human epidermal growth factor receptor (HER2)-positive and 71% were estrogen receptor (ER) positive. NT-proBNP was elevated in 34%. Mean NT-BNP level was higher (p=0.047) for those in years 4-5 (158 pg/mL) compared to those in years 1-3 (106 pg/mL) (See Table.) Models revealed years from diagnosis to serum draw (p=0.026), older age (p=0.006), more cardiac risk factors (p=0.064), and N2-3 (p=0.001) were associated with elevated NT-pro-BNP level. Use of trastuzumab, ER status, and tumor size were not associated with NT-proBNP. Conclusions: NT-proBNP is elevated in 1/3 of survivors who received anthracycline therapy for BC. As expected, cardiac risk factors and advancing age are associated with higher NT-proBNP. NT-proBNP values >300 were only found in patients who were 4-5 years after diagnosis. Additional research will be needed to further define the diagnostic and prognostic merit of NT-proBNP in survivors after receipt of anthracycline therapy. [Table: see text]

e17535 Background: Androgen Deprivation Therapy (ADT) is commonly used to treat prostate cancer (PC), but has been associated with cardiac morbidity and mortality. The exact mechanisms of this association are unclear. We sought to use an artificial intelligence (AI) enabled algorithm to identify ECG changes in PC patients who received ADT compared to PC patients who did not receive ADT. Methods: From 1,000,000 ECGs performed on 210,414 patients between 1993 and 2017 at our institution, a convolutional neural network was developed to detect predictive signatures for cardiac pathologies. During this process, the ability to predict “estimated sex” of the patient was developed, with output values ranging from 0 (female) to 1 (male). We applied this algorithm to 8,619 ECGs performed on 1,057 men age 75 or younger treated with radiation for high-risk or recurrent PC at our institution, and compared estimated sex after receiving ADT (n = 1,065) to ADT-naive ECGs (n = 7,554). We correlated ECG-identified estimated sex with serum testosterone levels using Spearman rank correlation. Results: Patients who had received ADT had a mean (SD) estimated sex value of 0.81 (0.26) compared to 0.92 (0.17) for those who did not (p < 0.001). Difference between estimated sex in post-ADT ECGs and ADT-naive ECGs remained significant across age groups (Table). Decreased serum total testosterone correlated with decreased estimated sex values in men receiving ADT (R = .57, p < 0.001). Conclusions: ADT for prostate cancer is associated with changes in AI-identified ECG parameters, including lower estimated male sex after receiving ADT. Lower ECG male sex estimate was associated with decreased serum testosterone. In this study, we provide preliminary proof of concept for a potential non-invasive means of monitoring treatment effect and physiologic change using ECGs. [Table: see text]

e14018 Background: Cancer survival rates are improving. Therefore, management of cardiovascular complications has now become a crucial clinical concern. Cardio-oncology is the sub-specialty that assists in the overall management of cancer patients in a multi-disciplinary manner. Mayo Clinic cardio-oncology practice was initiated to work closely with our oncology colleagues for early detection of cardiovascular complications in response to cancer-therapy. Majority of the patients visit our cardio-oncology clinic once, we thought it is important to study the group of patients that visited frequently due to cardiovascular complications. Aim: To evaluate the most common cardiovascular complication in patients with 2 or more visits to our cardio-oncology clinic. Methods: From 2012-2017, there were > 2500 patients visits to our clinic, with 24 patients having 2 or more visits. Data including patients’ demographics, ethnicity, chemotherapeutic medications, primary cancer type, cardiovascular risk factors, echocardiography and clinical outcomes were collected. Cardiotoxicity was defined as the decrease in left ventricular ejection fraction (LVEF) of > 10% to a value of < 53%. Heart failure was diagnosed based on Framingham’s criteria or by a cardiologist. Results: There were 19 women (80%) and 5 men (20%). Median age at the time of diagnosis was 56 years [19-76]. The most common malignancy was breast cancer (70%), followed by B-cell lymphoma (12%) and acute myeloid leukemia (8%). Thirty percent had > 2 risk factors for cardiovascular disease. 75% of the patients had an LVEF of < 53, of these 67% developed heart failure with 58% preserved and 42% reduced ejection fraction. Those with heart failure had received a mean anthracycline dose of 305 ± 91.8mg/m2. With initiation of ACEI, B-Blockers, and diuretics (GDMT) 79% showed recovery of LVEF to ≥53 during the follow up. Conclusions: In our experience, most patients who were seen at least twice in the cardio-oncology clinic for heart failure had received a dose of > 300mg/m2 anthracycline. With GDMT over 75% of the patients recovered. Care in the cardio-oncology clinic plays a key role in optimizing these clinical outcomes.

1044 Background: Trastuzumab is well-demonstrated to be associated with cardiotoxicity (typically reduced ejection fraction), most commonly in patients who also receive anthracycline. The vascular effects of trastuzumab and anthracycline are understudied; we aimed to compare change in endothelial function during and after trastuzumab and to assess how anthracycline receipt affects this. Methods: This is an observational prospective study of women with newly diagnosed HER2-positive breast cancer. All participants underwent baseline evaluation of endothelial function testing by use of the EndoPAT2000 device approximately every three months over the subsequent 18 months after the initiation of HER2-directed therapy +/- anthracycline. The primary endpoint was change in endothelial function over time using the reactive hyperemia index (RHI). Framingham Risk Score (FRS) and lower RHI are both known to be independent predictors of future cardiovascular events in the general population. RHI deterioration was defined as a 20% reduction from baseline RHI to any available follow-up RHI assessment. Univariate analyses assessed if age, FRS, baseline RHI, and RHI deterioration differed between recipients and non-recipients of anthracycline using the Wilcoxon test. A multivariate logistic model evaluated FRS, age, and anthracycline receipt as possible independent predictors of RHI deterioration. Results: Among 38 eligible patients who consented and completed baseline assessments in addition to at least one follow-up assessment, 17 (45%) subsequently received anthracycline. 145 total follow-up RHI assessments were available overall (5 per patient on average). There were no differences between recipients and non-recipients of anthracyclines with regard to age [mean 49 years (SD 12) vs 53 years (SD 11); p=0.25], baseline FRS [mean 1.0 (SD 1.0) vs 1.5 (SD 1.4); p= 0.28] or baseline RHI [mean 2.4 (SD 0.6) vs 2.1 (SD 0.7); p=0.09]. RHI deterioration was more common for anthracycline recipients (mean 43% vs 21%; p=0.004), and in the multivariate model, anthracycline use was the only independent predictor of RHI deterioration (odds ratio: 2.8; 95% confidence interval: 1.35-6.07; p=0.006). Conclusions: This study suggests that endothelial dysfunction is more common after combined anthracycline and HER2-directed therapy than after HER2-directed therapy alone. RHI should be further studied as a possible early biomarker of cardiovascular toxicity in patients receiving treatment for breast cancer.

AbstractQTc interval prolongation can lead to life‐threatening complications such as Torsade de Pointes (TdP), ventricular tachycardia (VT) and sudden cardiac death (SCD). It can occur with tyrosine kinase inhibitors (TKIs) but comparative real‐world analyses on the incidence and complication rates are scarce. We retrospectively reviewed all cancer patients treated with TKI therapy at Mayo Clinic between January 2005 and December 2018 and had at least two ECGs (before and after TKI). For each TKI type, we determined the administration rate and incidence of QTc prolongation. QTc prolongation was defined as a corrected QT interval (by Fridericia formula) ≥450 ms in men and ≥470 ms in women. A total of 618 cancer patients were included with 902 TKI administrations, of which 654 (72.5%) were accounted for by pazopanib, sunitinib, imatinib, nilotinib and dasatinib. QTc prolongation (any grade) was reported in 28.8%, most commonly with nilotinib (38.7%) and dasatinib (41.7%). A QTc interval ≥500 ms and a QTc increase ≥60 ms was documented in 46 and 63 administrations, respectively. Life‐threatening toxicity was seen in 14 cases (5.4% of QTc prolongation cases) including VT in 9, SCD in 3 and TdP in two administrations. The response to QTc prolongation was: discontinuation in 68%, dose reduction in 13.5%, temporary hold in 8.1% and no action in 10.4%. In conclusion, QTc prolongation with TKI therapy is very common (∼1/3 of cases) and in 5% (1.7% overall) associated with life‐threatening complications. These data support recommendations for careful ECG monitoring in cancer patients undergoing TKI therapy.

Background Temporal declines in cardiac stress tests results, coronary revascularization, and cardiovascular mortality have suggested a decline in the population burden of coronary disease until the 2000s. However, recent data indicate these favorable trends could be ending. We aimed to assess the evolution of the population burden of coronary disease in the community by examining trends in angiography and revascularization. Methods and Results We analyzed age‐ and sex‐adjusted trends from all coronary angiographic diagnostic procedures and revascularizations performed in Olmsted County, MN from 2000 to 2018. A total of 12 981 invasive angiograms were performed among 9049 individuals (64% men; 55% aged ≥65 years). Adjusted angiography rates decreased by 30% (95% CI , 25%–34%) between 2000 and 2009 and leveled off thereafter. Including computed tomography, angiography uncovered an increase in angiography use in recent years (risk ratio=1.15 [95% CI , 1.07–1.23] for 2018 versus 2014) and a decline in the prevalence of anatomic CAD from 2000 to 2018. CAD severity declined substantially from 2000 to 2009, followed by a plateau. Among 6570 revascularizations (72% men; 57% aged ≥65 years), 77% were percutaneous coronary interventions and 23% coronary artery bypass graft surgeries. The adjusted revascularization rates declined by 34% (95% CI , 27%–39%) from 2000 to 2009, followed by a plateau (risk ratio=1.10 [95% CI , 1.00–1.22]). Conclusions Between 2000 and 2018 in the community, coronary angiography use declined initially, leveled off, and then increased. Trends in CAD severity and revascularization use decreased then plateaued. The most recent trends are concerning as they suggest the burden of coronary disease is no longer declining. This warrants reinvigorated primary prevention and population surveillance.

Background: The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend consideration of the use of echocardiography 6 to 12 months after completion of anthracycline-based chemotherapy in at-risk populations. Assessment of BNP (B-type natriuretic peptide) has also been suggested by the American College of Cardiology/American Heart Association/Heart Failure Society of America for the identification of Stage A (at risk) heart failure patients. The real-world frequency of the use of these tests in patients after receipt of anthracycline therapy, however, has not been studied previously. Methods and Results: In this retrospective study, using administrative claims data from the OptumLabs Data Warehouse, we identified 31 447 breast cancer and lymphoma patients (age ≥18 years) who were treated with an anthracycline in the United States between January 1, 2008 and January 31, 2018. Continuous medical and pharmacy coverage was required for at least 6 months before the initial anthracycline dose and 12 months after the final dose. Only 36.1% of patients had any type of cardiac surveillance (echocardiography, BNP, or cardiac imaging) in the year following completion of anthracycline therapy (29.7% echocardiography). Surveillance rate increased from 37.5% in 2008 to 42.7% in 2018 (25.6% in 2008 to 40.5% echocardiography in 2018). Lymphoma patients had a lower likelihood of any surveillance compared with patients with breast cancer (odds ratio, 0.79 [95% CI, 0.74–0.85]; P <0.001). Patients with preexisting diagnoses of coronary artery disease and arrhythmia had the highest likelihood of cardiac surveillance (odds ratio, 1.54 [95% CI, 1.39–1.69] and odds ratio, 1.42 [95% CI, 1.3–1.53]; P <0.001 for both), although no single comorbidity was associated with a >50% rate of surveillance. Conclusions: The majority of survivors of breast cancer and lymphoma who have received anthracycline-based chemotherapy do not undergo cardiac surveillance after treatment, including those with a history of cardiovascular comorbidities, such as heart failure.