Anthracycline-treated Patients Research Articles

Sodium-Glucose Cotransporter 2 Inhibitors During Cancer Therapy: Benefits, Risks, and Ongoing Clinical Trials.

The goal of this paper is to summarize the data pertaining to the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) for the prevention of cardiotoxicity in patients receiving anthracyclines for cancer treatment. We discuss the potential efficacy of this class of medications, incorporating insights from existing literature and ongoing studies. SGLT2i are a class of medications which were initially developed for treatment of Type 2 diabetes and later extended to treat heart failure with reduced and preserved ejection fraction regardless of diabetes status. There remains a need for effective and safe treatments to preventing cardiotoxicity in anthracycline-treated patients. It has been proposed that SGLT2i may provide protection against the cardiotoxic effects of anthracyclines. Some of the proposed mechanisms include beneficial metabolic, neurohormonal, and hemodynamic effects, renal protection, as well as a decrease in inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ion homeostasis. There is emerging evidence from basic science and observational studies that SGLT2i may play a role in the prevention of chemotherapy-induced cardiotoxicity. Randomized controlled trials are needed to conclusively determine the role of SGLT2 inhibitors as a cardioprotective therapy in patients receiving anthracyclines for the treatment of cancer.

Neuromodulation of Cardiovascular Risks Associated With Cardiotoxic Chemotherapy: A First-in-Human Randomized Pilot Study. Neuromodulation in Cancer Study (NCAN).

Cardiotoxic chemotherapy is used to treat malignancies such as breast cancer and lymphoma. These treatments predispose patients to cardiotoxicity that can lead to cancer treatment-related cardiac dysfunction (CTRCD). The use of high doses of anthracyclines or in combination with human epidermal growth factor receptor 2 antagonists is associated with a progressively higher risk of CTRCD. CTRCD is preceded by increased activation of the sympathetic nervous system and abnormal left ventricular mechanical deformation as measured by abnormal global longitudinal strain (GLS). Low-level tragus stimulation (LLTS) is a new, safe, noninvasive technique that offers great potential to reduce increased sympathetic activation and improve GLS. Here, we describe a study method to examine the effects of LLTS on autonomic balance and cardiac function in breast cancer or lymphoma patients treated with anthracyclines. A first-in-human pilot, randomized, double-blind feasibility study will evaluate 104 patients (age >50y) with breast cancer or lymphoma who receive anthracyclines with one additional CTRCD risk factor. Patients undergo 2 weeks of LLTS daily (1 h/d). Autonomic balance will be measured using heart rate variability metrics. Strain imaging using GLS will be performed pre and post-LLTS. Endothelial inflammation and oxidative stress measures will be performed using in vitro assays at baseline and after 2 weeks. We hypothesize that LLTS stabilizes sympathovagal imbalance and improves cardiac performance in anthracycline-treated patients with breast cancer or lymphoma.

Cardioprotective Diet to Prevent Anthracycline-Induced Cardiotoxicity in Patients with Breast Cancer: A Randomized Open-Label Controlled Trial.

Objectives: Several studies have indicated that dietary interventions may offer protection against the development of cardiac damage in the case of anthracycline-induced cardiomyopathy (AIC). The goal of this study was to assess whether an evidence-based cardioprotective diet can be effective in preventing AIC in patients with breast cancer. Design: Randomized, open-label, controlled trial. The study period was set for 18 weeks, and the data were analyzed by generalized estimating equation modeling and one-way repeated measures analysis of variance. Setting/Location: Shahid Rajaie Hospital affiliated (Tehran, Iran). Subjects: Fifty anthracycline-treated patients with breast cancer. Interventions: Patients were randomized to receive either a 2-hour training in evidence-based cardio-protective diet or Carvedilol 6.25 mg bid. Outcome Measures: The primary outcome was the number of patients with abnormal left ventricular ejection fraction (LVEF) after 18 weeks. Results: At week 18, 12 (48%) out of 25 participants in the cardioprotective diet group had abnormal LVEF in comparison with 21 (84%) out of 25 in the carvedilol group (p = 0.007). Also, 2 (8%) out of 25 in the cardioprotective diet group compared with 7 (28%) out of 25 participants in the carvedilol group had abnormal global longitudinal strain (p = 0.066). The diet group showed significant improvements in the quality-of-life dimensions named "health change" and "general health" compared with the carvedilol group using the Short Form-36 Health Survey questionnaire. Conclusions: This study suggests that an evidence-based cardioprotective diet can contribute to the prevention of AIC. Although current treatments for AIC can be effective, further research is mandatory for more options.

Artificial intelligence-enabled prediction of chemotherapy-induced cardiotoxicity from baseline electrocardiograms

Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD) that adversely affects prognosis. Despite guideline recommendations, only half of the patients undergo surveillance echocardiograms. An AI model detecting reduced left ventricular ejection fraction from 12-lead electrocardiograms (ECG) (AI-EF model) suggests ECG features reflect left ventricular pathophysiology. We hypothesized that AI could predict CTRCD from baseline ECG, leveraging the AI-EF model’s insights, and developed the AI-CTRCD model using transfer learning on the AI-EF model. In 1011 anthracycline-treated patients, 8.7% experienced CTRCD. High AI-CTRCD scores indicated elevated CTRCD risk (hazard ratio (HR), 2.66; 95% CI 1.73–4.10; log-rank p < 0.001). This remained consistent after adjusting for risk factors (adjusted HR, 2.57; 95% CI 1.62–4.10; p < 0.001). AI-CTRCD score enhanced prediction beyond known factors (time-dependent AUC for 2 years: 0.78 with AI-CTRCD score vs. 0.74 without; p = 0.005). In conclusion, the AI model robustly stratified CTRCD risk from baseline ECG.

The Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Anthracycline-Treated Patients With Cancer

BackgroundSodium glucose cotransporter-2 inhibitors (SGLT2is) are hypothesized to reduce the risk of anthracycline-associated cardiotoxicity. ObjectivesThis study sought to determine the association between SGLT2is and cardiovascular disease (CVD) after anthracycline-containing chemotherapy. MethodsUsing administrative data sets, we conducted a population-based cohort study of people >65 years of age with treated diabetes and no prior heart failure (HF) who received anthracyclines between January 1, 2016, and December 31, 2019. After estimating propensity scores for SGLT2i use, the average treatment effects for the treated weights were used to reduce baseline differences between SGLT2i-exposed and -unexposed controls. The outcomes were hospitalization for HF, incident HF diagnoses (in- or out-of-hospital), and documentation of any CVD in future hospitalizations. Death was treated as a competing risk. Cause-specific HRs for each outcome were determined for SGLT2i-treated people relative to unexposed controls. ResultsWe studied 933 patients (median age 71.0 years, 62.2% female), 99 of whom were SGLT2i treated. During a median follow-up of 1.6 years, there were 31 hospitalizations for HF (0 in the SGLT2i group), 93 new HF diagnoses, and 74 hospitalizations with documented CVD. Relative to controls, SGLT2i exposure was associated with HR of 0 for HF hospitalization (P < 0.001) but no significant difference in incident HF diagnosis (HR: 0.55; 95% CI: 0.23-1.31; P = 0.18) or CVD diagnosis (HR: 0.39; 95% CI: 0.12-1.28; P = 0.12). There was no significant difference in mortality (HR: 0.63; 95% CI: 0.36-1.11; P = 0.11). ConclusionsSGLT2is may reduce the rate of HF hospitalization after anthracycline-containing chemotherapy. This hypothesis warrants further testing in randomized controlled trials.

Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice.

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients (n=30) and replicated key findings in a second cohort (n=31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx-/- mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

External validation of a heart failure risk score in patients with acute myeloid leukemia

A 21-point risk score for heart failure (HF) has been developed for patients with acute myeloid leukemia (AML), stratifying patients into three groups: low, moderate, and high-risk. In this study, 193 patients with AML treated with anthracycline-based therapy were stratified using the risk score, and its prognostic utility for HF events and all-cause mortality at one year of follow-up were evaluated. HF occurred in 18% (34/193) of anthracycline-treated patients. Global longitudinal strain (GLS) was more negative among patients without HF events (−19 ± 3 vs. −17 ± 4%). One year incidence of HF was increased in the higher risk groups: 12% of low-risk, 24% of moderate-risk, and 50% of high-risk (p < 0.001). However, a higher risk score was not associated with an increased risk of all-cause mortality. This study provides external validation of a 21-point risk score for HF events but not all-cause mortality at one year in patients with AML.

Cardiac Anthracycline Accumulation and B-Type Natriuretic Peptide to Define Risk and Predictors of Cancer Treatment-Related Early Diastolic Dysfunction.

Diastolic dysfunction (DD) was reported to precede heart failure (HF) in patients with cancer who were treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in patients with cancer treated mainly with anthracyclines. Data from 67 patients without comorbidities (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14 of 67 patients, and 5% risk doses were much lower for DD than HF (mg of anthracycline/m2: 210 vs. 470 or 190 vs. 450 for all patients or anthracycline-treated patients in isolation, respectively; P ≤ 0.01 for DD vs. HF). Patients with transient BNP elevations showed the lowest 5% risk dose (150 mg/m2), whereas patients with persistent elevations showed the highest risk dose (280 mg/m2; P < 0.05). Patients with or without DD were similar for systemic and cardiac exposure to anthracyclines; however, high-risk patients with transient BNP elevations and DD were older and presented at baseline with lower indices of transmitral flow. In conclusion, DD risk develops after lower anthracycline doses than HF and intertreatment levels of BNP help to identify patients with high or low DD risk. These findings are of potential value to monitor or treat the patient with cancer at risk of DD. SIGNIFICANCE STATEMENT: DD is an early manifestation of cardiotoxicity from anthracyclines and nonanthracycline chemotherapeutics. We show that merging preclinical characterization of cardiac anthracycline accumulation with clinical data from patients treated primarily with anthracyclines identifies DD risk from very low anthracycline doses. DD risk is associated with older age, baseline diastolic indices toward the lower limit of normal, and transient intertreatment elevations of the endogenous cardiac relaxant agent, BNP. These findings have numerous pharmacological implications.

Rationale, Design, and Feasibility of a Prospective Multicenter Registry Study of Anthracycline-Induced Cardiotoxicity (AIC Registry).

As the number of cancer survivors increases, cardiac management in anthracycline-treated patients has become more important. We planned to conduct a prospective multicenter registry study for comprehensive echocardiographic and biomarker data collection and an evaluation of the current practice in terms of diagnosis and management of anthracycline-induced cardiotoxicity (AIC registry). To examine the feasibility of this registry study, we analyzed the 1-year follow-up data of 97 patients registered during the first year of this registry. The AIC registry was launched in July 2016. Data on echocardiographic parameters (e.g., two-and three-dimensional [(2- and 3-D) left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS)) and biomarkers (e.g., troponin T and brain natriuretic peptide) were collected before anthracycline treatment, every 3 months during the first year after starting anthracycline, and every 6 months during the second year. Eighty-three patients (86%) completed a 1-year follow-up. The measurable rates of 2D LVEF, 3D LVEF, and GLS on each visit were nearly optimal (100%, 86–93%, and 84–94%, respectively). During the 1-year follow-up, 5 patients (6.0%) developed cardiotoxicity (a reduction in LVEF ≥ 10 percentage points from baseline and <55%). The AIC registry study is feasible and will be the first study to collect sizable echocardiographic and biomarker data on cardiotoxicity in Japanese patients treated with anthracycline in a real-world setting.

Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy

BackgroundIn patients at risk of cancer therapy-related cardiac dysfunction (CTRCD), initiation of cardioprotective therapy (CPT) is constrained by the low sensitivity of ejection fraction (EF) for minor changes in left ventricular (LV) function. Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction, but existing observational data have been insufficient to support a routine GLS-guided strategy for CPT. ObjectivesThis study sought to identify whether GLS-guided CPT prevents reduction in LVEF and development of CTRCD in high-risk patients undergoing potentially cardiotoxic chemotherapy, compared with usual care. MethodsIn this international, multicenter, prospective, randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n = 166) or >10% absolute reduction of LVEF (n = 165). Patients were followed for EF and development of CTRCD (symptomatic EF reduction of >5% or >10% asymptomatic to <55%) over 1 year. ResultsOf 331 randomized patients, 2 died, and 22 withdrew consent or were lost to follow-up. Among 307 patients (age: 54 ± 12 years; 94% women; baseline LVEF: 59 ± 6%; GLS: –20.6 ± 2.4%) with a median (interquartile range) follow-up of 1.02 years (0.98 to 1.07 years), most (n = 278) had breast cancer. Heart failure risk factors were prevalent: 29% had hypertension, and 13% had diabetes mellitus. At the 1-year follow-up, although the primary outcome of change in LVEF was not significantly different between the 2 arms, there was significantly greater use of CPT, and fewer patients met CTRCD criteria in the GLS-guided than the EF-guided arm (5.8% vs. 13.7%; p = 0.02), and the 1-year EF was 57 ± 6% versus 55 ± 7% (p = 0.05). Patients who received CPT in the EF-guided arm had a larger reduction in LVEF at follow-up than in the GLS-guided arm (9.1 ± 10.9% vs. 2.9 ± 7.4%; p = 0.03). ConclusionsAlthough the change in LVEF was not different between the 2 arms as a whole, when patients who received CPT were compared, those in the GLS-guided arm had a significantly lower reduction in LVEF at 1 year follow-up. Furthermore, GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The results support the use of GLS in surveillance for CTRCD. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628)

The Role of Biomarkers to Evaluate Cardiotoxicity.

Moderate-level evidence suggests that cardiac troponin and natriuretic peptides are useful for risk stratification and early identification of anthracycline cardiotoxicity; however, many of these studies used older chemotherapy regimens, and thus, the applicability to current anthracycline treatment regimens is uncertain. Further research is needed to determine optimal timing and thresholds for troponin and natriuretic peptides in anthracycline-treated patients and evaluate these and other promising biomarkers for anti-HER2 therapies, thoracic radiation, anti-VEGF therapy, and fluoropyrimidine therapy-related cardiotoxicity. Risk tools that combine cardiac risk factors, cancer treatment variables, biomarkers, and imaging parameters are most likely to accurately identify individuals at highest risk for cancer therapy cardiotoxicity. Clinical trials focusing cardioprotective strategies on high-risk individuals are more likely to result in clinically significant results compared with primary prevention cardioprotective approaches.

Abstract P3-08-65: PITX2 DNA methylation: A prognostic/predictive biomarker for anthracycline-based chemotherapy

Abstract Background: Published data on the basis of a research-use-only PITX2 methylation assay using fresh-frozen tissue showed that the PITX2 DNA methylation may be a predictive marker for response to (neo) adjuvant anthracycline-based chemotherapy in breast cancer patients, including high-risk lymph node positive, estrogen receptor-positive, HER2-negative breast cancer and triple-negative breast cancer (TNBC). A retrospective study showed that high-risk ER-positive patients with a high PITX2 methylation ratio (PMR&amp;gt;12) had a poor outcome after anthracycline-based chemotherapy [HR 2,28; 95%-Cl 1,49 - 3,49; p&amp;lt;0.001, median DFS 71 months] compared to patients with low PITX2 methylation ratios [PMR≤12, median DFS 105 months]. Nevertheless, the question regarding the prognostic versus predictive value of PITX2 methylation for anthracycline therapy remained unanswered so far. Within an exploratory study using archived tissue specimen, this question was addressed by comparing the impact of PITX2 methylation on outcome in an untreated versus treated TNBC population. Methods: Patient samples and clinical data from 144 TNBC patients of 2 cohorts were analyzed: 1) 66 untreated patients from the Karolinska Institute in Sweden (primary diagnosis 1971-1976) and 2) 78 patients treated with anthracycline-based chemotherapy from the Comprehensive Cancer Center TUM in Germany (primary diagnosis 1996 to 2014). The main eligibility criteria were as follows: ER-negative, PR-negative, HER2-negative breast cancer (TNBC); no endocrine therapy; untreated collective: no further therapy besides surgery and radiation therapy; treated collective: surgery followed by anthracycline based chemotherapy. Samples were assessed for PITX2 methylation using a CE marked PITX2 RGQ PCR Test. The study was designed to determine the PITX2 PMR cut-off value in the untreated population (n=66, prognostic value) and to subsequently determine if this cut-off provides statistical significance in the treated population (n=78, prognostic &amp; predictive value) as well. If no statistically significant cut-off value can be determined in the untreated population, cut-off determination was performed in the treated population and the cut-off was applied in the untreated population. The primary clinical endpoint for all cut-offs was 10-years DFS, secondary clinical endpoints were DFS censored at 5-years and OS censored at 5- and 10-years. Results: The untreated TNBC study population demonstrated a higher event rate at 10-years DFS/OS compared to the anthracycline-treated population [36 DFS/28 OS events vs 28 DFS/14 OS events]. Anthracycline treatment improved significantly overall survival [HR=0.42; p=0.008]. Risk recurrence increased continuously over 5 year and 10 years DFS/OS with increasing PITX2 DNA methylation in the anthracycline-treated population but not in the untreated patients over 5 years DFS/OS and only marginally over 10 years DFS/OS. PITX2 methylation identifies at the cut-off of PMR 2 a patient population with poor vs good overall survival with statistical significance [HR=3.96, p=0.011] in the treated patient cohort but did not identify patients with poor vs good outcome in the untreated patient cohort [HR=1.55, p=0.259]. Summary: In this hypothesis generating study DNA-methylation of PITX2 identifies with high statistical significance anthracycline-treated patients with poor vs good survival. Recurrence risk increases with increasing PITX2 DNA-methylation. PITX2 DNA-methylation shows no prognostic, but significant predictive value for anthracycline treatment in TNBC patients in this study. To confirm conclusively the predictive value of PITX2 DNA-methylation, the results warrant a confirmatory study with tumor specimens from a prospective trial of anthracycline-treated patients vs. anthracycline-free treated patients. Citation Format: Marion Kiechle, Gabriele Schricker, Rudolf Napieralski, Michaela Aubele, Gert Auer, Kurt Ulm, Jonathan Perkins, Stefan Paepke, Moritz Hamann, Olaf G. Wilhelm. PITX2 DNA methylation: A prognostic/predictive biomarker for anthracycline-based chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-65.

Left ventricular echocardiographic parameters as predictors of cardiotoxicity in Breast cancer patients with a left ventricular ejection fraction of 50–60% treated with anthracyclines

Anthracyclines are the gold standard adjuvant therapy for breast cancer patients but their use is limited by dose-dependent often irreversible cardiotoxicity. To evaluate the interest of baseline echocardiographic parameters of left ventricular (LV) size and function to identify anthracycline-treated patients at high risk to develop cardiotoxicity in patients with low normal LV ejection fraction (LVEF). We conducted a prospective longitudinal study in the cardio-oncology unit of Casablanca, the first cardio-oncology unit in Morocco. All the patients underwent echocardiography for pre-anthracycline assessment. LV volumes, LVEF, and peak longitudinal strain (GLS) were measured. Individuals were followed for cardiotoxicity and all-cause mortality over 23 months (from January 2017 to November 2018) Of 971 patients, 522 (56,7%) had a resting LVEF of 50–60%. Average LVEF was 55 ± 2%, global longitudinal strain (GLS) was −18.4 ± 3.2% and LV end-diastolic volume (LVEDV) was 108 ± 17 mL. Twenty six patients (4,9%) presented cardiotoxicity: congestive heart failure (HF) in 19 patients, arterial hypertension in 1 patient, 2 pericardial effusion, 2 cases of arrhythmias, 1 case of 3rd degree atrioventricular block and 1 right ventricular dysfunction. Age, diabetes, obesity, GLS and LVEDV were all predictive of MACE ( P = 0.028, 0.017, 0.041, 0,038 and 0.014 respectively). Age and GLS were also predictive of overall mortality ( P = 0.021 and 0.003 respectively). In patients treated with anthracyclines with an LVEF of 50-60%, both baseline EDV and GLS predict the development of cardiotoxicity. These results may enable select patients at higher risk of cardiotoxicity and thus initiate early cardioprotective medical therapy and a closer cardiac surveillance.

A Case of Pulmonary Edema Triggered by Tracheal Extubation in A Patient with Anthracycline-Induced Cardiomyopathy

Anthracyclines are the most commonly used drugs in the treatment of breast cancer. Although their adverse effects, especially life-threatening cardiotoxicity, are well recognized, anthracycline-related cardiac events have been rarely reported in the perioperative setting. Here, we present a case of massive pulmonary edema triggered by tracheal extubation in a patient with anthracycline-induced cardiomyopathy, undergoing mastectomy for breast cancer. This case highlights the potential risk of a cardiac event in anthracycline-treated patients undergoing surgery.

Cardioprotective Effects and Duration of Beta Blocker Therapy in Anthracycline-Treated Patients: A Systematic Review and Meta-analysis.

Anthracycline-containing chemotherapy is commonly associated with irreversible cardiovascular toxicity. Beta blockers are currently recommended as first-line drugs for improving cardiac function. However, the effects of beta blocker on cardiac preservation and the duration of beta blocker intervention therapy in anthracycline-treated patients remain unclear. We systematically searched PubMed, Embase, and Cochrane for randomized controlled trials (published between January, 2000 and January, 2019) to determine the effectiveness of cardiac preservation of beta blocker in anthracycline-treated patients by accessing the change in left ventricular ejection fraction (LVEF) from pre- to post-chemotherapy. In addition, we conducted subgroup analysis based on the duration of beta blocker cardioprotective intervention and accumulative anthracycline dose. 11 RCTs were finally included. Beta blockers were associated with a significant smaller drop in the LVEF change (MD = 2.87, 95% CI 0.64 to 5.11, p = 0.01) compared to control groups. Besides, a subgroup analysis according to duration of beta blocker-based cardioprotective intervention (< 6months vs = 6months) showed significant subgroup difference in the LVEF change (MD = - 0.05, 95% CI - 0.91 to 0.81, p = 0.91; MD = 6.48, 95% CI 2.44 to 10.52, p = 0.002). An additional subgroup analysis according to accumulative anthracycline dose showed statistically significant difference in the LVEF change (MD = 4.61, 95% CI 0.78 to8.45, p = 0.02) with moderate accumulative dose of anthracycline (doxorubicin between 250 and 400mg/m2). Prophylactic administration of beta blocker-based cardioprotective therapy may be beneficial to the myocardial preservation in anthracycline-treated patients. And long-term use of beta blocker appears to have a positive effect on ameliorating anthracycline-induced cardiomyopathy, especially in patients exposed to moderate accumulative doses of anthracycline.

Genetic Risk Factors for Cardiovascular Disease in Adult Lymphoma Patients

Purpose The development of cardiovascular disease (CVD) is a relatively rare but a clinically important adverse event in the treatment of lymphoma, particularly in individuals receiving anthracyclines. There are few studies assessing the role of germline genetic susceptibility as a predictor of CVD in this setting. We evaluated the association of 24 single nucleotide polymorphisms (SNPs) from candidate genes involved in anthracycline-induced cardiotoxicity, CVD, and venous thromboembolism with new-onset CVD in a prospective cohort of lymphoma patients treated in the modern era. Methods All patients were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE. Enrollment from 2002-2015 was offered to patients with newly diagnosed lymphoma who were age ≥18 years. Clinical, pathology and treatment data were abstracted using a standard protocol, and participants provided a peripheral blood sample, from which DNA was extracted. All patients were prospectively contacted every 6 months for the first 3 years from diagnosis and then annually thereafter to assess disease status, re-treatment and development of new morbidities, including CVD. Reported CVD events included congestive heart failure (CHF), coronary heart disease (CHD), arrhythmia, valvular heart disease (VHD), and other CVD. These events were identified during follow-up and validated against medical records. Genotyping was conducted using a custom Illumina iSelect platform with rigorous quality controls. For each SNP, Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) with time to first CVD, using death without CVD as a competing risk. HRs were also obtained for time to CHF, using death without CVD as a competing risk. We also modeled these events for all patients and for patients receiving frontline anthracyclines. Each SNP was modeled as having a log-additive (per minor allele) effect in the regression model. An ordinal test was used to assess the trend, with a nominal P&lt;0.05 considered statistically significant. Results There were a total of 3,063 newly diagnosed lymphoma patients (excluding chronic lymphocytic leukemia) with no history of CVD at time of lymphoma diagnosis, of which 1280 had genotype data available for analysis. The median age at diagnosis was 59 years (range, 18-95) and 56% were male. The most common subtypes were follicular (26.3%), diffuse large B-cell (23.2%), Hodgkin (11.3%), marginal zone (11.2%), mantle cell (6.3%) and T-cell (5.4%) lymphoma. Anthracycline-based chemotherapy as initial therapy was used in 52% of individuals. At a median follow-up of 6.9 years (range, 0.1-17.1), 363 (30.7%) patients died, and 173 (13.5%) had new-onset CVD after lymphoma diagnosis. There were 234 incident CVD events in the 173 patients: 49 CHD, 50 CHF, 27 VHD, 103 arrhythmias, and 5 other CVD. Results are shown in the Table. When assessing all CVD, F5 (rs4524) (HR=1.28, 95% CI=1.03-1.58) and F11 (rs4253399) (HR=1.30, 95% CI=1.06-1.61) were associated with CVD at P&lt;0.05; both associations attenuated slightly when restricted to anthracycline-treated patients (F5 HR=1.18, 95% CI=0.89-1.57; F11 HR=1.23, 95% CI=0.92-1.65). F11 was more strongly associated with CHF (HR=1.55, 95% CI=1.03-2.34) and CHF in anthracycline-treated patients (HR=1.64, 95% CI=0.98-2.76). NCF4 (rs1883112) was marginally associated with lower risk of CVD overall (HR=0.81, 95% CI=0.66-1.00), and this association strengthened when restricted to anthracycline-treated patients (HR=0.67, 95% CI=0.49-0.91) and showed similar trends in HRs for CHF (HR=0.77, 95% CI=0.51-1.16) and CHF in anthracycline-treated patients (HR=0.72, 95% CI=0.41-1.28), although neither estimate was statistically significant at P&lt;0.05. Finally, while XDH (rs2236168) was not associated with all CVD (HR=1.00, 95% CI=0.81-1.23), it was associated with CHF (HR=0.66, 95% CI=0.47-0.93) overall, but attenuated in anthracycline-treated patients (HR=0.81, 95% CI=0.55-1.18). Conclusions In this exploratory study of candidate SNPs from the literature, we found limited evidence for a role of germline genetic variability in predicting risk of CVD or CHF in a cohort of lymphoma patients, especially after accounting for multiple testing. To fully address this hypothesis, future studies will need larger sample sizes and more comprehensive genetic assessment. Disclosures Maurer: Celgene: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Nowakowski:NanoString: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Abstract P2-10-06: Identifying patients sensitive to anthracycline-containing therapy with quantitative proteomic and genomic profiling

Abstract Background: Selecting chemotherapy based on tumor biology can improve response rates and avert toxicity. Studies of the relationship between tumor expression of TOP2A protein and response to anthracycline-based chemotherapy have yielded contradictory results. Here we used mass spectrometry (MS) to evaluate associations between tumor molecular profiles and pathological complete response (pCR) in breast cancer patients treated with neoadjuvant anthracycline-containing therapy. Methods: Patients were selected from the ERNEST-B (Erlangen Neoadjuvant Study Breast), which is a retrospective cohort study. Archived tumor samples from anthracycline-treated breast cancer patients (n=133) were microdissected and solubilized. In each tumor sample, TOP2A and other target proteins were quantitated with a mass spectrometry assay. Molecular profiling also included RNA sequencing of the tumor and whole genome sequencing of both tumor and matched normal tissue sections. The cohort was dichotomized into high and low expressors of TOP2A using a protein level cutoff of 515 amol/ug of tumor protein. The difference in pCR (ypT0ypN0) rates between high and low expressors of TOP2A was assessed using a z-test for differences in proportion. Results: TOP2A protein was detected in 84 of 133 (63%) tumor samples from anthracycline-treated patients (range: 178 to 3044 amol/ug). Patients whose tumor expressed TOP2A protein above the cutoff of 515 amol/ug had higher pCR rates than patients with lower TOP2A expression (35.5% vs. 12.1%; odds ratio (OR): 4.48 [95% CI: 1.53-13.28], Fisher' exact test p = 0.004). The difference retained statistical significance in a logistic regression model adjusting for HR and HER2 status (OR: 2.23 [95% CI: 1.15-4.30], p=0.017). In a separate cohort of 19 breast cancer patients who did not receive anthracycline, there was no association between TOP2A protein expression level and pCR rate. Results from a validation cohort as well as the genomic analysis will be presented at the meeting. Conclusions: In a retrospective analysis of anthracycline-treated breast tumors, TOP2A expression was associated with a higher rate of pCR. Targeted proteomics may predict the response of breast cancer patients to anthracycline-based therapy. Citation Format: Schwartz S, Cecchi F, Tian Y, Yau C, Szeto C, Rübner M, Erber R, Beckmann MW, Hartmann A, Benz S, Hembrough T, Fasching P. Identifying patients sensitive to anthracycline-containing therapy with quantitative proteomic and genomic profiling [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-06.

Diastolic function in anthracycline-treated children.

Anthracyclines are effective medications for childhood cancer. Their limitation is the risk of cardiomyopathy. Although diastolic dysfunction has been described in patients who received anthracyclines, cardiac monitoring has focused on systolic function, which is abnormal in up to 41% of the patients. We conducted a study to assess diastolic function utilising transmitral inflow Doppler velocities and tissue Doppler imaging in anthracycline-treated children 5 years post-therapy. This was a retrospective study on 63 anthracycline-treated patients. Echocardiographic parameters included peak early and late transmitral inflow Doppler velocities (E, A), E/A ratio, E deceleration time, and tissue Doppler imaging early and late diastolic mitral annulus velocities (E', A'), E/E' ratio, and E'/A' ratio. All indices of diastolic function that we measured were normal in the anthracycline-treated patients. We conclude that diastolic function assessed by transmitral inflow Doppler velocities and tissue Doppler imaging is normal in anthracycline-treated children 5 years after completion of treatment. Further longitudinal study is needed to determine whether diastolic function becomes abnormal with time in this patient population.

Highly frequent and enhanced injection site reaction induced by peripheral venous injection of fosaprepitant in anthracycline-treated patients.

Background: Fosaprepitant-associated injection site reaction (ISR) has been reported in patients treated with cisplatin, an irritant drug. We conducted this retrospective study to clarify the incidence and symptoms of fosaprepitant-associated ISR in patients treated with anthracycline.Patients and methods: Fifty six patients receiving 159 injections administering doxorubicin/cyclophosphamide (AC), fluorouracil/epirubicin/cyclophosphamide (FEC), or rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-)CHOP regimen through a peripheral vein at ambulatory treatment centers reviewed for this study from patients' medical records. Incidence of ISR was compared between 24 patients with fosaprepitant injection (fosaprepitant group) and 32 patients without fosaprepitant (control group). Frequency and symptoms of ISR per injection were also compared between 61 injections with fosaprepitant and 98 injections without fosaprepitant.Results: Both the ISR incidence rate per patient and per injection were significantly higher in the fosaprepitant group than in the control group (67% vs. 16%; P=0.0002, 34% vs. 8.2%; P<0.0001, respectively). By multivariate analysis, fosaprepitant injection was found to be a significant independent variable correlated with ISR risk. Symptoms observed in 61 injections of fosaprepitant were pain (n=14, 23%), erythema (n=10, 16%), swelling (n=6, 10%), and delayed drip infusion (n=6, 10%). After the observation period, no ISR occurred when the administration route was changed to central venous injection or oral aprepitant was administered despite the continuation of chemotherapy.Conclusion: ISR occurred more frequently and severely when fosaprepitant was injected through the peripheral vein in patients treated with anthracyclines compared to those without fosaprepitant.

Cardiac MRI in the Assessment of Cardiac Injury and Toxicity From Cancer Chemotherapy

During the past 30 years, there has been a significant decrease in cancer mortality rates, predominantly attributable to improvements in treatment options.1 However, survivors are at increased risk of premature cardiac disease,2 both because of the overlap in risk factors for cancer and cardiovascular disease3 and the cardiotoxic effects of cancer chemotherapy. Two chemotherapeutic agent classes that are commonly associated with cardiotoxicity are the anthracyclines and tyrosine kinase inhibitors, both of which can cause left ventricular (LV) dysfunction and heart failure (HF).4,5 Mechanisms of cardiac injury from cancer therapy have been summarized elsewhere.4,6 Briefly, anthracycline cardiotoxicity has been attributed to reactive oxygen species formation, transcriptional changes in intracellular adenosine triphosphate production in cardiac myocytes, and, more recently, through interaction with cardiac topoisomerase IIβ.4,6 Trastuzumab cardiotoxicity seems to be because of inhibition of cardiomyocyte human epidermal growth factor receptor 2, resulting in ATP depletion and contractile dysfunction.4 Other proposed mechanisms include immune-mediated destruction of cardiomyocytes.4,6 At the tissue level, early anthracycline toxicity has been associated with myocardial inflammation,7–9 vacuolization,9–12 and cell swelling/edema.11,13 These changes seem to occur before myocardial functional abnormalities.11,13 Later stages of toxicity are associated with myocardial fibrosis.14,15 Unfortunately, the use of myocardial biopsy is not feasible for diagnostic purposes in this setting. However, once HF manifests, the 2-year mortality can be as high as 60%.16 This emphasizes the importance of early recognition of cardiac injury and institution of cardioprotective therapy in an effort to prevent development of HF and allow uninterrupted completion of cancer therapy.17 Thus, the diagnosis is dependent on either direct evidence of myocardial damage or functional disturbance. Either signal may be identified …