Chest Radiation Research Articles

Identification of novel hypermethylated or hypomethylated CpG sites and genes associated with anthracycline-induced cardiomyopathy

Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at ‘CpG’ sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case–control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe ‘cg15939386’ in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy.

Estimating transition intensity rate on interval-censored data using semi-parametric with EM algorithm approach

Phase IV clinical trials are designed to monitor long-term side effects of medical treatment. For instance, childhood cancer survivors treated with chest radiation and/or anthracycline are often at risk of developing cardiotoxicity during their adulthood. Often the primary focus of a study could be on estimating the cumulative incidence of a particular outcome of interest such as cardiotoxicity. However, it is challenging to evaluate patients continuously and usually, this information is collected through cross-sectional surveys by following patients longitudinally. This leads to interval-censored data since the exact time of the onset of the toxicity is unknown. Rai et al. computed the transition intensity rate using a parametric model and estimated parameters using maximum likelihood approach in an illness-death model. However, such approach may not be suitable if the underlying parametric assumptions do not hold. This manuscript proposes a semi-parametric model, with a logit relationship for the treatment intensities in two groups, to estimate the transition intensity rates within the context of an illness-death model. The estimation of the parameters is done using an EM algorithm with profile likelihood. Results from the simulation studies suggest that the proposed approach is easy to implement and yields comparable results to the parametric model.

Clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas.

We examined the clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas (NECs) to offer additional guidance for the clinical treatment of small-cell lung cancer (SCLC), which is a type of advanced intrapulmonary NEC (IPNECs). The clinical data and survival of 123 patients with advanced IPNECs and extrapulmonary NECs (EPNECs) were obtained. We retrospectively examined the corresponding clinical diagnosis and treatment and investigated the significant factors influencing the survival prognosis of patients with NECs. There were 90 cases of IPNECs (including 81 cases of SCLC), and 33 cases of EPNECs. The median overall survival (OS) of IPNECs was significantly longer than that of the EPNECs in the gastrointestinal tract and in the other regions (P < 0.05). The median OS of patients with other IPNECs was longer than that of patients with SCLC (P > 0.05). Multivariate analysis demonstrated that age, liver metastasis, number of cycles of first-line chemotherapy, and chest radiotherapy were risk factors influencing OS in patients with NECs (P < 0.05). The survival of IPNECs was significantly longer than that of EPNECs in the gastrointestinal tract and other regions. Nevertheless, patients with advanced NECs who were older and had liver metastases had a poorer prognosis. Multidisciplinary treatments including multicycle chemotherapy and a combination of chemotherapy and radiotherapy should function significantly in extending the survival of NECs.

Recommendations for the Screening of Breast Cancer of the Brazilian College of Radiology and Diagnostic Imaging, Brazilian Society of Mastology and Brazilian Federation of Gynecology and Obstetrics Association.

To present the update of the recommendations of the Brazilian College of Radiology and Diagnostic Imaging, the Brazilian Society of Mastology and the Brazilian Federation of Associations of Gynecology and Obstetrics for breast cancer screening in Brazil. Scientific evidence published in Medline, EMBASE, Cochrane Library, EBSCO, CINAHL and Lilacs databases between January 2012 and July 2022 was searched. Recommendations were based on this evidence by consensus of the expert committee of the three entities. Annual mammography screening is recommended for women at usual risk aged 40-74 years. Above 75 years, it should be reserved for those with a life expectancy greater than seven years. Women at higher than usual risk, including those with dense breasts, with a personal history of atypical lobular hyperplasia, classic lobular carcinoma in situ, atypical ductal hyperplasia, treatment for breast cancer or chest irradiation before age 30, or even, carriers of a genetic mutation or with a strong family history, benefit from complementary screening, and should be considered individually. Tomosynthesis is a form of mammography and should be considered in screening whenever accessible and available.

Pseudoprogression of thoracic tumor after radiotherapy in the era of immunotherapy: a case series.

Pseudoprogression is rarely mentioned after radiotherapy except for central nervous system tumors. With the widespread of immunotherapy, the incidence of pseudoprogression of thoracic tumor after radiotherapy is increasing. This study summarized the clinical features of pseudoprogression in 4 patients who had underwent thoracic radiotherapy after and/or followed by immunotherapy. All of them had received chemotherapy and immunotherapy before thoracic radiotherapy. After radiotherapy, pseudoprogression occurred within 3 months after initiation of immune consolidation/rechallenge therapy. At least a 20% increase in the sum of the longest diameter of target lesions were measured on their chest image. During this period, patients' ECOG PS scores remained stable, specific serum tumor markers did not increase significantly. Treatment strategies did not change after pseudoprogression. The causes of radiographic pseudoprogression in this case series may be attributed to disturbances such as pneumonitis, atelectasis, mucus blockages and infection. In the era of immunotherapy, pseudoprogression of thoracic tumors after chest radiotherapy might become a common phenomenon. It is important for us to identify pseudoprogression based on patient's general status, radiological changes, and laboratory tests.

Clinical characteristics of patients referred to cardio-oncology clinic

To explore characteristics of outpatients in a single cardio-oncology clinic, patients visiting cardio-oncology clinic of Fuwai Hospital CAMS&PUMC (Beijing, China) from January 2020 to December 2021 were analyzed retrospectively. In total, 330 patients were included, the median age (Q1, Q3) was 58(46, 66) years, and there were 192 females (58.2%). The purposes for visit included an evaluation and treatment of cardiovascular adverse reactions (n=247, 74.8%), pre-antitumor therapy assessment (n=51, 15.5%), and management of primary or metastatic cardiac tumors (n=32, 9.7%). For patients with cardiovascular adverse reactions, the most common tumor type was breast cancer (n=88, 29.5%), followed by gastrointestinal cancer (n=70, 23.5%), and hematological cancers (n=62, 20.8%). Among them, 236 cases (95.5%) had received antitumor drugs in the past; 38 cases (15.4%) had a history of chest radiotherapy; some cases were complicated with hypertension (n=69, 23.2%) and/or hyperlipidemia (n=69, 23.2%); 42 cases (14.1%) had a history of coronary heart disease; and 16 cases (5.4%) were complicated with atrial fibrillation or flutter. Among 32 patients with cardiac tumors, 11 cases (34.4%) had primary malignant tumors; 6 cases (18.8%) had benign tumors; 2 cases (6.3%) had metastatic tumors; and 13 (40.6%) had unknown pathological types. This study explores the epidemiology of cardio-oncology in China and provides clinical insights for the future development of cardio-oncology. In the future, it is still necessary to study the benefits of cardio-oncology clinics and develop standardized indicators to evaluate their benefits.

When Breasts Become a Liability—Discussing Risk-Reducing Mastectomy With Individuals Following Chest Irradiation for Childhood Cancer

This essay describes a woman who had received chest irradiation for childhood cancer and the considerations for and against breast cancer risk–reducing mastectomy.

Automation Radiomics in Predicting Radiation Pneumonitis (RP)

Radiomics has shown great promise in predicting various diseases. Researchers have previously attempted to include radiomics in their automated detection, diagnosis, and segmentation algorithms, taking these steps based on the promising outcomes of radiomics-based studies. As a result of the increased attention given to this topic, numerous institutions have developed their own radiomics software. These packages, on the other hand, have been utilized interchangeably without regard for their fundamental differences. The primary purpose of this study was to explore benefits of predictive model performance for radiation pneumonitis (RP), which is the most frequent side effect of chest radiotherapy, and through this work, we developed a radiomics model based on deep learning that intends to increase RP prediction performance by combining more data points and digging deeper into these data. In order to evaluate the most popular machine learning models, radiographic characteristics were used, and we recorded the most important of them. The high dimensionality of radiomic datasets is a major issue. The method proposed for use in data problems is the synthetic minority oversampling technique, which we used in order to create a balanced dataset by leveraging suitable hardware and open-source software. The present study assessed the efficacy of various machine learning models, including logistic regression (LR), support vector machine (SVM), random forest (RF), and deep neural network (DNN), in predicting radiation pneumonitis by utilizing specific radiomics features. The findings of the study indicate that the four models displayed satisfactory efficacy in forecasting radiation pneumonitis. The DNN model demonstrated the highest area under the receiver operating curve (AUC-ROC) value, which was 0.87, suggesting its superior predictive capacity among the models considered. The AUC-ROC values for the random forest, SVM, and logistic regression models were 0.85, 0.83, and 0.81, respectively.

Risk of male breast cancer after Hodgkin lymphoma

AbstractFemale survivors of Hodgkin lymphoma (HL) treated with chest radiotherapy have a strongly increased risk of breast cancer (BC), but the treatment-specific BC risk in male survivors of HL has not been evaluated. We assessed BC risk in a cohort of 3077 male survivors of 5-year HL treated at age ≤51 years in 20 Dutch hospitals between 1965 and 2013. We estimated standardized incidence ratios (SIRs), absolute excess risks per 10 000 person-years, and cumulative BC incidences. After a 20-year median follow-up, we observed 8 cases of male with BC. Male survivors of HL experienced a 23-fold (95% confidence interval [CI], 10.1-46.0) increased BC risk compared with the general population, representing 1.6 (95% CI, 0.7-3.3) excess BC incidences per 10 000 person-years. The 20- and 40-year cumulative BC incidences after HL treatment were 0.1% (95% CI, 0.02-0.3) and 0.7% (95% CI, 0.3-1.4), respectively. Treatment with chest radiotherapy without alkylating chemotherapy yielded a strongly increased SIR (20.7; 95% CI, 2.5-74.8), which was not significantly different for chest radiotherapy and alkylating chemotherapy (41.1; 95% CI, 13.4-96.0). Males treated with chest radiotherapy and anthracyclines had an SIR of 48.1 (95% CI, 13.1-123.1). Two patients died from BC (median follow-up, 4.7 years). To ensure early diagnosis and treatment, clinicians should be alert to BC symptoms in male survivors of HL.

Longitudinal strain analysis for assessment of early cardiotoxicity during anthracycline treatment in childhood sarcoma: A single center experience.

The growing population of long-term childhood cancer survivors encounter a substantial burden of cardiovascular complications. The highest risk of cardiovascular complications is associated with exposure to anthracyclines and chest radiation. Longitudinal cardiovascular surveillance is recommended for childhood cancer patients; however, the optimal methods and timing are yet to be elucidated. We aimed to investigate the feasibility of different echocardiographic methods to evaluate left ventricular systolic function in retrospective datasets, including left ventricular ejection fraction (LVEF), fractional shortening (FS), global longitudinal strain (GLS) and longitudinal strain (LS) as well as the incidence and timing of subclinical left ventricular dysfunction detected by these methods. A retrospective longitudinal study was performed with re-analysis of longitudinal echocardiographic data, acquired during treatment and early follow-up, including 41 pediatric sarcoma patients, aged 2.1-17.8 years at diagnosis, treated at Astrid Lindgren Children's Hospital, Stockholm, Sweden, during the period 2010-2021. All patients had received treatment according to protocols including high cumulative doxorubicin equivalent doses (≥250 mg/m2 ). In 68% of all 366 echocardiograms, LS analysis was feasible. Impaired LS values (<17%) was demonstrated in >40%, with concomitant impairment of either LVEF or FS in 20% and combined impairment of both LVEF and FS in <10%. Importantly, there were no cases of abnormal LVEF and FS without concomitant LS impairment. Our findings demonstrate feasibility of LS in a majority of echocardiograms and a high incidence of impaired LS during anthracycline treatment for childhood sarcoma. We propose inclusion of LS in pediatric echocardiographic surveillance protocols.

Changes in left ventricular strain and cardiac biomarkers in a six-year prospective follow-up after breast cancer radiotherapy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Finnish public grant Aims Breast cancer radiotherapy (RT) can lead to slowly developing cardiac dysfunction and increased incidence of heart failure with preserved ejection fraction (HFpEF). In fact, the risk for HFpEF is shown to be 16-fold after chest radiotherapy. We aimed to study the changes in left ventricular strain six years after radiotherapy as well as changes in cardiac biomarkers during the follow-up. Methods Early left-sided breast cancer patients (n=31) were prospectively followed-up for six years after RT. Left ventricular strain analysis and pro-brain natriuretic peptide (proBNP) tests were performed at baseline, after RT and at three-year and six-year controls. In addition, cardiac magnetic resonance imaging (CMR) was performed at the six-year follow-up. The results were compared with cardiac RT doses. Results Global longitudinal strain (GLS) declined only modestly from baseline 17.9±4.1% to 17.6±2.7% at six-year control (p = 0.731) while apical regions showed significant decline from baseline 24.6±6.6% to 19.8±3.5% at six-year control (p&amp;lt;0.001). ProBNP increased from baseline 63.0 [37.0, 124.0] ng/l to 98.0 [50.0, 215.0] ng/l at six-year follow-up (p = 0.022). Patients with (n=14) and without (n=16) worsening of apical strain and increase in proBNP had maximal left ventricular radiation doses 46.9±4.8 Gy versus 40.1±12.9 Gy (p = 0.049), respectively. Lower values in CMR strain were concentrated in the apical regions with an association with regional RT doses. Each 1 Gy of regional radiation dose decreased local regional strain value in CMR by 0.356 % [95%CI; 0.244, 0.468] (p&amp;lt;0.001). Conclusions A significant increase in proBNP and a significant decrease in apical strain were observed after RT in six-year follow-up. A higher left ventricular maximal radiation dose was significantly associated with worsening in apical strain and proBNP. In addition, a worse regional strain values in CMR had a dose-dependent association with corresponding RT doses. These results indicate that even contemporary breast cancer RT induces progressive cardiac changes.

A deep-learning method using single phantom to enhance megavoltage image quality for patient positioning in chest radiotherapy: a feasibility study

A deep-learning method using single phantom to enhance megavoltage image quality for patient positioning in chest radiotherapy: a feasibility study

Updated safety and efficacy results of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC) from a phase II trial.

8580 Background: CAPSTONE-1 study showed that SHR-1316 (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival in patients (pts) with ES-SCLC. Previous studies have shown that radiotherapy could potentially promote tumor antigen presentation and reverse immunosuppressive microenvironment in tumor. The purpose of this study was to explore the efficacy and safety of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts included in this study received 4~6 cycles of SHR-1316 (20mg/kg, D1, q3w) combined with EP/EC (cisplatin, 75mg/m², D1-3, q3w or carboplatin, AUC = 5, D1, q3w and etoposide, 100mg/m2, D1-5, q3w), sequentially SHR-1316 combined with chest radiotherapy (≥3Gy*10f or ≥2Gy*25f, involved-field irradiation), and then entered the maintenance treatment stage until disease progression or intolerable side effects. The main endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to January 2023, 63 pts with ES-SCLC were enrolled and received at least one dose of SHR-1316, 33 of them have received chest radiotherapy. The median age was 63 (range: 38-75), and most pts were male (53, 84.1%), former smokers (42, 66.7%) with an ECOG performance status 1 (60, 95.2%). At baseline, 24 (38.1%) pts were diagnosed with brain metastasis and 19 (30.2%) pts had liver metastasis. At the data cutoff date, the average number of treatment cycles was 6.9, 17 pts remained on treatment. 55 pts had at least one post-treatment tumor assessment. 41 pts achieved a confirmed partial response, and 12 pts had stable disease. The confirmed ORR and DCR were 74.5% and 96.4%, respectively. The median PFS was 7(CI: 4.3~9.7) months. Adverse events (AEs) occurred in 47 (74.6%) pts. Grade 3 or 4 AEs occurred in 35 (55.6%) pts. The most common grade 3 or 4 AEs included neutropenia (27, 42.9%), leukopenia (13, 20.6%), lymphocytopenia (5, 7.9%), pneumonia (4, 6.3%), anemia (3, 4.8%), and thrombocytopenia (2, 3.2%). Conclusions: SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. It is worthy of further clinical exploration. Clinical trial information: NCT04562337 .

Intermediate-Term Outcomes Following Transcatheter Aortic Valve Implantation in Patients with a History of Chest Radiation Therapy: A Propensity Score Matched Analysis.

Chest radiation therapy (XRT) has been associated with a higher rate of mortality following surgical aortic valve replacement. We performed a single-center retrospective analysis of patients with severe AS who underwent TAVI from January 1 2012 to July 31 2020 comparing patients with and without XRT. A total of 915 patients met inclusion criteria, with a total of 50 patients found to have a history of XRT. At a mean follow-up of 2.4 years, unadjusted and propensity score matching analysis demonstrated no differences in mortality, heart failure or bleeding-related hospitalization, overall stroke, and 30-day pacemaker implantation in patients with and without XRT.

A genome-wide association study for doxorubicin-induced cardiomyopathy in childhood cancer survivors from the St. Jude lifetime cohort (SJLIFE) and the childhood cancer survivor (CCSS) studies.

12088 Background: Treatment of childhood cancer using doxorubicin is associated with a well-established dose-related risk of cardiomyopathy, which can lead to heart failure and affects ~7-10% of exposed children and adolescents. Here, we identified a genetic variant associated with risk of doxorubicin-induced cardiomyopathy (diCM) in survivors of childhood cancer. Methods: A genome-wide association study using common variants (MAF≥5%; whole-genome sequencing data) was performed among 993 SJLIFE survivors of European ancestry (median age, 36.6 years; range, 8.7-62.2 years) treated with doxorubicin only (210 with diCM; defined as CTCAE grade ≥2 clinically assessed cardiomyopathy). Replication analyses were performed separately among 1,430 CCSS survivors of European ancestry (median age, 35.4 years; range, 15.8-60.7 years) and 159 SJLIFE survivors of African ancestry (median age, 32.6 years; range, 8.9-61.1 years) exposed to doxorubicin only. Analyses were adjusted for age at primary cancer diagnosis, sex, doxorubicin dose, age at last contact and top five principal components. Results: We identified a genome-wide significant association between a novel locus near HS3ST4 and diCM risk in SJLIFE survivors of European ancestry (rs112474856; OR = 2.78; P= 3.3×10-8). This association replicated in CCSS survivors of European ancestry (OR = 1.74, P= 0.036) but had an opposite effect among SJLIFE survivors of African ancestry (OR = 0.34, P= 0.028). SNP rs112474856 did not show significant association with diCM risk in two independent datasets including survivors of European ancestry in SJLIFE (OR = 1.20; P= 0.71) and CCSS (OR = 1.02; P= 0.98) who were not exposed to doxorubicin but were treated with daunorubicin or chest radiotherapy, suggesting doxorubicin specificity. No association was observed between rs112474856 and risks of cardiomyopathy (OR = 1.00; P= 0.88) or heart failure (OR = 1.00; P= 0.59) in 361,194 UK Biobank participants from the general population. HS3ST4 was significantly upregulated ( P= 4.7×10-6) in response to doxorubicin treatment in human induced pluripotent stem-cell-derived cardiomyocytes from patients with diCM. HS3ST4 encodes heparan sulfate, the latter was recently linked to immune activation, cardiac fibrosis, and heart failure. Conclusions: Leveraging the two largest cohorts of childhood cancer survivors in North America, we identified and replicated a novel locus for diCM which was associated with increased risk in survivors of European ancestry but decreased in their African counterpart.

The cardiac outcomes of radiation therapy to thoracic malignancies: Nationwide analysis.

e20565 Background: Radiation therapy (RT) is a therapeutic and palliative treatment option for thoracic neoplasms, including lung cancer (LC), breast cancer (BC), esophageal cancer (EC), and lymphomas. However, chest irradiation's long-term cardiac side effects continue to lead to a wide range of heart conditions. While the immediate side effects are usually in form of pericardial diseases, the long-term complications, usually manifest manifesting in the average of 20 years, include Congestive Heart Failure(CHF), Coronary Artery Disease (CAD), Cardiomyopathy (CMP), Conduction Disorders, Constrictive Pericarditis, and Valvular heart diseases. We aimed to demonstrate most common cardiac outcomes in cancer patients with thoracic RT. Methods: Adult patients with a history of primary Thoracic Malignancies (BC, LC, Thymic Cancer, EC, and Mediastinal Cancer) who had RT are extracted from Nationwide Inpatient Sample 2016 - 2019 by using ICD-10 codes. Other malignancies which can be treated with radiation therapy and all secondary malignancies are excluded from the primary comparison group. Cardiac outcomes are defined as the prevalence of CHF, CAD, CMP, Conduction Disorders, Pericardial diseases, and Valvular heart diseases in the primary group. Multivariate logistic regression analysis was conducted to adjust for confounders. Results: A total of 454.229 adult hospitalizations with primary Thoracic Malignancies who had RT were defined in the NIS 2016-2019 database. The patients with Thoracic malignancies who had RT were older ( mean age 68 vs. 57 years) and had a greater white race population ( %76 vs. %67, P &lt; 0.001). The patients with Thoracic malignancies who had RT have greater odds of developing Chronic Pericarditis [AOR 2, 95% CI 1.9–2.2, P &lt; 0.001], Acute Pericarditis [AOR 2.3, 95% CI 1.9–2.9, P &lt; 0.001], Constrictive Pericarditis [AOR 2.8, 95% CI 2.1–3.7, P &lt; 0.001], Conduction Disorders [AOR 1.3, 95% CI 1.2–1.35, P &lt; 0.001], CAD [AOR 1.24, 95% CI 1.2-1.27, P &lt; 0.001], CHF [AOR 1.44, 95% CI 1.4-1.5, P &lt; 0.001], Valvular Heart Disease [AOR 1.37, 95% CI 1.3-1.4, P &lt; 0.001] and no statistically different odds of developing Cardiac Arrest [AOR 1, 95% CI 0.9-1.10, P = 0.6] or MI [AOR 1.1, %95 CI 1–1.15] compared to the general adult population. Conclusions: The introduction of RT led to improvement in survival for thoracic malignancies. However, radiation-induced cardiovascular disease (CVD) can sometimes limit the benefits from RT. For example, CVD is the most common nonmalignant cause of death in patients with breast cancer and Hodgkin's lymphoma. In this large database study, we found an increase in the prevalence of multiple CVD in patients with a history of RT to the chest, with odds particularly high for pericardial disease, CAD and CHF. These findings highlight the importance of continuing to develop techniques to limit RT-related complications, and ensuring close cardiovascular follow up, possibly including screening.

Polygenic risk of anthracycline-related cardiomyopathy in childhood cancer survivors: Report from children’s oncology group and childhood cancer survivor study.

12090 Background: Considerable inter-patient variability in anthracycline-related cardiomyopathy (aCM) risk exists among childhood cancer survivors (CCS). A polygenic risk score (PRS) that accounts for combined effects of multiple genetic variants is established in other clinical situations, but remains understudied in anthracycline-exposed CCS. Methods: For discovery, a case-control set of 278 anthracycline-exposed non-Hispanic White (NHW) CCS (129 aCM cases; 149 controls) matched on primary cancer diagnosis, year of diagnosis and duration of follow-up was included from a Children’s Oncology Group study (COG-ALTE03N1). Genomic DNA underwent whole exome sequencing (100X depth). We searched Medline and Embase databases between 2005 and 2022 to curate evidence for published single nucleotide polymorphisms (SNPs) associated with CM. We identified 1,156 SNPs on 343 genes with minor allele frequency [MAF] ≥0.05 in white populations. We constructed a weighted PRS using sequenced SNPs that were linkage disequilibrium pruned, yielding a final list of 279 independent SNPs. Conditional logistic regression models adjusted for anthracycline dose, age at diagnosis, sex, chest radiation and cardiovascular risk factors (CVRFs; diabetes, hypertension, dyslipidemia) were used to estimate PRS-aCM associations. An independent population of 475 anthracycline-exposed NHW CCS from the Childhood Cancer Survivor Study (CCSS: 96 cases; 379 matched controls) was used to replicate the PRS-aCM association. Area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of a model including the PRS. Results: Median age at primary cancer diagnosis was 7y for cases and controls in the Discovery and 11y in the Replication set. Mean anthracycline dose was higher for cases (Discovery: 312 v 186 mg/m2; Replication: 333 v 289 mg/m2). Cases were more likely to have received chest radiation (Discovery: 35.7% v 24.8%; Replication: 34.3% v 23.2%); and were more likely to have a CVRF (Discovery: 37.2% v 8.7%; Replication: 55.2% v 31.9%). PRScontinuous was significantly associated with aCM (aOR = 2.09, 95%CI: 1.1-4.0, p = 0.024) in the Discovery set. Compared to a model with clinical variables only, a model including the PRS had significant predictive performance: AUCclin= 0.72, 95% CI: 0.65-0.79. v AUCclin+PRS= 0.91, 95% CI: 0.87-0.95, p &lt; 0.001. In the Replication set, the top PRS quartile (top 25%) was significantly associated with aCM (aOR = 2.14, 95%CI: 1.05-4.37, p = 0.036; reference: lowest PRS quartile). Conclusions: The significant association between this comprehensively curated PRS and aCM in CCS could serve as an important tool to identify survivors at increased risk for CM and inform targeted interventions.

Cardiac iron overload in pediatric oncology and bone marrow transplant survivors.

e22022 Background: Cardiovascular late effects are a leading cause of mortality and morbidity in childhood cancer and Bone Marrow Transplant (BMT) survivors. In patients receiving chronic red blood cell transfusions, excess iron may be deposited in the liver, heart, and pituitary gland. Iron overload cardiomyopathy is characterized as a restrictive physiology with early diastolic dysfunction ultimately progressing to end-stage dilated cardiomyopathy. Iron loading in the heart can also lead to arrhythmias and increase myocardial ischemia reperfusion injury due to increased formation of reactive oxygen species. It is not yet known whether high transfused packed red blood cell (PRBC) volumes in cancer and BMT patients leads to cardiac iron deposition, and whether iron-induced cardiac injury contributes to the known cardiovascular late effects in these patients. Methods: 83 childhood cancer and BMT survivors with elevated serum ferritin levels and subsequent liver Magnetic Resonance (MR) imaging were identified. 18 patients (21.7%) who had liver iron content of &gt; 12mg/g (mean 16.0 ± 7.36 mg/g) also underwent Cardiac MRI (CMR) to determine cardiac iron content. Results: Median transfused blood volume was 393 ml/kg [95% Confidence Interval (CI) 170-780 ml/kg]. All 18 patients had at least one echocardiogram showing normal ventricular ejection fractions [mean 65.1 ± Standard Deviation (SD) 3.53%] and normal shortening fractions (mean 35.4 ± 3.67%). All patients had myocardial iron content within normal ranges (T2* relaxation time mean 35.1 msec ± 7.1 [normal &gt;20 msec], mean ± SD iron content 0.63± 0.2 mg/g dry weight, range 0.5-1.1). There was no association of cardiac iron content with transfused blood volume, anthracycline dose (mg/m2) or liver iron content (Pearson Correlation Coefficients 0.27, 0.29 and 0.89 respectively). Conclusions: Childhood cancer and BMT patients receive multiple PRBC transfusions to treat symptomatic anemia. It is currently unknown whether excess iron deposition in the heart contributes to the cardiac effects of impaired diastolic function and ultimately systolic dysfunction. In this study, 11 of 18 patients (61.1%) with high levels of liver iron had at least 1 other risk factor for the development of future cardiac dysfunction (either anthracycline exposure, radiation to the chest or total body irradiation or both). Larger studies are needed to determine whether oncology patients with high levels of iron deposition in their liver are also at risk for clinically significant cardiac iron loading, and what risk factors may exist for elevated myocardial iron content.

Treatment and treatment-related toxicity following subsequent breast cancer: A report from the Childhood Cancer Survivor Study (CCSS).

10051 Background: Long-term survivors of childhood cancer are at high risk for treatment-related breast cancer and have elevated mortality risk after a breast cancer diagnosis than the general population. There is no standard of care for women with treatment-related breast cancer, and treatment patterns and risk for toxicity are not known. Methods: Female survivors in CCSS diagnosed and treated for childhood cancer between 1970-1999 who developed a subsequent breast cancer (N = 344) were matched with females with sporadic breast cancer (multi-institution sampling; 1:1 matching ratio) on age at breast cancer diagnosis, breast cancer treatment decade, race/ethnicity, histology, and hormone receptor status. Conditional logistic regression evaluated univariate associations with treatments, toxicities, and synchronous breast cancer (≤12 months from diagnosis). Hazard ratios (HR) for metachronous disease risk ( &gt; 12 months from diagnosis) were estimated using proportional hazard models with robust variance estimation. Results: Among survivors, the median time between the primary cancer and initial breast cancer diagnosis at median age 40 years (IQR 35-45) was 26 years (IQR 21-30). Two-thirds received chest radiation therapy (RT) and 44% were treated with anthracyclines for their childhood cancer. In the matched sample, breast cancer clinical features were similar between survivors vs. controls, but the odds of synchronous bilateral disease at diagnosis was 4.8-fold greater (95% CI 2.2-10.2) among survivors. Surgical interventions (99% vs. 98%, P = 0.22) and treatment with chemotherapy (46% vs. 45%, P = 0.43) were similar between groups. However, women with sporadic breast cancers were more likely to receive RT (OR 4.4, 95% CI 2.9-6.8) or anthracyclines (OR 2.4, 95% CI 1.5-3.8). Survivors were more likely to undergo mastectomy (OR 3.0, 95% CI 2.1-4.2) and experience surgical complications (OR 2.2, 95% CI 1.4-3.4), and had 1.4-fold greater odds (95% CI 1.01-1.98) of experiencing any treatment-related toxicity compared to controls. The 15-year cumulative incidence of developing a metachronous breast cancer was 20% (95% CI 13-25%) in survivors versus 9% (95% CI 5-13%) in controls (P &lt; 0.001). Risk of metachronous disease remained higher among survivors (HR 2.4, 95% CI 1.5-4.0) after adjusting for breast cancer treatments (mastectomy, RT, and anthracyclines). Conclusions: Female survivors of childhood cancer who develop subsequent treatment-related breast cancer are more likely to develop synchronous and metachronous breast cancer compared to controls. Despite similar biologic characteristics, survivors are treated differently from females with sporadic breast cancer and are more likely to experience treatment-related toxicities. Further study of how treatment of subsequent breast cancers and corresponding toxicities impact prognosis and survival is needed.

Enhancing prediction of cancer therapy-related cardiomyopathy from surveillance echocardiograms: A Children’s Oncology Group (COG) report.

10012 Background: Many childhood cancer patients receive cardiotoxic therapies and need surveillance for therapy-related cardiomyopathy (CM). (Echo)cardiography is used to screen for cardiac dysfunction but has relatively poor discriminatory ability to predict who will develop CM. We sought to identify combinations of echo parameters that can better predict which patients subsequently develop CM. Methods: Longitudinal echos (obtained per routine care) of patients diagnosed with cancer &lt; 21y who subsequently met CM criteria (left ventricular [LV] ejection fraction ≤50% / fractional shortening ≤28%, ≥2 times, with ≥1 time after completion of cancer therapy) plus clinical data were collated from COG sites. Echos and data from patients without CM were also collated. All echos were centrally remeasured for 42 routinely reported parameters in blinded fashion. We applied least absolute shrinkage and selection operator (LASSO) to fit logistic models to identify the most influential predictors for CM development within 2 and 5y of echo, plus age and sex. Data were randomly split into training (85%) and test (15%) sets with 10-fold cross validation. Prediction accuracy was calculated using area under the ROC curve (AUC), based on the model that provided the minimum mean cross-validated error. Results: Echos from 88 CM cases (248 echos predating CM) and 126 non-cases (518 echos) were available. Patients (n = 214) were diagnosed at mean age 7.7±5.2y with mean 9.5±4.0y follow-up. Mean doxorubicin equivalent doses for cases and non-cases were 350±188 and 272±199 mg/m2, respectively. For 2y CM prediction, models achieved training AUC 0.85 (95%CI 0.78-0.92; 261 echos) and test AUC 0.74 (95% CI 0.74-0.90; 46 echos). Factors selected included age, 2-dimensional (2D) measurements of LV geometry (LV systolic and end-systolic dimensions, and posterior wall thickness), systolic function (M-mode fractional shortening), diastolic function (mitral inflow E wave, septal E’, septal A’), and a measurement of combined systolic and diastolic function (myocardial performance index). For 5y CM prediction, models achieved training AUC 0.90 (95%CI 0.85-0.95; 175 echos) and test AUC 0.89 (95%CI 0.78-0.99; 30 echos). Age, LV end-systolic dimension (2D and M-mode), M-mode LV posterior wall thickness, 2D wall thickness-dimension ratio, mitral inflow E, septal E’, septal A’, and the myocardial performance index were selected. At both times 2D end-systolic dimension was the most influential parameter. Inclusion of anthracycline and chest radiotherapy dose did not meaningfully improve the AUCs. Conclusions: Prediction models that incorporate conventional echo data may be able to accurately identify childhood cancer patients at high risk of developing CM 2-5y prior to CM diagnosis. This may provide a window of opportunity to introduce interventions that may arrest or slow CM progression.