Advancing the care of individuals with cancer through innovation & technology: Proceedings from the cardiology oncology innovation summit 2020 and 2021.

As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era.

Novel Radiomic Measurements of Tumor-Associated Vasculature Morphology on Clinical Imaging as a Biomarker of Treatment Response in Multiple Cancers.

PURPOSE: The tumor-associated vasculature (TAV) differs from healthy blood vessels by its convolutedness, leakiness, and chaotic architecture, and these attributes facilitate the creation of a treatment-resistant tumor microenvironment. Measurable differences in these attributes might also help stratify patients by likely benefit of systemic therapy (e.g., chemotherapy). In this work, we present a new category of computational image-based biomarkers called quantitative tumor-associated vasculature (QuanTAV) features, and demonstrate their ability to predict response and survival across multiple cancer types, imaging modalities, and treatment regimens involving chemotherapy. EXPERIMENTAL DESIGN: We isolated tumor vasculature and extracted mathematical measurements of twistedness and organization from routine pretreatment radiology (CT or contrast-enhanced MRI) of a total of 558 patients, who received one of four first-line chemotherapy-based therapeutic intervention strategies for breast (n = 371) or non-small cell lung cancer (NSCLC, n = 187). RESULTS: Across four chemotherapy-based treatment strategies, classifiers of QuanTAV measurements significantly (P < 0.05) predicted response in held out testing cohorts alone (AUC = 0.63-0.71) and increased AUC by 0.06-0.12 when added to models of significant clinical variables alone. Similarly, we derived QuanTAV risk scores that were prognostic of recurrence-free survival in treatment cohorts who received surgery following chemotherapy for breast cancer [P = 0.0022; HR = 1.25; 95% confidence interval (CI), 1.08-1.44; concordance index (C-index) = 0.66] and chemoradiation for NSCLC (P = 0.039; HR = 1.28; 95% CI, 1.01-1.62; C-index = 0.66). From vessel-based risk scores, we further derived categorical QuanTAV high/low risk groups that were independently prognostic among all treatment groups, including patients with NSCLC who received chemotherapy only (P = 0.034; HR = 2.29; 95% CI, 1.07-4.94; C-index = 0.62). QuanTAV response and risk scores were independent of clinicopathologic risk factors and matched or exceeded models of clinical variables including posttreatment response. CONCLUSIONS: Across these domains, we observed an association of vascular morphology on CT and MRI-as captured by metrics of vessel curvature, torsion, and organizational heterogeneity-and treatment outcome. Our findings suggest the potential of shape and structure of the TAV in developing prognostic and predictive biomarkers for multiple cancers and different treatment strategies.

Novel Non-Invasive Radiomic Signature on CT Scans Predicts Response to Platinum-Based Chemotherapy and Is Prognostic of Overall Survival in Small Cell Lung Cancer.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy characterized by initial chemosensitivity followed by resistance and rapid progression. Presently, there are no predictive biomarkers that can accurately guide the use of systemic therapy in SCLC patients. This study explores the role of radiomic features from both within and around the tumor lesion on pretreatment CT scans to a) prognosticate overall survival (OS) and b) predict response to chemotherapy. METHODS: One hundred fifty-three SCLC patients who had received chemotherapy were included. Lung tumors were contoured by an expert reader. The patients were divided randomly into approximately equally sized training (Str = 77) and test sets (Ste = 76). Textural descriptors were extracted from the nodule (intratumoral) and parenchymal regions surrounding the nodule (peritumoral). The clinical endpoints of this study were OS, progression-free survival (PFS), and best objective response to chemotherapy. Patients with complete or partial response were defined as "responders," and those with stable or progression of disease were defined as "non-responders." The radiomic risk score (RRS) was generated by using the least absolute shrinkage and selection operator (LASSO) with the Cox regression model. Patients were classified into the high-risk or low-risk groups based on the median of RRS. Association of the radiomic signature with OS was evaluated on Str and then tested on Ste. The features identified by LASSO were then used to train a linear discriminant analysis (LDA) classifier (MRad) to predict response to chemotherapy. A prognostic nomogram (NRad+Clin) was also developed on Str by combining clinical and prognostic radiomic features and validated on Ste. The Kaplan-Meier survival analysis and log-rank statistical tests were performed to assess the discriminative ability of the features. The discrimination performance of the NRad+Clin was assessed by Harrell's C-index. To estimate the clinical utility of the nomogram, decision curve analysis (DCA) was performed by calculating the net benefits for a range of threshold probabilities in predicting which high-risk patients should receive more aggressive treatment as compared with the low-risk patients. RESULTS: A univariable Cox regression analysis indicated that RRS was significantly associated with OS in Str (HR: 1.53; 95% CI, [1.1-2.2; p = 0.021]; C-index = 0.72) and Ste (HR: 1.4, [1.1-1.82], p = 0.0127; C-index = 0.69). The RRS was also significantly associated with PFS in Str (HR: 1.89, [1.4-4.61], p = 0.047; C-index = 0.7) and Ste (HR: 1.641, [1.1-2.77], p = 0.04; C-index = 0.67). MRad was able to predict response to chemotherapy with an area under the receiver operating characteristic curve (AUC) of 0.76 ± 0.03 within Str and 0.72 within Ste. Predictors, including the RRS, gender, age, stage, and smoking status, were used in the prognostic nomogram. The discrimination ability of the NRad+Clin model on Str and Ste was C-index [95% CI]: 0.68 [0.66-0.71] and 0.67 [0.63-0.69], respectively. DCA indicated that the NRad+Clin model was clinically useful. CONCLUSIONS: Radiomic features extracted within and around the lung tumor on CT images were both prognostic of OS and predictive of response to chemotherapy in SCLC patients.

Outcomes in patients with anthracycline-induced cardiomyopathy undergoing left ventricular assist devices implantation.

AIMS: Improved cancer survivorship has led to a higher number of anthracycline-induced cardiomyopathy patients with end-stage heart failure. We hypothesize that outcomes following continuous-flow LVAD (CF-LVAD) implantation in those with anthracycline-induced cardiomyopathy are comparable with other aetiologies of cardiomyopathy. METHODS AND RESULTS: Using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 2008 to 2017, we identified patients with anthracycline-induced cardiomyopathy who received a CF-LVAD and compared them with those with idiopathic dilated (IDM) and ischaemic cardiomyopathies (ICM). Mortality was studied using the Cox proportional hazards model. Other adverse events were evaluated using competing risk models. Overall, 248 anthracycline-induced cardiomyopathy patients underwent CF-LVAD implantation, with a median survival of 48 months, an improvement compared with those before 2012 [adjusted hazards ratio (aHR): 0.53; confidence interval (CI): 0.33-0.86]. At 12 months, 85.1% of anthracycline-induced cardiomyopathy, 86.0% of IDM, and 80.2% of ICM patients were alive (anthracycline-induced cardiomyopathy vs. IDM: aHR: 1.12; CI: 0.88-1.43 and anthracycline-induced cardiomyopathy vs. ICM: aHR: 0.98; CI: 0.76-1.28). Anthracycline-induced cardiomyopathy patients had a higher major bleeding risk compared with IDM patients (aHR: 1.23; CI: 1.01-1.50), and a lower risk of stroke and prolonged respiratory support compared to ICM patients (aHR: 0.31 and 0.67 respectively; both P < 0.05). There was no difference in the risk of major infection, acute kidney injury, and venous thromboembolism. CONCLUSIONS: After receiving a CF-LVAD, survival in patients with anthracycline-induced cardiomyopathy is similar to those with ICM or IDM. Further research into differential secondary endpoints-related disparities is warranted.

Cardiovascular adverse events associated with BRAF versus BRAF/MEK inhibitor: Cross-sectional and longitudinal analysis using two large national registries.

BACKGROUND: Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood. METHODS: This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques. RESULTS: In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045). CONCLUSIONS AND RELEVANCE: In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

MET alterations and their impact on the future of non-small cell lung cancer (NSCLC) targeted therapies.

Introduction: The MET gene and its pathway normally plays a crucial role in cell homeostasis, motility, and apoptosis. However, when the MET gene is altered, there is an imbalance toward cell proliferation and invasion commonly seen in numerous different types of cancers. The heterogeneous group of MET alterations that includes MET amplification, MET exon 14 skipping mutation, and MET fusions has been difficult to diagnose and treat. Currently, treatments are focused on tyrosine kinase inhibitors but now there is emerging data on novel MET-targeted therapies including monoclonal antibodies and antibody-drug conjugates that have emerged.Areas covered: We introduce new emerging data on MET alterations in non-small cell lung cancer (NSCLC) that has contributed to advances in MET targeted therapeutics. We offer our perspective and examine new information on the mechanisms of the MET alterations in this review.Expert opinion: Given the trends currently involving the targeting of MET altered malignancies, there will most likely be a continued rapid expansion of testing, novel tyrosine kinase inhibitors and potent antibody approaches. Combination treatments will be necessary to optimize management of advanced and early disease.

Novel, non-invasive imaging approach to identify patients with advanced non-small cell lung cancer at risk of hyperprogressive disease with immune checkpoint blockade.

PURPOSE: Hyperprogression is an atypical response pattern to immune checkpoint inhibition that has been described within non-small cell lung cancer (NSCLC). The paradoxical acceleration of tumor growth after immunotherapy has been associated with significantly shortened survival, and currently, there are no clinically validated biomarkers to identify patients at risk of hyperprogression. EXPERIMENTAL DESIGN: A total of 109 patients with advanced NSCLC who underwent monotherapy with Programmed cell death protein-1 (PD1)/Programmed death-ligand-1 (PD-L1) inhibitors were included in the study. Using RECIST measurements, we divided the patients into responders (n=50) (complete/partial response or stable disease) and non-responders (n=59) (progressive disease). Tumor growth kinetics were used to further identify hyperprogressors (HPs, n=19) among non-responders. Patients were randomized into a training set (D1=30) and a test set (D2=79) with the essential caveat that HPs were evenly distributed among the two sets. A total of 198 radiomic textural patterns from within and around the target nodules and features relating to tortuosity of the nodule associated vasculature were extracted from the pretreatment CT scans. RESULTS: The random forest classifier using the top features associated with hyperprogression was able to distinguish between HP and other radiographical response patterns with an area under receiver operating curve of 0.85±0.06 in the training set (D1=30) and 0.96 in the validation set (D2=79). These features included one peritumoral texture feature from 5 to 10 mm outside the tumor and two nodule vessel-related tortuosity features. Kaplan-Meier survival curves showed a clear stratification between classifier predicted HPs versus non-HPs for overall survival (D2: HR=2.66, 95% CI 1.27 to 5.55; p=0.009). CONCLUSIONS: Our study suggests that image-based radiomics markers extracted from baseline CTs of advanced NSCLC treated with PD-1/PD-L1 inhibitors may help identify patients at risk of hyperprogressions.

Cardiovascular Events Associated with Chimeric Antigen Receptor T Cell Therapy: Cross-Sectional FDA Adverse Events Reporting System Analysis.

Chimeric antigen receptor (CAR) T cell therapy is approved in the United States for the treatment of acute lymphocytic leukemia and aggressive B cell lymphomas. Multiple cardiovascular adverse events (CVEs) associated with CAR-Ts have been observed in small studies, but no large-scale studies exist. Leveraging the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), we identified all reported adverse events (AEs) associated with CAR-T therapy (tisagenlecleucel and axicabtagene ciloleucel) from 2017 to 2019. Reports with missing age and sex were excluded. CVEs were classified into arrhythmias, heart failure (HF), myocardial infarction (MI), and other CVEs. Logistic regression and hierarchical clustering were used to identify factors associated with CVEs. A total of 996 reported AEs were observed (39.1% associated with tisagenlecleucel and 60% with axicabtagene ciloleucel). Of all patients experiencing AEs, the median age was 54 (interquartile range, 21 to 65) years; 38.9% were females. In total, 19.7% (196) of all AEs reported to the FDA were CVEs. The most common CVEs were arrhythmia (77.6%), followed by HF (14.3%) and MI (0.5%). In adjusted analysis a positive association was observed between those presenting with CVE with neurotoxicity (odds ratio, 1.76; 95% confidence interval, 1.20 to 2.60; P = .004). Additionally, when both CVE and cytokine release syndrome (CRS) are present, neurotoxicity is the most common noncardiac AE, which clusters with them (Jaccard similarity: 73.1). The mortality rate was 21.1% overall but 30.1% for those reporting CVEs. In FAERS, reported CVEs with CAR-T are associated with high reported mortality. The development of either CRS or neurotoxicity should prompt vigilance for cardiovascular events.

Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases.

BACKGROUND & AIMS: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. METHODS: DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS: Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSIONS: In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.

Predicting pathologic response to neoadjuvant chemoradiation in resectable stage III non-small cell lung cancer patients using computed tomography radiomic features.

OBJECTIVE: The use of a neoadjuvant chemoradiation followed by surgery in patients with stage IIIA NSCLC is controversial and the benefit of surgery is limited. There are currently no clinically validated biomarkers to select patients for such an approach. In this study we evaluate computed tomography (CT) derived intratumoral and peritumoral texture and nodule shape features in their ability to predict major pathological response (MPR). MPR being defined as ≤10% of residual viable tumor, assessed at the time of surgery. MATERIAL AND METHODS: Ninety patients with stage III NSCLC treated with chemoradiation prior to surgical resection were selected. The patients were divided randomly into two equal sets, one for training and one for independent testing. The radiomic texture and shape features were extracted from within the nodule (intra) and from the parenchymal regions immediately surrounding the nodule (peritumoral). A univariate regression analysis was performed on the image and clinicopathologic variables and then included into a multivariable logistic regression (MLR) for binary outcome prediction of MPR. The radiomic signature risk-score was generated by using a multivariate Cox regression model and association of the signature with OS and DFS was also evaluated. RESULTS: Thirteen stable and predictive intratumoral and peritumoral radiomic texture features were found to be predictive of MPR. The MLR classifier yielded an AUC of 0.90 ±â€¯0.025 within the training set and a corresponding AUC = 0.86 in prediction of MPR within the test set. The radiomic signature was also significantly associated with OS (HR = 11.18, 95% CI = 3.17, 44.1; p-value = 0.008) and DFS (HR = 2.78, 95% CI = 1.11, 4.12; p-value = 0.0042) in the testing set. CONCLUSION: Texture features extracted within and around the lung tumor on CT images appears to be associated with the likelihood of MPR, OS and DFS to chemoradiation.

Implementation of an electronic medical record tool for early detection of deep vein thrombosis in the ambulatory oncology setting.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and hospitalization in cancer patients. OBJECTIVES: To evaluate the feasibility of an electronic alert to identify and screen at-risk individuals and gather rates of early detection of deep vein thrombosis (DVT). PATIENTS/METHODS: An alert was built into the electronic medical record based on a validated risk tool (Khorana Score [KS]) and outcomes evaluated in an initial silent phase. The alert functioned in real time to warn physicians of high-risk patients (KS ≥ 3) and suggested lower extremity screening ultrasonography in a subsequent active phase. RESULTS: Of 194 consecutive patients identified as high risk in the silent phase, 14 (7.2%) developed subsequent DVT or pulmonary embolism (PE) over 90-day follow-up, with a median of 27 days. Mean 90-day emergency room (ER) visits, all-cause admissions, and length of stay (days) for patients with DVT were 1.2, 1.6, and 9.1 compared to 0.89, 0.93, and 5.1 for all patients, respectively. In the active phase, 197 consecutive alerts met inclusion criteria, and 40 patients (20.3%) received a screening ultrasound. Five (12.5%) had a DVT and were started on therapeutic anticoagulation. Of patients with alerts who had screening deferred, 13 (8.3%) were later diagnosed with DVT (median 50.5 days) and 7 (4.5%) with PE. CONCLUSION: An automated alert may have value in early detection of DVT in high-risk cancer patients leading to earlier intervention, and could potentially prevent VTE-related morbidity.

Safety and Efficacy of PD-1/PD-L1 Inhibitors in Treatment-Naive and Chemotherapy-Refractory Patients With Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small-cell lung carcinoma (NSCLC). However, there is a relative lack of data on comparative efficacy of these drugs in the first-line setting versus chemotherapy-treated patients. We compared the efficacy and toxicity of these drugs in these 2 distinct groups of patients. MATERIALS AND METHODS: Electronic databases (PubMed-Medline, EMBASE, Scopus) and major conference proceedings were systematically searched for all phase I to III clinical trials in NSCLC using PD-1/PD-L1 inhibitors. Objective response rate (ORR) and progression-free survival (PFS) data were collected and combined using DerSimonian and Laird random effects model meta-analysis. The I2 statistic was used to assess heterogeneity. RESULTS: Seventeen distinct trials (8 with treatment-naive patients [n = 937]; 14 with chemotherapy-treated patients [n = 3620]; 5 with separate treatment-naive and previously treated arms) were included. Treatment-naive patients had a statistically significant higher ORR (30.2%; 95% confidence interval [CI], 22.70-38.2) than patients previously treated with chemotherapy (ORR, 20.1%; 95% CI, 17.5-22.9; P = .02). No significant differences in PFS were observed between the 2 groups. Treatment-naive patients had statistically significant higher rates of all grade pneumonitis compared with previously treated patients (4.9%; 95% CI, 3.4-6.7 vs. 3.0%; 95% CI, 2.0-4.1; P = .04); however, no significant differences in any other immune-related adverse events were observed. CONCLUSION: PD-1/PD-L1 inhibitor therapy for advanced NSCLC has a significantly higher ORR and a higher rate of immune-mediated pneumonitis when used in the first-line setting compared with chemotherapy treated patients.

Role of immune-checkpoint inhibitors in lung cancer.

Immune checkpoint inhibitors, mainly drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) pathways, represent a remarkable advance in lung cancer treatment. Immune checkpoint inhibitors targeting PD-1 and PD-L1 are approved for the treatment of patients with non-small-cell lung cancer, with impressive clinical activity and durable responses in some patients. This review will summarize the mechanism of action of these drugs, the clinical development of these agents and the current role of these agents in the management of patients with lung cancer. In addition, the review will discuss the role of predictive biomarkers for optimal patient selection for immunotherapy and management of autoimmune side effects of these agents.

Afatinib and lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have an established role in the treatment of non-small-cell lung cancer (NSCLC). First-generation reversible ATP-competitive EGFR-TKIs are approved for the initial treatment of patients with EGFR mutation-positive advanced NSCLC. Afatinib is an irreversible second-generation EGFR-TKI with potent preclinical activity against EGFR (wild type and mutant), HER2, HER4 and EGFR-mutant NSCLC with acquired resistance to reversible EGFR-TKI. LUX-Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment-naïve patients with advanced adenocarcinoma of the lung and EGFR mutation. Based on these results, afatinib was recently approved for the first-line treatment of NSCLC patients with EGFR mutation. This article summarizes current status of preclinical and clinical development of afatinib in NSCLC.

Breast cancer with brain metastases in pregnancy.

Breast cancer during pregnancy is a therapeutic challenge. Evidence to guide management in metastatic breast cancer during pregnancy is limited, mainly because of a lack of randomized trials. Care needs to be individualized with interdisciplinary collaboration. Various case reports and case series in the literature have shown the safety of some chemotherapeutic agents during the second and third trimesters of pregnancy. Surgery is also safe after the first trimester. Brain metastasis from breast cancer during pregnancy is an especially challenging clinical situation and has been reported only in one other case. We present the case of a young woman with HER2/neu overexpressed inflammatory breast cancer who became pregnant while on treatment, refused termination of pregnancy, and developed brain metastasis during the second trimester of pregnancy, posing a management dilemma.