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Supplementary Data from 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.

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., In two independent real‐world cohorts, combination BRAF/MEK inhibitors were associated with increased cardiovascular adverse events compared to monotherapy, especially HF, and hypertension.

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 proli...

Purpose: Tumor-associated vasculature differs from healthy blood vessels by its chaotic architecture and twistedness, which promotes treatment resistance. Measurable differences in these attributes may help stratify patients by likely benefit of systemic therapy (e.g. chemotherapy). In this work, we present a new category of radiomic biomarkers called quantitative tumor-associated vasculature (QuanTAV) features, and demonstrate their ability to predict response and survival across multiple cancers, imaging modalities, and treatment regimens. Experimental Design: We segmented tumor vessels and computed mathematical measurements of twistedness and organization on routine pre-treatment radiology (CT or contrast-enhanced MRI) from 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 4 chemotherapy-based treatment strategies, classifiers of QuanTAV measurements significantly (p, This manuscript has been accepted for publication in Clinical Cancer Research, which is published by the American Association for Cancer Research

BackgroundSmall 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.MethodsOne 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.ResultsA 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.ConclusionsRadiomic 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.

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.

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

Background Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related stroke events can have high morbidity and mortality. Neurological monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterisation of such rare, but fatal adverse events requires integration of real-world data. Methods U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011–2018. Patients ≥18 years of age, treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. All strokes (ischemic or haemorrhagic), comorbidities, and treatment details were identified using diagnosis and billing codes. Patients from the ICI cohort were matched 1:1 to those in the chemotherapy cohort according to age, gender, NCI comorbidity score, and primary cancer as presented in the study design (figure 1). The matched cohorts were split by the specific type of chemotherapy (targeted or cytotoxic) used in the control patients. This yielded a total of 2,177 pairs of matched patients where the control arm received targeted chemotherapy, and 3,550 pairs of matched patients where the control arm received cytotoxic chemotherapy. Analyses included descriptive statistics and Cox proportional hazards regression. Results A total of 16,574 patients received at least one dose of ICI therapy for any advanced cancer. Overall 9,496 patients who were treated with ICI met the study eligibility criteria. Stroke was identified in 489 (5.14%) patients. Mean age (±standard deviation, SD) was 60 (±12), male 62%, mean (±SD) NCI comorbidity index 2.3 (±2.12), median time to stroke was 168 days. 51.3% patients received anti-PD1 monotherapy, 37.6% received anti-CTLA4, 3.3.% anti-PD-L1 and 7.8% received combination therapy (anti-PD1 plus anti-CTLA4). One-year cumulative incidence (CI) in the matched ICI vs. targeted and ICI vs. cytotoxic chemotherapy were 6.3% vs. 5.7% (p=0.07) and 4.95% vs. 4.08% (p=0.90) respectively (table 1). Within the ICI cohort, CI of stroke events with anti-CTLA4 monotherapy vs. anti-PD1/PD-L1 and anti-CTLA-4 plus anti-PD-1 combination vs. PD1/PD-L1 monotherapy were 9.89% vs. 4.54% and 6.69% vs. 3.73%, respectively (table 2). On multivariable regression analyses, patients with malignant melanoma, and those receiving anti-CTLA-4 monotherapy were associated with higher risk of stroke events, while the risk was lower in patients with head and neck cancer and those who received anti-PD-1 monotherapy (table 3 and 4). Conclusions To the best of our knowledge, this is the largest and comprehensive real-world longitudinal study for stroke events in advanced cancer patients treated with ICI. Cumulative incidence of stroke was significantly higher in patients on anti-CTLA-4 monotherapy and anti-CTLA-4 plus anti-PD-1 combination therapy in comparison to anti-PD-1/PD-L1 monotherapy. Malignant melanoma and anti CTLA-4 therapy were independent risk factors for stroke. Acknowledgements This work was funded by pilot award in Big Data/Cancer Informatics to Prantesh Jain, MD from University Hospitals Research & Education Institute Ethics Approval The IBM MarketScan national database contains de-identified linked inpatient, outpatient, and pharmacy claims data. University Hospitals’ Institutional Review Board determined this study to be exempt from review and requirement of an informed consent.

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.

Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients. We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution’s ethical research committee. A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2). The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

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.

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 ± 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.

8572 Background: Small Cell Lung Cancer (SCLC) is an aggressive malignancy with a rapid growth, and Chemotherapy remains mainstay of treatment. Identifying therapeutic targets in SCLC presents a challenge, partially due to a lack of accurate and consistently predictive biomarkers. In this study we sought to evaluate the utility of a combination of computer-extracted radiographic and pathology features from pretreatment baseline CT and H&E biopsy images to predict sensitivity to platinum-based chemotherapy and overall survival (OS) in SCLC. Methods: Seventy-eight patients with extensive and limited-stage SCLC who received platinum-doublet chemotherapy were selected. Objective response to chemotherapy (RECIST criteria) and overall survival (OS) as clinical endpoints were available for 51 and 78 patients respectively. The patients were divided randomly into two sets (Training (Sd), Validation (Sv)) with a constraint (equal number of responders and nonresponders in Sd)—Sd comprised twenty-one patients with SCLC. Sv included thirty patients. CT scans and digitized Hematoxylin Eosin-stained (H&E) biopsy images were acquired for each patient. A set of CT derived (46%) and tissue derived (53%) image features were captured. These included shape and textural patterns of the tumoral and peritumoral regions from CT scans and of tumor regions on H&E images. A random forest feature selection and linear regression model were used to identify the most predictive CT and H&E derived image features associated with chemotherapy response from Sd. A Cox proportional hazard regression model was used with these features to compute a risk score for each patients in Sd. Patients in Sv were stratified into high and low-risk groups based on the median risk score. Kaplan-Meier survival analysis was used to assess the prognostic ability of the risk score on Sv. Results: The risk score comprised nine CT (intra and peri-tumoral texture) and six H&E derived (cancer cell texture and shape) features. A linear regression model in conjunction with these 15 features was significantly associated with chemo-sensitivity in Sv (AUC = 0.76, PRC = 0.81). A multivariable model with these 15 features was significantly associated with OS in Sv (HR = 2.5, 95% CI: 1.3-4.9, P = 0.0043). Kaplan-Meier survival analysis revealed a significantly reduced OS in the high-risk group compared to the low-risk group. Conclusions: A combined CT and H&E tissue derived image signature model predicted response to chemotherapy and improved OS in SCLC patients. Image features from baseline CT scans and H&E tissue slide images may help in better risk stratification of SCLC patients. Additional independent validation of these quantitative image-based biomarkers is warranted.

PurposeHyperprogression 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 designA 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.ResultsThe 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).ConclusionsOur 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.

e15100 Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]

4623 Background: The role of neoadjuvant chemotherapy (NAC) for resectable pancreatic cancer (RPC) remains controversial. We sought to compare the outcomes of NAC with upfront surgery (UFS). Methods: The study retrospectively enrolled patients with RPC who had UFS or received neoadjuvant FOLFIRINOX (FFX) or gemcitabine plus albumin-bound paclitaxel (GA). Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher’s exact test for categorical variables. The overall survival (OS) and recurrence-free survival (RFS) were determined by the Kaplan-Meier method with Wilcoxon test for the difference between groups. The effects of NAC vs. UFS on OS and RFS were further estimated using Cox regression controlling the effects of age and CA 19-9. Results: Between 2011 and 2019, 131 patients with RPC underwent UFS followed by adjuvant chemotherapy (gemcitabine, n = 65; gemcitabine/capecitabine, n = 18; FFX, n = 9). Up to 32 patients (24.4%) could not receive adjuvant chemotherapy due to surgical complications or poor recovery. Total 50 patients with RPC received NAC (FFX, n = 32; GA, n = 18). Median of 5.5 cycles of FFX or 3 cycles of GA were given prior to surgery. Resection rate was 72% (FFX 62.5%; GA 88.9%). The rest (28%) were no longer surgical candidates due to disease progression rather than toxicities from NAC. On surgical pathological review, complete resection (R0) was achieved in 83.3% of resected cases after NAC (FFX 90%; GA 75%) and 79.4% with UFS. The tumor size distribution was: pT1 11.1%, pT2 41.7%, pT3 44.4% with NAC; pT1 5.4%, pT2 18.3%, pT3 76.3% with UFS. The nodal status distribution was: pN0 27.8%, pN1 55.5%, pN2 16.7% with NAC; pN0 23.7%, pN1 71.0%, pN2 5.3% with UFS. Median pre-treatment CA 19-9 was 321.95 unit/mL in the NAC group and 79.99 unit/mL in the UFS group (p = 0.009). Median age was 70.5 in the NAC group and 72 in the UFS group (p = 0.374). There was no significant difference in the performance status between the two groups. In Kaplan-Meier analysis, there was a significant difference of OS between UFS and NAC with median OS of 648 days under UFS versus 884 days under NAC (p = 0.029); the median of RFS was 390 days under UFS versus 392 days under NAC (p = 0.953). The hazard ratio (NAC vs UFS) adjusted for CA19-9 and age was 0.7 (p = 0.176) for OS and 0.98 (p = 0.918) for RFS. Conclusions: We observed a signal of tumor downstaging, higher R0 rate, and improved OS with NAC compared with UFS. Further prospective trials are needed to validate these results.

BRAF and MEK inhibitors have revolutionized the treatment of melanoma, lung and colon cancers. Recent reports suggest increased cardiovascular toxicity with the combination (BRAF/MEK inhibition) therapy but large-scale post-marketing data is lacking. We used the FDA adverse events reporting system

37 Background: Immune related thyroiditis is a common adverse effect of Immune checkpoint inhibitors (ICI). We sought to determine if the incidence of hypothyroidism (HT) in patients with primary head and neck cancers (pHNC) who received ICI, is increased compared to other primary cancers (lung, gastrointestinal (GI), skin melanoma or urinary system(GU). Methods: Data were obtained from a commercial de-identified database (IBM Explorys Solutions, IBM, Inc.). Cases included patients ≥ 18 years with a diagnosis of pHNC and controls included patients with a diagnosis of lung, GI, skin melanoma or GU cancer. All patients received one of 5 ICI (Avelumab, Atezolizumab, Durvalumab, Nivolumab or Pembrolizumab). Incidence of HT was defined as patient with a new diagnosis of HT at least 1 day following initiation of ICI. All patients with diagnosed HT, thyroid cancer (previous/concurrent), lymphomas were excluded. Odds ratios (OR) and confidence intervals (CI) were calculated using chi-square test. Results: There were 238,490 patients with a diagnosis of pHNC, and 616,850 patients with a diagnosis of other cancers in the database. Out of 710 pHNC patients, 80 patients (18.6%) and out of 7420 patients with other primary cancers, 850 (12.57%) had a new diagnosis of HT. When compared to non-HNC patients, HNC cases had a 1.6 (CI = 1.23 - 2.05) times higher odds of developing HT. In subgroup analyses, HNC cases were significantly more likely to develop HT compared to patients with GI or lung cancer, but not with skin melanomas or GU cancers. Overall, male cases and adults aged 18 - 65 years were significantly more likely to develop HT. (Table). Conclusions: The risk of developing HT after ICI is higher in patients with HNC compared to other primary cancers. Men and patients between the ages 18-65 years with pHNC were more likely to become HT. [Table: see text]

498 Background: Primary liver angiosarcoma (LAS) is a rare and aggressive tumor of the liver. In this analysis of the national cancer database (NCDB) we sought the risk of mortality and factors associated with survival amongst patient diagnosed with LAS. Methods: Patients diagnosed with hepatocellular carcinoma (HCC) or LAS from 2004 – 2014 were identified in the NCDB. The Kaplan-Meier method with the log-rank test was used to calculate survival for HCC and LAS patients. Additional analyses were performed on the cohort with LAS to assess the impact of surgery, chemotherapy, radiation therapy (RT) and facility type on overall survival (OS). Multivariable analyses using cox proportional methods, adjusted for age, sex, Charlson/Deyo score, race, ethnicity, insurance status, facility location and type, surgery status, and chemotherapy status were performed to obtain adjusted hazard ratio (aHR). Results: Total of 118,066 patients with HCC and 346 patients with LAS were identified in the database. Median survival for HCC patients was 11.9 months (95% CI: 11.7-12.2) and 2.0 months for LAS patients (95% CI: 1.8 – 2.4). Risk of mortality was higher for patients with LAS compared to those with HCC (aHR (95% CI): 2.23 (1.97 - 2.53), p < .0001). Among the LAS patients, those who received surgery had a median survival of 8.6 months (95% CI: 5.6 - 17.3), and 1.8 months for those who did not (95% CI: 1.48 - 1.94). Risk of mortality was lower in patients who received surgery compared to those who did not (aHR (95% CI): 0.23 (0.15 - 0.37), p < .0001). Patients treated at and academic center had a higher median survival (3.3 months, 95% CI: 2.2 - 4.1) then those treated at a non-academic center (1.5 months, 95% CI: 1.2 - 1.8). Though, there was no significant difference in OS (aHR (95% CI): 0.48 (0.21 - 1.10), p = 0.082). A very small number of patients received chemotherapy or RT to conduct a meaningful analysis. Conclusions: Patients diagnosed with primary LAS have a worse OS compared to those with HCC. Amongst patients with primary LAS, surgical resection is associated with best survival outcomes. Treatment at an academic center is associated with better median survival, although OS did not reach statistical significance in our analysis.

e24314Background: Currently there are no clinically validated biomarkers to identify which locally advanced non-small cell lung cancer (NSCLC) patients (pts) will benefit from trimodality therapy (...

e20646 Background: Drugs targeting the PD-1/PD-L1 pathway show significant clinical activity in non-small cell lung carcinoma (NSCLC). Nivolumab, pembrolizumab and atezolizumab are currently approved for NSCLC patients who have progressed while on platinum-based chemotherapy. Recently, pembrolizumab received FDA approval for treatment naive NSCLC patients with tumor PD-L1 expression of ≥50%. However, there is relative lack of data on comparative efficacy of these drugs in the chemotherapy naive versus post-chemotherapy setting. In the current meta-analysis we compare the efficacy and toxicity of these drugs in chemotherapy naïve patients with those who receive them as subsequent therapy (after previous chemotherapy). Methods: A systematic search of electronic databases (PubMed-Medline, EMBASE, Scopus) and major conference proceedings was done for all clinical trials using PD1/PD-L1 inhibitors. Objective response rates (ORR) for patients determined to have positive tumor PD-L1 expression (Tumor Proportion Score ≥1%) from all phase I-III trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab and avelumab for NSCLC were collected. Only single agent PD-1/PDL-1 inhibitor trials were included. The ORR across trials was combined using DerSimonian-Laird random effects models. Higgins’ I2 statistic was used to assess heterogeneity. Results: 19 trials (7 with treatment naïve patients [n = 651]; 14 with chemotherapy treated patients [n = 2205]; 2 with separate treatment naïve and previously treated arms) were included. Treatment naïve patients were found to have statistically significant higher efficacy [ORR 28.27%(95% CI 20.70-36.52)] than those who received these drugs as subsequent therapy [ORR 20.13% (95%CI 17.53-22.85) (p = 0.02). Treatment naive patients had statistically significant higher rates of all grade pneumonitis as comapred to previously treated patients (4.9, 95%CI 3.4-6.7 vs 3.0 95% CI 2.0-4.1). Conclusions: PD1/PDL1 therapy for advanced NSCLC has a significantly improved efficacy (based on ORR) when used in treatment naïve patients as compared to its use in patients who have been previously treated with chemotherapy.

e20647 Background: PD-1/PD-L1 inhibitors show clinical activity in non-small cell lung carcinoma (NSCLC). However, these agents are sometimes associated with potentially fatal immune related pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis associated with PD-1 and PD-L1 inhibitors. In this meta-analysis, we sought to determine the overall incidence of pneumonitis, and differences by type of inhibitor and prior chemotherapy use. Methods:We systematically searched databases (PubMed-Medline, Embase, Scopus) and conference proceedings until December 2016 for clinical trials using PD-1/PD-L1 inhibitors. Rates of pneumonitis of any grade and grade 3 or higher from all phase I-III trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab and avelumab for NSCLC were collected. Only single agent PD-1/PDL-1 inhibitor trials were included. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors, as well as between treatment naïve and previously treated patients (pts). Results: 19 distinct published trials (12 with PD-1 inhibitors [n = 3232] and 7 with PD-L1 inhibitors [n = 1806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis as compared to PD-L1 inhibitors (3.6%, 95%CI 2.4%-4.9% vs 1.3%, 95%CI 0.8%-1.9%; p = 0.001). There was also a higher incidence of grade 3 or greater pneumonitis with PD-1 inhibitors (1.1%, 95%CI 0.6%-1.7% vs 0.4%, 95%CI 0%-0.8%, p = 0.02). Pts who received PD-1 or PD-L1 inhibitors in the front line setting experienced more grade 1-4 pneumonitis as compared to previously treated pts (4.3%, 95%CI 2.4%-6.3% vs 2.8%, 95%CI 1.7%- 4%, p = 0.03, however the rates of grade 3 or greater pneumonitis were not significantly different in treatment naïve and previously treated pts. Conclusions: Pneumonitis was more frequently associated with use of PD-1 inhibitors than PD-L1 inhibitors. There was a higher incidence of all grade pneumonitis with PD-1 inhibitors in treatment naïve patients as compared to previously treated patients.

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.

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.

Background: Hepatocellular cancer (HCC) is the fifth most frequently diagnosed cancer in the world and the second leading cause of cancer-related death across the globe. There are few small and old studies that tried to correlate levels of alpha-fetoprotein (AFP) with patient outcomes. Currently with more screening there is early diagnosis of HCC and the therapeutic options for non-surgical candidates have also improved in the past decade. We undertook this study to see if the level of elevation of AFP is related to patient prognosis in the current era.

1611 Background: County Hospital (CCH) with its HIV clinic, the CORE Center (CC) is the largest provider for HIV patients (pts) in Chicago, treating over 5,500 HIV pts yearly. There is paucity of data on characteristics of HIV+ cancers (ca) in the inner city. The CHAMP cohort is a retrospective study of all HIV associated cancers at CC and CCH over past 14 years (yrs). We analyzed all of the NADC from this cohort. Methods: All HIV pts with NADC were identified from the CHAMP cohort and retrospectively reviewed for HIV and cancer characteristics, overall survival (OS), and pt demographics. Statistics: Survival data was analyzed using Kaplan-Meier analysis and Cox Proportional Hazards model. Results: Of 438 pts identified, 157 were NADC representing 21 ca. The average (ave) age was 48 yrs (range 44-57), with prostate ca having highest age presentation. Over the past 10 yrs, the number of NADC has risen from 10 to over 20 each yr. Unlike historical controls (HC) where lung ca is most common, anal ca (21%) was most frequent followed by lung ca (17%). Prostate, head and neck (HNSCC), liver, and colorectal ca were seen in 9, 9, 8, and 7% respectively. 65% of pts were African Americans (AA) and 18% Caucasians. 78% of all NADC were men. 45% of anal ca present with stage IIIa/b disease, moderately to poorly differentiated ca in 48%, with a median OS of 34 mo. CD4 count did not alter OS but stage predicted better outcomes. 86% lung ca presented as stage III/IV disease with ave CD4 count 204. Histologically, 36% were SCC, 28% adenosquamous and 20% adenocarcinoma. OS was 5.5 mo and did not change by histology, CD4, or age. 68% HNSCC present with stage IVa/b but no IVc. Ave age was 48 yrs with an OS of 18mo. 50% were oropharyngeal compared to 22% in HC. Conclusions: Based on data by Sheilds et. al, CCH treats just over 1% of the country’s NADC population. We demonstrate a higher incidence of NADC over time, dominated by a younger, AA and male population. Each ca presents with advanced stage 45-86% and poorly differentiated tumors ranging from 15-30%. The OS of each cancer is consistent with HC with exception of HNSCC. As HIV pts age becoming prone to cancers of elderly, education and screening of inner city HIV pts will help improve cancer rates.

663 Background: Capecitabine (XELODA) is an orally active fluoropyrimidine that is absorbed intact through the gastrointestinal tract and converted in to 5FU. Standard chemotherapy for advanced colon cancers includes infusional 5FU with leucovorin in combination of oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). With the national shortage of 5FU we had to switch our FOLFOX and FOLFIRI regimens to XELOX or XELIRI. Although in trials the xeloda regimens were non-inferior, the PFS (progression free survival) and OS (overall survival), survival curves tailed behind the infusional 5FU regimens. Methods: At our institution over one month period from August 18th 2011 to September 18th 2011, all patients who were switched from 5FU to xeloda due to national shortage were identified. All charts were retrospectively reviewed identifying patients with colon cancer. Patients with other cancer histologies, were excluded. The charts were reviewed for number of cycles, clinical toxicity, admission to hospital. Results: A total of 90 patients were switched form 5FU to xeloda. 51 had colon cancer. Out of which, 6 (11.7%) patients had the drug discontinued due to toxicity and 4 out of the 6 required hospitalization due to adverse effects of xeloda, mainly diarrhea and vomiting. 80% of these had left sided colon cancer and 50% each received oxaliplatin and irinotecan respectively. The total number of hospitalization days was 20. The average wholesale price (AWP) of one cycle of xeloda for body surface area range from 1.5m2 to 2m2 ranges from 2605.68$ to 3474.24$ for every 3 week cycle. In comparison the corresponding AWP for 2 cycles of 5FU over a month is 51.81$ to 69.08$. This would become a net higher price of 2553.87$ to 3405.16$ for BSA of 1.5 to 2m2 per month for the switch to xeloda. There were 51 patients who received xeloda at least one cycle which costed about 151,954.50$ if we average the body surface area. Additionally there were 20 admission days costing about 50,000$, making the net costs of switching to xeloda more than 200,000$ in a single month. Conclusions: Although xeloda is non-inferior to 5FU and can be a substitute, left sided colon cancers tend to do have more adverse effects. Additionally Xeloda is associated with higher administration costs.