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// Safoora Deihimi 1,2,3,7 , Avital Lev 1,2,3 , Michael Slifker 4 , Elena Shagisultanova 3,9 , Qifang Xu 2 , Kyungsuk Jung 5 , Namrata Vijayvergia 3 , Eric A. Ross 4,6 , Joanne Xiu 8 , Jeffrey Swensen 8 , Zoran Gatalica 8 , Mark Andrake 2 , Roland L. Dunbrack 2 and Wafik S. El-Deiry 1,2,3,7 1 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA 2 Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA 3 Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA 4 Biostatistics and Bioinformatics Department, Fox Chase Cancer Center, Philadelphia, PA, USA 5 Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA, USA 6 Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA 7 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA 8 Caris Life Science, Phoenix, AZ, USA 9 University of Colorado Denver Cancer Center, Denver, CO, USA Correspondence to: Wafik S. El-Deiry, email: // Keywords : BRCA2, EGFR, NTRK, colorectal cancer, MLH1 Received : April 14, 2017 Accepted : April 26, 2017 Published : May 23, 2017 Abstract Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors ( P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.

Introduction: Comprehensive management for patients with hemophilia has drastically improved outcomes, quality of care, and longevity. Because of increases in life span, patients with hemophilia may be at risk for other chronic conditions including cardiovascular disease (CVD). Though initially it was thought that hemophilia might have been protective for cardiovascular disease further research has shown that CVD remains a significant risk for the aging hemophilia population. This study aims to determine the prevalence of risk factors and outcomes for CVD in hospitalized adult and pediatric patients with the discharge diagnosis of Hemophilia A or B compared to patients without Hemophilia. We examine longitudinal changes over the previous decade. WMethods: The Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (HCUP-NIS) was utilized for analysis of years 2007 and 2017. The NIS uses a stratified probability sample of 20% of all inpatient discharges (representing more than 97% of the US population). Hemophilia-A and B were identified using ICD-9 code 286.0 and 286.1, ICD-10 codes D66 and D67 respectively and sampling weights were applied to generate nationally representative estimates. Cardiovascular risk factors and outcomes were determined by evaluating ICD-9 codes for 2007 data and ICD-10 codes for 2017 data. For comparative historical data, 2007 NIS data from a prior published study [Goel et al., Hemophilia (2012), 18, 688-692] were used. The NIS is a de-identified, publicly available data set. This study was deemed exempt from review from the Johns Hopkins Institutional Review Board. This analysis was conducted in accordance with the HCUP data use agreement guidelines. Results: In 2017, there were 10,555 admissions with Hemophilia A or B listed as one of all diagnoses. The mean age of hemophilia patients was 44.31 years compared to 49.57. years for all admissions. The most prevalent risk factor in 2017 was hypertension (32.4% for admissions with hemophilia as compared to 35.3% for all admissions) followed by hyperlipidemia (19.4% compared to 27.5%), diabetes (17.4% compared to 22.8%) and obesity (10.8% compared to 14.4%). CVD outcomes, in descending order of frequency were atherosclerotic coronary artery disease (11.6% for admissions with hemophilia compared to 16.9% for all admissions), heart failure (10.2% compared to 14.2%), acute myocardial infarction (AMI) (2.2% compared to 3.9%), and stroke (2.2% compared to 2.4% respectively). Comparing to 10 year prior data, in 2007, there were 9,737 admissions with Hemophilia A or B listed as one of all diagnoses. The mean age of hemophilia patients was 30.89 years compared to 47.16 years for all admissions. The most prevalent risk factor in 2007 was hypertension (27.0% in admissions with hemophilia compared to 36.7% for all admissions); followed by diabetes (11.2% compared to 18.5%), hyperlipidemia (9.5% compared to 17%), and obesity (3.6% compared to 5.8%). CVD outcomes, in descending order of frequency were, atherosclerotic coronary artery disease (10.1% compared to 16.7%), heart failure (6.6% compared to 10.8%), AMI (2.1% compared to 2.4%), and stroke (2.0% compared to 1.7%). Between 2007 and 2017 the crude prevalence rates of all CVD risk factors as well as CVD outcomes generally increased for admissions with hemophilia as well as all-cause hospitalizations. Conclusions: The frequency of all CVD risk factors (obesity, diabetes, hypertension, and hyperlipidemia) as well as CVD outcomes (atherosclerosis, congestive heart failure, AMI, and stroke) increased between 2007 and 2017 in hospitalized patients both with and without hemophilia. While the unadjusted prevalence rates for all CVD risk factors and CVD outcomes were less in hospitalized patients with hemophilia compared to the general hospitalized population in both 2007 and 2017, CVD remains a significant risk for the hemophilia population. An improved understanding of the various risk factors will help to improve CVD outcomes in the aging hemophilia population. Disclosures Takemoto: Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB Aplastic Anemia Trial.

Introduction Venous thromboembolism (VTE) (deep vein thrombosis [DVT] and pulmonary embolism [PE]) is a cause of significant morbidity and mortality. Over the last decade, there has been an increase in awareness and major advances in early diagnosis and treatment of VTE. This study sought to estimate the mortality and associated diagnoses in hospitalized patients with a primary diagnosis of DVT or PE using a nationally representative database. Methods The 2017 Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (HCUP-NIS) was used for analysis. The NIS uses a stratified probability sample of 20% of all inpatient discharges, representing over 97% of the US population. Sampling weights were applied to hospital discharges for DVT and PE using applicable ICD-10 codes to generate nationally representative estimates. Pearson's chi-squared test and the Mann-Whitney U test were used for comparisons to assess statistical significance. Results Of the nearly 36 million hospital admissions in 2017, 579,860 had DVT included in the index list of diagnoses during the hospitalization, and 105,635 had DVT as the primary admission diagnosis. Within the primary DVT admissions (median age (interquartile range (IQR)): 64 years (51-77)), 102,505 were acute DVT, and 3,130 were chronic DVT. There were 376,140 admissions with PE as one of all diagnoses and 188,245 with PE as the primary admission diagnosis. Among primary PE admissions (median age (IQR): 64 years (52-75)), 16,205 (8.6%) were saddle PE (Figure 1a). Overall, there were 826,155 people diagnosed with PE or DVT as one of any diagnoses, and 129,845 were diagnosed with both DVT and PE. Mortality The all-cause mortality in admissions with a primary diagnosis of DVT (0.8%) was significantly lower than for all other NIS admissions at 1.96% (p For primary PE admissions, the all-cause mortality (3.0%) was significantly higher than all other NIS admissions (p Besides the known cardiovascular disease risk factors such as hypertension, obesity, smoking, Type 2 diabetes mellitus, and hyperlipidemia, the most common diagnoses in those who died with DVT or PE as a primary diagnosis were acute kidney failure, cancer, and chronic kidney disease (CKD) (Table 1). Health Care Utilization The median (IQR) hospital charges for DVT and PE admissions were $27,476 ($15,053-$54,874) and $29,158 ($17,471-$52,636) respectively. These were comparable to all NIS hospitalizations at $26,841 ($12,969-$54,568). For hospitalizations for DVT and PE resulting in death, the median (IQR) hospital charges were $60,689 ($24,775-$137,830), and $55,218.50 ($29,373-$106,313) respectively which were comparable to all NIS deaths at $56,107 ($23,117-$131,768). Discussion/Conclusions In the United States, DVT or PE was listed as one of the discharge diagnoses in approximately 825,000 admissions in 2017 and was the primary reason for admission in 300,000 cases (0.8% of all admissions). PE was seen more often as a primary cause for hospitalization, while DVT was more often seen as a comorbidity. The all-cause mortality among admissions for PE was greater than that for DVT. The subset of PE patients with saddle embolism had the highest mortality rate of all admissions for VTE. Besides cardiovascular risk factors, cancer, acute kidney failure, and CKD were among the most common comorbidities seen in admissions with PE and DVT that had in-hospital mortality. Disclosures Streiff: Bayer: Consultancy, Speakers Bureau; Portola: Consultancy; Boehringer-Ingelheim: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; NovoNordisk: Research Funding; Sanofi: Research Funding; Dispersol: Consultancy; BristolMyersSquibb: Consultancy; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Speakers Bureau. Takemoto:Novartis: Other: DSMB Aplastic Anemia Trial; Genentech: Membership on an entity's Board of Directors or advisory committees.

Squamous cell carcinoma of head and neck (SCCHN) is a group of cancer arising from mucosal surfaces of the head and neck. Optimal management of SCCHN requires a multidisciplinary team of surgical oncologists, radiation oncologists, medical oncologists, nutritionist, and speech-language pathologists, due to the complexity of anatomical structure and importance of functional outcome. Human papilloma virus (HPV)-related SCCHN represents a distinct subset from HPV negative SCCHN which is associated with carcinogen exposure such as cigarette smoking, betel nut use and alcohol. HPV related SCCHN responds better to concurrent chemoradiation and has better overall prognosis, compared to HPV negative SCCHN. Radiation therapy has been introduced to the treatment of SCCHN, administered concurrently with systemic chemotherapy for locoregional SCCHN, as well as a palliative measure for recurrent and/or metastatic (R/M) SCCHN. Recently, immune checkpoint inhibitors have been shown to improve overall survival in R/M-SCCHN and have been incorporated into the standard of care. Combination approaches with immune therapy and targeted therapy for biomarker enriched population based on genomics are being actively investigated and will shape the future of SCCHN treatment.

The landscape of head and neck squamous cell carcinoma (HNSCC) has been changing rapidly due to growing proportion of HPV-related disease and development of new therapeutic agents. At the same time, there has been a constant need for individually tailored treatment based on genetic biomarkers in order to optimize patient survival and alleviate treatment-related toxicities. In this regard, aberrations of PI3K pathway have important clinical implications in the treatment of HNSCC. They frequently constitute ‘gain of function’ mutations which trigger oncogenesis, and PI3K mutations can also lead to emergence of drug resistance after treatment with EGFR inhibitors. In this article, we review PI3K pathway as a target of treatment for HNSCC and summarize PI3K/mTOR inhibitors that are currently under clinical trials. In light of recent advancement of immune checkpoint inhibitors, consideration of PI3K inhibitors as potential immune modulators is also suggested.

Background Immune checkpoint inhibitors are changing the landscape of oncology treatment as they are significantly improving treatment for multiple malignancies. Nivolumab, an anti-programmed death 1 antibody, is a US Food and Drug Administration-approved treatment for melanoma, non-small cell lung cancer, and kidney cancer but can result in a spectrum of autoimmune side effects. Adverse effects can occur within any organ system in the body including the colon, lung, liver, endocrine systems, or kidneys. Case presentation A 70-year-old male with clear cell kidney cancer was admitted with acute kidney injury while on nivolumab. A kidney biopsy revealed diffuse tubular injury and immune complex-mediated glomerulonephritis. Electron microscopy of the specimen showed hump-like subepithelial deposits. Nivolumab was discontinued and the patient was started on a high dose of steroids. After 5 months of systemic corticosteroids and hemodialysis, the patient’s kidney function improved to his baseline level. Despite a prolonged interruption to treatment, immunosuppressive therapy did not compromise the anticancer effects of nivolumab. Conclusion Immune-related adverse effects in the kidney can cause autoimmune glomerulonephritis as well as tubulointerstitial injury. In the literature, immune-related nephritis generally responded well to systemic corticosteroid treatment. Based on our experience, a prolonged course of a high dose of steroids and hemodialysis may be required to achieve an adequate treatment effect.

BACKGROUND: Small cell carcinoma of the bladder is a rare, aggressive and poorly differentiated neoplasm. There has been no standard treatment guideline for the disease. METHODS: Retrospective chart analysis was performed for the patients who were diagnosed and treated for small cell carcinoma of the bladder at our institution during the period between 1995 and 2015. Survivals were compared between different treatment periods and among different treatment modalities. RESULTS: 38 patients were diagnosed and treated for small cell carcinoma of the bladder at Fox Chase Cancer Center during a 20-year period. Median survival was 11.8 months. Overall survival rates after 1, 3, 5 years were 46.6%, 26.2% and 14%, progression free rates after 1, 3, 5 years were 36.9%, 19.5% and 7.3% respectively. There was no tendency in improvement of survival at our institution before and after 2010(p=0.63). In survival analysis with adjustment of age, histology and stage, there was no single treatment strategy that was significantly superior than others(95% CI 0.27-2.6;p=0.783 for surgery, 95% CI 0.31-3.01;p=0.963 for neoadjuvant chemotherapy, 95% CI 0.67-5.16;p=0.233 for radiation treatment). Existence of nodal or organ metastases was the only significant indicator of survival(HR 2.92;95% CI 1.14-7.51;p=0.026). Almost all of the lengthy survivors received platinum-based neoadjuvant chemotherapy and radical cystectomy. Down staging occurred at the time of surgery after neoadjuvant chemotherapy(≤T2N0M0). CONCLUSIONS: Like its counterpart in the lung, small call carcinoma of bladder is rapidly growing but sensitive to platinum-based chemotherapy. Neoadjuvant chemotherapy provides clinical benefit as it may halt the progression or even down stage of the disease until the time of cystectomy. At our institution, the best treatment response was observed in patients who had neoadjuvant chemotherapy followed by radical cystectomy.

e13025 Background: A few patients with metastatic cancer survive exceptionally longer than others under the same treatment. We hypothesized that there is a specific biologic signature in genetic profiles of long-term survivors that plays a key role in sensitivity to systemic treatment. Methods: Twenty-six patients with metastatic cancer treated at Fox Chase cancer center with exceptional response were included in the study. Exceptional response was defined as complete response > 1 year or stable disease/partial response > 2 years at any time during the disease course. Archived tumor specimens of 16 patients were sequenced and analyzed using Ambry Genetics 142 gene panel. In addition, genes expressions in tumor tissues from 23 exceptional responders and 23 matched controls (age, sex and tumor type) were analyzed using two NanoString nCounter PanCancer panels (Pathway and Immune Profiling). Results: See Table. Conclusions: Multiple common mutations of NOTCH2, NF1, FANCD2, PIK3CB and EPHA5 were found in tumors that responded exceptionally well to treatments. Additionally, certain genes were significantly over-expressed or under-expressed in these tumors compared to matched controls. Underlying mechanisms that these genetic alterations foster, leading to susceptibility to treatment and prolonged patient survival, should be further studied. [Table: see text]

465 Background: Small cell carcinoma of the bladder (SCBC) is a rare but aggressive neuroendocrine neoplasm. It accounts for only 0.35-0.70% of all bladder tumors. Because of its low incidence, there has been no consensus on the standard treatment of SCBC. We hypothesized that patients (pts) treated over the past 10 years would have better outcomes than those treated earlier, given recent treatment advances in oncology. Methods: We performed retrospective analysis of pts treated at FCCC with confirmed pathologic diagnosis of either SCBC or mixed urothelial and SCBC from 1995 to 2015. Kaplan-Meier estimates were made of the median times and log rank tests were used to compare OS and PFS. Results: We identified 38 pts, 10 women and 28 men who met inclusion criteria. The mean age at diagnosis was 68.2 years, all were Caucasians and 26 pts were smokers. Three pts (8%) had Stage I, 22 (58%) had Stage II, 6 (16%) had Stage III and 7 pts (18%) had Stage IV disease. Radical cystectomy was performed in 26 pts, 3 pts underwent surgery followed by radiation therapy, and 5 pts received primary radiation therapy alone. All but 1 pt received chemotherapy: 32 pts received neoadjuvant chemotherapy, 3 pts received adjuvant chemotherapy and 2 pts received both adjuvant and neoadjuvant chemotherapy. The number of prior lines of therapy, including perioperative chemotherapy as a line, was 1 in 25 pts, 2 in 7, 3 in 2 and 4 in 3 pts. Sixteen pts progressed after the primary treatment with the median time to progression of 7.7 months. The median OS was 397 days (95% CI: (309,633)), and median PFS was 332 days (95% CI: (427,608)). OS estimates are based on all 38 pts; PFS are based on 21 pts. There was no difference in OS (p = 0.752) in 19 pts who were treated before 12/31/2010 vs 19 pts treated after 12/31/2010. No difference was detected in PFS (p = 0.37) based on the earliest 10 (up to February 2010) vs final 11 pts (after February 2010) for whom data was available. Conclusions: No significant improvement in the treatment of SCBC or pt outcomes over the past 10 years was observed. Further data analysis will be aimed at comparing different treatment modalities and pt outcomes.