Citations

7047 Background: In addition to secondary AML (sAML), important lifestyle and environmental exposures associated with increased risk of AML development have been identified in recent case-control studies including obesity (BMI>30kg/m2), smoking, regular acetaminophen use, and rural/farm habitat. The association of these exposures with AML cytogenetic risk groups is unknown. We therefore evaluated relevant exposures in a cohort of 301 AML patients with confirmed central cytogenetics analysis diagnosed and treated at Mayo Clinic FL and AZ since 1995. Methods: Documented patient exposures were extracted from central electronic medical records, including: prior chemotherapy/radiation or hematologic malignancy, occupation, select medications, “toxins” (esp. benzene) and solid organ transplantation (SOT). Standard cytogenetic risk categories (including intermediate abnormal) were applied. The association of epidemiologic exposures with cytogenetic risk was evaluated on multivariable analysis using logistic regression models. Results: sAML was significantly associated with cytogenetic risk groups, as was prior SOT, healthcare occupation, farm habitat and toxin exposures [see Odds Ratios (OR), Table). In contrast, prior radiation for epithelial malignancies, smoking and BMI were not independently associated with specific cytogenetic risk categories. Conclusions: Specific epidemiologic exposures are significantly associated with AML cytogenetic risk categories suggesting a unique clinical phenotype. This supports a link to leukemogenesis and requires validation in a controlled prospective therapeutic study. [Table: see text]

2579 Background: HA, a glycosaminoglycan, accumulates in ~25% of solid tumors and is associated with poor prognosis. Tumors that accumulate HA develop high interstitial fluid pressure (IFP) and become resistant to chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA and increased efficacy of chemotherapy. Methods: This ongoing phase 1 study was designed to assess safety, tolerability, PK, PD, and the maximum tolerated dose (MTD) of PEGPH20 as a single agent in patients with treatment-refractory solid tumors. IV PEGPH20 was administered in a twice weekly or a once weekly dosing schedule with oral dexamethasone (dex) pre-and post dose. Biomarkers included tumor histochemistry to detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET. Results: Fifteen patients have been enrolled into the study. Dose administration ranged from 0.5 µg/kg to 5 µg/kg. Musculoskeletal events (MSEs) were the most common and dose limiting toxicities. To date, up to 3 µg/kg twice weekly IV infusions of PEGPH20 were well tolerated with manageable Grade 1 MSEs in most patients. MTD has not been reached. Plasma concentrations of PEGPH20 showed dose proportional exposure with a terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor biopsies from 2 colon patients demonstrated 23-60% reduction in tumor HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 in one patient each. Doses of ≤3 µg/kg were tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels > 3 µg/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in dose-dependent systemic exposure and is tolerated with concomitant dex treatment. HA catabolites in plasma demonstrated the in vivo enzymatic activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI and FDG-PET images confirmed PD activity. Increased tumor perfusion by PEGPH20 may enhance drug delivery to tumor. Combination studies of PEGPH20 with cytotoxic chemotherapy are planned.

4136 Introduction: BV prolongs overall survival (OS) and progression-free survival (PFS) when added to 1st- or 2nd -line chemotherapy (CT) in mCRC. Though serious toxicities specific to BV are uncommon, a retrospective pooled analysis of 5 randomized trials showed an association of arterial thromboembolic events (ATEs) with BV use (3.8% vs 1.7% with CT alone), with age ≥65 and prior history (Hx) of ATE identified as associated risk factors (Skillings, JCO 2005). The BRiTE mCRC registry evaluated BV-associated serious adverse events (SAEs), including ATEs presenting as SAEs (sATE), in a general practice setting. Methods: Pts and methods have been described (Hedrick ASCO 2006). Hx of sATE, timing of prior sATE relative to starting BV, and anti-platelet agent (anti-plt) use were summarized. Definition of sATE included myocardial infarction (MI), cerebral vascular accident (CVA), transient ischemic attack (TIA), and peripheral arterial disease. Incidence rate of sATE was expressed as events per pt-yr of follow-up. Fisher’s exact test and multiple logistic regression was used to assess the univariate and multivariate associations. Results: Median follow- up was 17.5 mo. Of 1953 evaluable pts, 45.9% (n=896) were ≥65, 18.0% (n=352) had Hx of sATE, and 11.2% (n=219) received anti-plt. A total of 38 sATE [CVA (n=14), MI (n=11), sudden cardiac death (n=1), TIA (n=7), and other (n=5)] were reported in 34 (1.7%) pts. Median time to sATE was 3.6 mo. The calculated sATE rate was 2.2/100 pt-yr overall and 4.7/100 pt-yr in pts with prior sATE. Table 1 summarizes the results of univariate and multivariate analyses. Conclusions: In this series of BV-treated pts, the incidence of sATE associated with BV use was comparable with the rate of analogous events reported in previous controlled trials of BV in mCRC. In this series, prior history of sATE and ECOG PS were found to be associated with sATE risk in multivariate analyses. [Table: see text] [Table: see text]

4036 Background: While BV prolongs OS when used with standard 1st- or 2nd-line chemotherapy (CT) in mCRC, no data exist on the effects of BBP. A previous report from BRiTE showed favorable median OS (27.1 mo, 95% CI 24.8-NE), with 1st line PFS (median 10.1 mo, 95% CI:9.7–10.4) comparable to historical mCRC trials, suggesting significant impact of post-progression survival on OS. This exploratory analysis evaluates the association of various pre- and post-treatment variables with OS in BRiTE. Methods: Pt population and methods have been described previously (Kozloff, ASCO 2006). All pts in BRiTE received BV as part of 1st-line therapy. The use of BBP and choice of CT were at investigator’s discretion. Kaplan-Meier methods were used to estimate PFS and OS. Cox’s proportional hazard model was used to assess the independent effects of pre- and post-treatment pt- related factors on OS, including age, ECOG PS, albumin, alkaline phosphatase, site of primary tumor, 1st-line CT regimen, 1st-line PFS, exposure to all 3 active CT agents, receipt of any 2nd-line CT, exposure to cetuximab, and BBP. Though there was variability observed in patterns of BBP, including continuous and discontinuous use, for the purpose of this analysis, BBP was defined as any exposure to BV after 1st progression (PD). Results: A total of 1,953 pts were treated in BRiTE. At median follow-up of 17.5 mo, there were 1,369 1st PD and 839 deaths. Among pts with 1st PD, 65.2% received any 2nd-line CT, 34.8% received cetuximab, and 53.8% received BBP. In a multivariate analysis, BBP and exposure to any 2nd-line CT were independently associated with increased OS (both p<0.0001). Age ≥65, PS ≥1, low albumin, elevated alkaline phosphatase, colon primary, and use of IFL were associated with inferior OS. Conclusions: BBP appears to be associated with longer OS in BRiTE. This finding supports the evaluation of BBP in prospective randomized clinical trials. Other factors that may have impacted this finding, including physician-related variables, will be investigated in future analyses. [Table: see text]

PURPOSE The Fast Healthcare Interoperability Resources (FHIR) is emerging as a next-generation standards framework developed by HL7 for exchanging electronic health care data. The modeling capability of FHIR in standardizing cancer data has been gaining increasing attention by the cancer research informatics community. However, few studies have been conducted to examine the capability of FHIR in electronic data capture (EDC) applications for effective cancer clinical trials. The objective of this study was to design, develop, and evaluate an FHIR-based method that enables the automation of the case report forms (CRFs) population for cancer clinical trials using real-world electronic health records (EHRs). MATERIALS AND METHODS We developed an FHIR-based computational pipeline of EDC with a case study for modeling colorectal cancer trials. We first leveraged an existing FHIR-based cancer profile to represent EHR data of patients with colorectal cancer, and then we used the FHIR Questionnaire and QuestionnaireResponse resources to represent the CRFs and their data population. To test the accuracy of and overall quality of the computational pipeline, we used synoptic reports of 287 Mayo Clinic patients with colorectal cancer from 2013 to 2019 with standard measures of precision, recall, and F1 score. RESULTS Using the computational pipeline, a total of 1,037 synoptic reports were successfully converted as the instances of the FHIR-based cancer profile. The average accuracy for converting all data elements (excluding tumor perforation) of the cancer profile was 0.99, using 200 randomly selected records. The average F1 score for populating nine questions of the CRFs in a real-world colorectal cancer trial was 0.95, using 100 randomly selected records. CONCLUSION We demonstrated that it is feasible to populate CRFs with EHR data in an automated manner with satisfactory performance. The outcome of the study provides helpful insight into future directions in implementing FHIR-based EDC applications for modern cancer clinical trials.

Background: The effective self-management of heart failure (HF) is highly dependent on cognitive function. Dementia frequently coexists with HF, but its exact prevalence and impact on health care utilization and death is not well understood. Methods: Residents from 7 southeast Minnesota counties with a first-ever code for HF (ICD-9 428 and ICD-10 I50) between 1/1/2012 and 12/31/2017 were identified. Dementia before and after the HF diagnosis was ascertained with codes recommended by the US Department of Health and Human Services. Patients were followed through 12/31/2018 for death and hospitalizations. Cox and Andersen-Gill models were used to examine associations between dementia (prior and post HF) and death and hospitalizations, respectively. Dementia after HF was analyzed as a time-dependent variable. Results: Among 6,312 patients with HF (mean age 75 years, 49% female), 636 (10%) had a prior diagnosis of dementia. After a mean (SD) follow-up of 3.1 (1.8) years, 601 (9.5%) patients were diagnosed with dementia post HF. The median time from HF to dementia was 1.3 years, with 43% of dementia cases occurring within 1 year and 64% within 2 years post HF. During follow-up, 2,678 deaths and 15,095 hospitalizations occurred. After adjustment, patients with dementia before HF had nearly a 2-times increased risk of death and 10% increased risk of hospitalization compared to those that did not have dementia (Table). Dementia after HF was associated with a 78% increased risk of death and 63% increased risk of hospitalization compared to those that did not have dementia. Conclusions: Approximately 10% of patients had dementia prior to HF and 10% develop dementia shortly after HF diagnosis. Patients with HF and dementia have an increased risk of death and hospitalization compared to dementia-free counterparts. These data underscore the importance of recognizing the presence and impact of dementia on outcomes in HF to optimize care delivery.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other ‘synucleinopathies’. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.

TPS592 Background: For advanced CCA, standard of care 1L systemic treatment is GEM + CIS. Genetic alterations in intrahepatic CCA provide potential therapeutic targets. Fibroblast growth factor receptor (FGFR) 2 gene rearrangements driving CCA tumorigenesis were identified almost exclusively in intrahepatic CCA patients (pts) (incidence, 10–16%). In phase 2, PEM (INCB054828), a selective, potent, oral FGFR1–3 inhibitor elicited an objective response rate (ORR) of 35.5% and median progression-free survival (PFS) of 6.9 months (mo) in previously treated, locally advanced or metastatic CCA with FGFR2 rearrangements (NCT02924376). FIGHT-302, a randomized, open-label, phase 3 study will evaluate efficacy and safety of 1L PEM vs GEM + CIS in unresectable/metastatic CCA with FGFR2 fusions or rearrangements (NCT03656536). Methods: Eligible pts are adults with confirmed unresectable/metastatic CCA; no prior systemic therapy for advanced disease < 6 mo before enrollment; radiographically measurable/evaluable disease (per RECIST v1.1); ECOG PS ≤1; documented FGFR2 fusions or rearrangements. Exclusions include clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification; untreated CNS metastases or history of uncontrolled seizures. Pts will be randomized (1:1; stratified by region and tumor burden) to PEM 13.5 mg QD on a 21-day (d) cycle or GEM (1000 mg/m2) + CIS (25 mg/m2) on D1 and D8 of 21-d cycles (max 8). Crossover to PEM allowed after confirmed progression. PEM titration to 18 mg from cycle 2 allowed for pts without hyperphosphatemia (serum phosphate > 5.5 mg/dL) and Grade ≥2 treatment-related adverse events during cycle 1. Hyperphosphatemia will be managed with diet modifications, phosphate binders, diuretics, or dose adjustments. Treatment will continue until progression or unacceptable toxicity. Primary endpoint is PFS (by independent review). Secondary endpoints are ORR, overall survival, duration of response, disease control rate, safety, and quality of life. Four pts (target N = 432) are enrolled as of Sep 25, 2019. Clinical trial information: NCT03656536.