Abstract: Introduction: There is considerable heterogeneity in the clinical outcome of newly diagnosed multiple-myeloma (NDMM) with some patients having a good prognosis while others fail to respond or relapse quickly after therapy progressing rapidly to death. Using risk scores based on clinical, biochemical and genetic features it is possible to predict some of this variation giving an ability to segment the disease into risk strata. Clinical studies have suggested that patients with standard-risk disease have benefited more from the recent advances in therapy compared to those with high-risk disease. The development of clinical trials specifically recruiting patients with high-risk disease features offers the potential to improve the outcome of a subgroup of patients with a very poor clinical outcome. To perform such studies is it important to have a unifying definition of high-risk including standard parameters, group size and outcome of individual risk strata so that clinical trial rigor can be achieved (e.g., common entry criteria, statistical power). In order to understand the size and feasibility of such studies we analyzed the Myeloma Genome Project (MGP) dataset to assess multiple risk factors and scores to determine and compare how they perform as risk stratifiers with each other. Methods: The MGP dataset is a large set of molecular and clinical data from 1273 patient with NDMM. Data were available on clinical variables (Albumin (Alb), B2-microglobulin (B2M), LDH, age), cytogenetic variables [t(4;14), t(14;16), t(14;20), 17p-, TP53 mutations, 1q+ and 1p-] and gene expression analysis (GEP70). A literature search was used to identify risk models used in clinical studies. Survival analysis was performed in R. The median follow-up at the time of analysis was 54.5 (53.2-56.5) months. Results: The median patient age was 66 years, with 641 (50.4%) patients over age 65. The sex ratio (M:F) was 1:0.66. African American, White, and Asian constituted 17%, 76%, and 2%, of cases respectively. 26.7% received a stem cell transplant. We determined the size of the strata and actual risk (measure by the hazard ratios, HR) compared to standard risk cases for both PFS and OS of the various clinical models available, data are summarized in Figure 1. When looking at individual risk scores, the HR for progression for t(4;14), TP53 inactivation (deletion and mutations), gain(1q), and del(1p) were 1.4, 1.1, 1.3, and 1.1 respectively. When considering overall survival these HR were 1.4, 1.7, 1.5, and 1.4 respectively. We went on to analyze the impact of these events in combination and show that combined, there is increased specificity, especially for OS (HR 2.3-5.1) but they identify small subsets making up & lt;10% of patients. We then analyzed the purely clinical scores (ISS) and combined clinical/genetic scores. We show again, that the more specific risk scores (double hit, Boyd IV, GEP70) identify between 7-13% of cases with HR (2-3.1) for OS. When we looked specifically at the younger patients (= & lt; 65), similar trends were seen with GEP70 by RNA-seq offering one of the most interesting means of identifying HR cases. Conclusion: In this large NDMM dataset, we demonstrate the clear variation in risk groups that occur dependent upon the approach used resulting in heterogeneous levels of risk, strata size, and performance. With the exception of GEP70, none of the single features are sensitive or specific enough to identify all cases. Risk models based on a combination of markers improve the ability to detect true high-risk disease but there remains variability. At a molecular level the inclusion of TP53 inactivation, and 1q+ improve the performance of the ISS. This analysis provides insights into standardizing the definition of high-risk and the generation of consensus definitions for clinical trial entry. Figure 1 Figure 1 Figure 1. Disclosures Braunstein: Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pawlyn: Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cairns: Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Davies: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract: 597 Background: To evaluate the overall response rate of HAI with floxuridine (FUDR) in the refractory setting in patients with mCRC LM. Methods: After obtaining an IRB waiver a computerized search was performed for patients with mCRC treated with 5FU, oxaliplatin and irinotecan +/- EGFR and VEGF inhibitor from 2003-2012. Charts were reviewed to ensure patients (pts) had received all standard therapies prior to HAI pump placement. All pts received HAI FUDR and no new systemic targeted or cytotoxic therapies were used with HAI pump. Imaging was re-reviewed for confirmation of progression prior to HAI pump placement and for best response using RECIST 1.1 criteria. Results: 75 pts were identified; of these 23 had radiographic disease progression on all standard chemotherapies (5FU, irinotecan and oxaliplatin) prior to having a pump placed. Of the 23 evaluable pts, the median age was 53 (range 37-75). Six pts had low volume extrahepatic metastases at the time of pump placement. The overall response rate (ORR) was 8/23 (35%); 10/23 (43%) pts had stable disease (SD). The median duration of SD was 4 months (range 1-10). Median follow up, measured from the date of HAI initiation, was 24 months and median overall survival (OS) was 22 months (95% CI 13-16). The median hepatic progression free survival (hPFS) was 4.5 months [CI: 3.8-6.7]. Thirteen pts developed extrahepatic disease progression (including 5 pts with preexisting extrahepatic disease). The median overall PFS was 3.9 months [95% CI 2.24-5.33] . Median number of HAI treatments was 4 cycles (range 1-13). Six out of 23 (26%) pts required a 50-75% dose reduction by the second cycle due to elevated liver function tests and 18/23 (78%) required a dose reduction after the 3 rd cycle. No pts required stents or developed long term liver or biliary toxicity. Conclusions: In a cohort of 23 patients with mCRC LM, refractory to all standard agents, treatment with HAI FUDR resulted in an ORR by RECIST 1.1 of 35% and median OS of 22 months. Further studies focusing on locoregional therapy in patients with liver predominant disease are warranted. Studies to molecularly characterize these tumors are ongoing.

Abstract: Chromosome 1 (chr1) copy-number abnormalities (CNA) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and are associated with a heterogeneous impact on outcomes, the drivers of which are largely unknown. Experimental Design: A multiomic approach comprising CRISPR, gene mapping of CNAs and SVs, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilization. Results: We identified two distinct groups of gain(1q): focal gains associated with limited gene-expression changes and a neutral prognosis, and whole-arm gains, which are associated with substantial gene-expression changes, complex genetics, and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT), and two of templated insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. Conclusions: Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.

Abstract: Background: Obesity is a public health problem and an increasing number of colorectal cancer patients will be obese. The impact of obesity on the efficacy of colorectal cancer treatment and patient outcomes has only recently been elucidated. However, evidence is lacking on the mechanism linking obesity to poor outcomes among colorectal cancer patients. There are emerging data to suggest that the underlying mechanism for this association is mediated in part by hyperinsulinemia and insulin resistance, via the insulin-insulin-like growth factor (IGF) axis, and modulated in part by adiponectin. Using a multidisciplinary approach, the Colorectal Cancer Outcomes, Prognosis and Epidemiology Study will elucidate the biological effects of elevated insulin and IGF-factors on tumor gene expression and their impact on quality of life. Objective: The objectives of this presentation are to present the study design and baseline characterize of colorectal cancer participants enrolled to date in the COPE study. Methods: We are establishing a cohort of 350 colorectal cancer patients identified at the Moffitt Cancer Center. All patients will be followed at regular intervals to obtain data on health outcomes, health behaviors, symptoms, and quality of life, and blood draws will occur at (∼6 and 12 months post-enrollment). An electronic intake form collected use of dietary supplements and of medications (including multivitamins, folate, and NSAIDs, with type and frequency); smoking, and a brief assessment of physical activity at baseline. BMI, waist and hip measures are taken at each visit. The assessment of quality of life and symptoms will be based on validated standard instruments (European Organization for Research and Treatment of Cancer QLQ-C30) administered at baseline, 3, 6 and 12 month follow-up time points, with slight adaptations in timing for patients undergoing chemotherapy. Results: Overall, a total of seventy five colorectal cancer patients have been enrolled. Among these patients, 60% have colon cancer and 40% were diagnosed with rectal cancer. A majority of the patients were married with some higher education. Sixty percent of the participants were female. There was an equal distribution of cases enrolled across stages I – III, with very few stage IV patients. A full characterization of the cohort will be presented. Conclusion: Overall, the COPE study is designed to recruit a hospital based cohort of colorectal cancer cases to evaluate the association between body size, insulin/IGF and colorectal cancer outcomes. We have successfully recruited and followed patients over a twelve month period. We are now poised to evaluate our primary objectives among a cohort of colorectal cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1919. doi:10.1158/1538-7445.AM2011-1919

Abstract: In the mid-nineties, the New York City Schools Chancellor created a citywide improvement zone to take over a significant proportion of the city's lowest performing schools whose local community school districts had failed to improve them. This "Chancellor's District" defined centralized management, rather than local control, as the critical variable necessary to initiate, enforce and ensure the implementation of school improvement. This large-scale intervention involved both a governance change and a set of capacity-building interventions presumably unavailable under local sub-district control. Our study retrospectively examined the origins, structure and components of the Chancellor's District, and analyzed the characteristics and outcomes of the elementary schools mandated to receive these interventions. Our longitudinal analysis compared Chancellor's District schools to New York City's other state-identified low performing schools, based on a school-level panel of performance, demographic, human resource, and expenditure data collected from district Annual School Report Cards and School Based Expenditure Reports from 1998-99 through 2001-02. The results suggest that the Chancellor's District intervention improved these schools' instructional capacity and academic outcomes, both relative to where these schools would have been and relative to comparable schools.