Citations

Abstract Background: Prospective validation of breast cancer risk models integrating classical risk factors and genetic variants is required for risk-stratified prevention and screening strategies. The objective of this study was to validate a breast cancer risk model integrating classical risk factors and a 313-variant polygenic risk score (PRS) in multiple prospective cohort studies, and to project five-year risk of breast cancer in six different countries. Methods: The study population included 7,529 cases and 230,103 controls from 14 prospective cohort studies in Australia, Germany, the Netherlands, Sweden, UK, and USA. We used the Individualized Coherent Absolute Risk Estimator (iCARE) tool for risk model building, validation, and risk projection. Expected five-year risk of invasive or in situ breast cancer was compared to observed risk, overall and within deciles of expected risk using goodness of fit statistics. We evaluated calibration of the relative risk through meta-analysis across cohorts, and of the absolute risk within each cohort. Model discrimination was evaluated using the area under the curve (AUC), and percentages of women crossing risk thresholds. Projections of five-year risk distributions were estimated for women of European ancestry aged 50-70 years in the general populations of these six countries. Results: Analysis showed overall good calibration of the integrated iCARE-based model relative risk for both women younger than 50 years (χ2=14.9, P=0.09) and aged 50 years or older (χ2=14.6, P=0.10), with a small overestimation of risk for women in the highest decile of expected risk (RR = 3.5 expected vs 2.3 (95% CI 1.6 to 3.2) observed for women <50 years; and 2.8 expected vs 2.3 (95% CI 2.0 to 2.7) observed for women 50+ years). The age-adjusted AUCs for the integrated model were 63.1 (95% CI 60.9 to 65.3) and 62.9 (95% CI 61.8 to 64.0), for the two age groups respectively. The calibration of absolute risk showed substantial variation across cohorts, particularly for the older group, but had no systematic bias. Model based projections in the general populations showed that compared to the population average, women in the 1st and 99th percentiles of the integrated risk score had relative risks 0.19 and 3.56 respectively. The proportion of women of European ancestry aged 50-70 years with a five-year risk greater than 3% (threshold for consideration of risk-lowering drugs by U.S. Preventive Services Task Force) ranged from 7.1% in Germany to 18.2% in the US, which corresponds to ~5.5 million women in the US. Conclusions: Five-year risk predictions from a model with classical risk factors and PRS are well calibrated and provide substantial risk stratification across multiple cohorts in six different countries. Further studies are needed to evaluate the clinical utility of the validated model for risk stratified screening and prevention of breast cancer. Citation Format: Parichoy Pal Choudhury, Amber Wilcox, Chi Gao, Brian Carter, Anika Husing, Mark Brook, Mikael Eriksson, Kara Martin, Chris Scott, Min Shi, Thomas Ahearn, Michael Jones, Nick Orr, Minouk Schoemaker, Kamila Czene, Jenny Chang-Claude, Jacques Simard, Doug Easton, Marjanka K. Schmidt, Dale Sandler, Clarice R. Weinberg, Celine Vachon, Roger Milne, Per Hall, Anthony Swerdlow, Rudolph Kaaks, Myrto Barrdahl, Mia Gaudet, Antonis Antoniou, Peter Kraft, Montserrat Garcia-Closas, Nilanjan Chatterjee. Validation of breast cancer risk model incorporating classical risk factors and polygenic risk scores in 14 prospective cohort studies in 6 countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 962.

Abstract Recent years have seen an explosion in the availability of paired molecular profiling and drug screen data, providing an unprecedented opportunity for the development of targeted therapies based on an individual’s genetic background. Despite a number of recent successes in diseases ranging from cystic fibrosis to cancer, significant hurdles remain in our ability to accurately predict treatments based on molecular profiling data. In particular, few such tools exist that allow the integration of heterogeneous data types (e.g. genomic, transcriptomic, and somatic mutations), along with high-throughput drug screen data to make predictions about treatment efficacy. Here, we describe a generalized open-source pipeline developed for the analysis of precision medicine data, Pharmacogenomics Prediction Pipeline, or “P3”. The modular design of P3 enables the inclusion of arbitrary input data types and the selection from multiple alternative machine learning algorithms, while automated statistical and visualization reporting steps incorporated throughout the pipeline assist in parameter tuning and early detection of problematic data components. Molecular profiling data is further enriched by the incorporation of external biological information in the form of pathway and gene set annotations such and Gene Ontology (GO) and The Molecular Signatures Database (MSigDB). To demonstrate the use of P3 for preclinical biomarker prediction, we applied P3 to an unpublished multiple myeloma dataset consisting of exome, RNA-Seq, CNV, and drug screen data for 1,912 compounds across 47 tumor cell lines. Specifically, P3 was used to predict molecular features associated with response to treatment for all drugs where a differential response to treatment was observed across patients. Furthermore, molecular profiling and drug screen data for 267 drugs and over a thousand cell lines spanning multiple cancer types from the Genomics of Drug Sensitivity in Cancer (GDSC) project were analyzed using P3, providing insights into shared mechanisms of drug sensitivity and resistance across different cancer and treatment types. Citation Format: V Keith Hughitt, Sayeh Gorjifard, Aleksandra M. Michalowski, John K. Simmons, Ryan Dale, Eric C. Polley, Jonathan J. Keats, Beverly A. Mock. A flexible pipeline for precision medicine biomarker detection and prediction of treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5113.

Abstract Purpose: The majority of patients with high-grade serous ovarian cancer (HGSC) develop progressive disease following primary treatment, with a five-year survival rate of ~30%. However, a subset of patients have an extraordinary response to treatment and ~15% survive more than ten years (long-term survivors). The Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG) aims to uncover factors that influence long-term survival of HGSC patients. Here, we investigated the genomic and immunologic determinants of exceptional survival of this deadly disease. Experimental Design: Patient characteristics and clinical histories were evaluated to identify patients diagnosed with advanced stage (Stage IIIC/IV) and histopathologically confirmed HGSC with greater than 10-year overall survival. Whole-genome sequencing (WGS) was performed on primary tumors (median 78x coverage) and germline samples (median 39x coverage) of 55 long-term survivors. Primary tumor samples were also characterised by RNA sequencing, DNA methylation profiling and immunohistochemistry. Results: A total 38 (69%) of long-term surviving patients had residual disease following surgery, suggestive of highly chemo-sensitive disease. Most patients (41, 75%) were alive at last follow-up and 26 (47%) were progression-free. Somatic mutation burden was higher in primary tumors of long-term survivors relative to controls (316 unselected HGSC patients in The Cancer Genome Atlas). Genome-wide mutational signatures were predominantly Signature 3 (associated with homologous recombination deficiency), Signature 1 (age related) and Signatures 5, 8 and 16 (unknown etiology). Inactivation of the tumor suppressor RB1 by structural rearrangements or homozygous deletion was frequent in long-term survivors, with 33% of tumors showing associated loss of RB1 protein expression by immunohistochemistry compared to 13% of unselected HGSC controls (n=207; P = 0.001). Staining of adjacent tumor tissue revealed that RB1 loss was associated with increased numbers of PD-1+ tumor-infiltrating lymphocytes (P = 0.015) and MHC class I on tumor cells (P = 0.002). In an independent HGSC cohort (n=847), RB1 protein loss was associated with prolonged survival (HR: 0.75, P < 0.001) compared to patients with RB1 positive tumors. Furthermore, co-occurrence of germline mutations in BRCA1 or BRCA2 and RB1 loss was associated with a significantly longer overall survival compared to patients with retained RB1 protein expression and no germline BRCA mutation (HR: 0.44, P < 0.001). Conclusions: This study delineates the full landscape of genomic alterations in HGSC of long-term survivors. Our findings indicate that specific mutations might be associated with enhanced host immune responses and long-term survival. Citation Format: Dale W. Garsed, Ahwan Pandey, Sian Fereday, Kathryn Alsop, Maartje C. Wouters, Flurina Saner, Jessica A. Beach, Katy Milne, Catherine J. Kennedy, Joy Hendley, Nadia Traficante, Celeste L. Pearce, Malcolm C. Pike, Multidisciplinary Ovarian Cancer Outcomes Group, Susan J. Ramus, Martin Köbel, Brad H. Nelson, Ellen L. Goode, Anna deFazio, David D. Bowtell. The genomic landscape of high-grade serous ovarian cancer in long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2722.

Abstract Medical nutrition therapy for long‐chain fatty acid oxidation disorders (LC‐FAODs) currently emphasizes fasting avoidance, restricted dietary long‐chain fatty acid intake, supplementation with medium chain triglycerides, and increased carbohydrate intake. We hypothesize that increasing dietary protein intake relative to carbohydrate intake would preserve metabolic control yet induce physical benefits including reduced hepatic lipogenesis. Therefore, we compared two dietary approaches with similar fat intake but different carbohydrate to protein ratios in participants diagnosed with LC‐FAODs. Thirteen participants were enrolled and randomized into either a high‐protein (PRO) or a high‐carbohydrate (CHO) diet for 4 months. Baseline and 4‐month assessments included body composition, ectopic lipid deposition, and resting energy expenditure. End of study assessments also included total energy expenditure, metabolic responses to oral feedings, and whole‐body fatty acid oxidation capacity. At the end of the dietary intervention, both groups had similar energy expenditure, fat and glucose oxidation rates, and glucolipid responses to mixed meal and oral glucose loads. Neither dietary group experienced worsening symptoms related to their LC‐FAOD. Compared to the CHO group, the PRO group exhibited increased blood levels of short‐chain acylcarnitines, reduced intrahepatic lipid content, and maintained lean body mass while the CHO group lost lean mass. In patients with LC‐FAODs, increasing protein intake maintained metabolic control, reduced liver fat without risk of metabolic decompensation, and helped preserve lean body mass. We propose that a modest increase in dietary protein along with fasting avoidance and fat restriction may improve body composition and energy expenditure in patients with LC‐FAODs.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

Background:Injectable azacitidine (AZA) has been evaluated in a variety of malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and solid tumors. CC‐486, the oral formulation of AZA, allows extended dosing schedules (>7 days per 28‐day treatment cycle) to increase AZA exposure to malignant cells over the course of the cycle. CC‐486 is under investigation in phase 3 clinical trials as maintenance therapy for patients with AML in first complete remission after induction chemotherapy (NCT01757535) and in lower‐risk MDS with concurrent thrombocytopenia and RBC transfusion dependence (NCT01566695). In these studies, patients receive CC‐486 300 mg QD administered in two 150 mg tablets. A single 300 mg CC‐486 tablet is in development for market approval.Aims:Evaluate the bioequivalence (BE) of a single 300 mg CC‐486 tablet relative to two 150 mg CC‐486 tablets, and the food effect (FE) on the bioavailability of the CC‐486 300 mg tablet.Methods:This was a phase 1, randomized, crossover study (NCT01519011). Adult patients had hematologic malignancies or solid tumors relapsed/refractory to prior therapy for which no standard treatments were available, and ECOG PS scores 0‐2. The BE phase assessed pharmacokinetic (PK) parameters of CC‐486 administered as two 150 mg tablets (formulation A) and as one 300 mg tablet (formulation B). Patients were randomized 1:1 to receive each formulation at least 48 hours apart. In the FE phase, patients were randomized to receive formulation B on each of 2 PK study days under fed (high fat, ∼800‐1000 calories) and fasted conditions. PK parameters, including area under the plasma concentration‐time curve from time 0 extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal half‐life (t1/2), apparent total clearance (CL/F) and volume of distribution (Vz/F) were analyzed. BE of formulations A and B, and absence of FE on formulation B, were indicated when the 90% CI of the ratios of geometric means (RGM) based on log‐transformed data for AUC∞ and Cmax between formulations A and B, and between fed and fasted conditions, were within 80%>125%.Results:30 patients were enrolled in the BE phase (median age 68.5 yrs, range 46‐86); 3 patients (10%) had hematologic malignancies and 27 (90%) had solid tumors. Formulations A and B were bioequivalent: the Cmax RGM was 101.5% (90% CI 89.9, 114.7) and AUC∞ RGM was 105.7% (95.0, 117.6). Median Tmax was 1.0 hour for both formulations.57 patients enrolled in the FE phase (median age 62 yrs, 31‐88); all had solid tumors. Despite a lower Cmax under fed condition (RGM 78.9% [90%CI 68.6, 90.7]), overall drug exposure was similar (AUC∞ RGM 108.9% [90%CI 98.5, 120.5]) (Figure A). Consistent with an effect of gastric emptying, median Tmax was reached at 2 hrs and 1 hr post‐dose in fed and fasted states, respectively (Figure B) and mean t1/2 was 0.78 and 0.58 hr postdose. CL/F and Vz/F were comparable in fed and fasted states. Moderate to high intersubject variability was observed for all CC‐486 PK parameters (Figure A).Summary/Conclusion:A single oral CC‐486 300 mg tablet is bioequivalent to two 150 mg tablets. The PK profile for the CC‐486 300 mg tablet under fed and fasted conditions was comparable although Cmax occurred later and was decreased in fed vs. fasted condition. Systemic drug exposure (AUC∞) in fed and fasted states was similar and within the bioequivalence limits. Limited differences in other CC‐486 PK parameters between fed and fasted states are not expected to have a clinical impact.image

Abstract An estimated 14.1 million patients survive sepsis each year. Many survivors experience poor long-term outcomes, including new or worsened neuropsychological impairment; physical disability; and vulnerability to further health deterioration, including recurrent infection, cardiovascular events, and acute renal failure. However, clinical trials and guidelines have focused on shorter-term survival, so there are few data on promoting longer-term recovery. To address this unmet need, the International Sepsis Forum convened a colloquium in February 2018 titled “Understanding and Enhancing Sepsis Survivorship.” The goals were to identify gaps and limitations of current research and shorter- and longer-term priorities for understanding and enhancing sepsis survivorship. Twenty-six experts from eight countries participated. The top short-term priorities identified by nominal group technique culminating in formal voting were to better leverage existing databases for research, develop and disseminate educational resources on postsepsis morbidity, and partner with sepsis survivors to define and achieve research priorities. The top longer-term priorities were to study mechanisms of long-term morbidity through large cohort studies with deep phenotyping, build a harmonized global sepsis registry to facilitate enrollment in cohorts and trials, and complete detailed longitudinal follow-up to characterize the diversity of recovery experiences. This perspective reviews colloquium discussions, the identified priorities, and current initiatives to address them.

In 2011, we initiated a sentinel surveillance network to assess changes in Clostridioides (formerly Clostridium ) difficile antimicrobial susceptibility to fidaxomicin from 6 geographically dispersed medical centers in the United States. This report summarizes data from 2013 to 2016. C. difficile isolates or toxin-positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution. CLSI, EUCAST, or FDA breakpoints were used, where applicable.