Levels R1 Research Articles

Abstract 2228: Usage of ctDNA analysis to identify alterations with strong evidence for response or resistance to targeted therapy in patients with NENs

Abstract Background: Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. For nonresectable advanced NENs, the main treatment approaches including somatostatin analog, multiple TKIs, mTOR inhibitors and peptide receptor radionuclide therapy, whereas platinum-based chemotherapy is the main treatment for advanced high-grade and poorly differentiated NECs. Currently, there is no standard second-line treatment for NECs when disease progression. ctDNA as a non-invasive diagnostic avenue, which might potentially provide treatment guidance in NENs. Methods: We queried consecutive data from 40 NENs patients who underwent a targeted next-generation sequencing (NGS) assay performed by 3DMed Clinical Laboratory Inc., a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory of 3D Medicines Inc. between January, 2017 and June, 2020 in China, to identify the alterations detected in ctDNA. The alterations were classified based on the ranking in the OncoKB database as of January 2020. Results: In total, 40 of NENs patients detected with at least one alteration in ctDNA. The median age was 54 years, including 28 males and 12 females. Overall, 40.0% of patients had a Level 1 alteration, 22.5% of patients had a Level 2 alteration, and 22.5% of patients had a R1 alteration (selected alterations were outlined in Table). Conclusion: ctDNA analysis could provide information of alterations with strong evidence for targeted therapy or drug resistance based on the OncoKB database classification for NENs. Though the alterations are associated with other specific cancer types, the alterations still illustrate a part of NENs patients might have chance to be benefited from targeted therapy. AlterationsNumber of patients (%)Total Level 1 Alterations16 (40.0%)PIK3CA7 (17.5%)BRAF V600E2 (5.0%)BRCA22 (5.0%)MSI-H1 (2.5%)Total Level 2 Alterations9 (22.5%)ERBB2 activating4 (10.0%)MET amplication1 (2.5%)Total Level R1 alterations9 (22.5%)KRAS mut9 (22.5%) Citation Format: Kunli Du, Xueke She, Depei Huang, Xudong Shen, Hushan Zhang, Jianyong Zheng. Usage of ctDNA analysis to identify alterations with strong evidence for response or resistance to targeted therapy in patients with NENs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2228.

Comprehensive analysis of advanced-stage solid tumors from TCGA reveal widespread variation of genomics evidence levels across cancer types.

e13547 Background: Improved scalability and affordability of next generation sequencing (NGS) has pivoted cancer care toward genomics-driven treatment decisions. Particularly in advanced-stage or refractory cancer, clinical insights gleaned from NGS have become an integral option as these patients have typically exhausted all lines of available therapy. As precision oncology evolves, NGS is expected to have a differential impact based on the cancer type. In this study, a comprehensive NGS panel was used to determine the strength of clinical evidence in various advanced stage tumor samples from The Cancer Genome Atlas (TCGA). Methods: A hybrid capture panel, Oncofoco, was developed to evaluate SNVs, INDELs, CNVs and TMB in 366 genes. The panel’s utility was validated by interrogating a broader cohort of 2847 TCGA samples (advanced tumors with T3 or T4; or N > = 1; or M > = 1). Watsonä for Genomics, an artificial intelligence offering, was used for variant interpretation and annotation of the 366 genes. A clinical evidence classification system that evaluated the strength of biomarker/drug response associations was used for annotation with level 1/R1 strongest and level 4 weakest from clinical literature, FDA drug labels and guidelines (PMID:28890946). Results: The highest level of evidence for the top nine frequently occurring advanced stage cancers in TCGA is shown in Table. Conclusions: Thyroid cancer and cutaneous melanoma have emerged as the cancer types with the most level 1 evidence (FDA approved drugs) owing to BRAF V600E mutations. Kidney and prostate cancers show no cases with level 1 evidence and also had the largest fraction of unactionable tumors. Over half of colorectal cancer cases had level R1 resistance evidence attributed to KRAS and NRAS mutations. The clinical utility of NGS in late-stage refractory cancer varies widely by tumor type. The presence of level 3 and level 4 evidence in all cancer types bodes well for the development of new targeted drugs. [Table: see text]

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

PurposeDiabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.MethodsA genome‐wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta‐analysis using multiple Caucasian cohorts.ResultsFive hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10−9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10−8 and 1.23 × 10−8, respectively). In the meta‐analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429).ConclusionThis genome‐wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

Multi-resurgence and connection-to-Stokes formulæ for some linear meromorphic differential systems

In this article, we consider a linear meromorphic differential system with several levels r 1 < . . . < r p . For any k , we prove that the Borel transforms of its r k -reduced formal solutions are resurgent and we give the general form of all their singularities. Next, under some convenient hypotheses on the geometric configuration of singular points, we display exact formulæ to express some Stokes multipliers of level r k of initial system in terms of connection constants in the Borel plane, generalizing thus formulæ already obtained by M. Loday-Richaud and the author for systems with a single level. As an illustration, we develop one numerical example.

A genome‐wide association study suggests that the NADPH Oxidase 4 (NOX4) gene is associated with severe diabetic retinopathy in a Scottish diabetic population

SummaryDiabetic retinopathy is one of the devastating eye complications in patients with diabetes. The purpose of this study is to investigate the genetic contributors of severe diabetic retinopathy using a Scottish diabetic population through a genome‐wide association approach. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. 560 cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10−9. This genome‐wide association study of severe diabetic retinopathy suggests that the NOX4 gene might play a role in retinopathy.