ORCID Profile
0000-0002-3938-8490
Current Organisation
University of Oxford
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Publisher: Ferrata Storti Foundation (Haematologica)
Date: 16-12-2009
Publisher: Wiley
Date: 30-04-2018
DOI: 10.1002/PATH.5081
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.SEMCANCER.2021.07.003
Abstract: Whole-genome sequencing either alone or in combination with whole-transcriptome sequencing has started to be used to analyze clinical tumor s les to improve diagnosis, provide risk stratification, and select patient-specific therapies. Compared with current genomic testing strategies, largely focused on small number of genes tested in idually or targeted panels, whole-genome and transcriptome sequencing (WGTS) provides novel opportunities to identify and report a potentially much larger number of actionable alterations with diagnostic, prognostic, and/or predictive impact. Such alterations include point mutations, indels, copy- number aberrations and structural variants, but also germline variants, fusion genes, noncoding alterations and mutational signatures. Nevertheless, these comprehensive tests are accompanied by many challenges ranging from the extent and ersity of sequence alterations detected by these methods to the complexity and limited existing standardization in interpreting them. We describe the challenges of WGTS interpretation and the opportunities with comprehensive genomic testing.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2022
DOI: 10.1200/PO.22.00245
Abstract: The combination of whole-genome and transcriptome sequencing (WGTS) is expected to transform diagnosis and treatment for patients with cancer. WGTS is a comprehensive precision diagnostic test that is starting to replace the standard of care for oncology molecular testing in health care systems around the world however, the implementation and widescale adoption of this best-in-class testing is lacking. Here, we address the barriers in integrating WGTS for cancer diagnostics and treatment selection and answer questions regarding utility in different cancer types, cost-effectiveness and affordability, and other practical considerations for WGTS implementation. We review the current studies implementing WGTS in health care systems and provide a synopsis of the clinical evidence and insights into practical considerations for WGTS implementation. We reflect on regulatory, costs, reimbursement, and incidental findings aspects of this test. WGTS is an appropriate comprehensive clinical test for many tumor types and can replace multiple, cascade testing approaches currently performed. Decreasing sequencing cost, increasing number of clinically relevant aberrations and discovery of more complex biomarkers of treatment response, should pave the way for health care systems and laboratories in implementing WGTS into clinical practice, to transform diagnosis and treatment for patients with cancer.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.SEMCANCER.2021.06.009
Abstract: Interrogating the tumor genome in its entirety by whole-genome sequencing (WGS) offers an unprecedented insight into the biology and pathogenesis of cancer, with potential impact on diagnostics, prognostication and therapy selection. WGS is able to detect sequence as well as structural variants and thereby combines central domains of cytogenetics and molecular genetics. Given the potential of WGS in directing targeted therapeutics and clinical decision-making, we envision a gradual transition of the method from research to clinical routine. This review is one out of three within this issue aimed at facilitating this effort, by discussing in-depth analytical validation, clinical interpretation and clinical utility of WGS. The review highlights the requirements for implementing, validating and maintaining a clinical WGS pipeline to obtain high-quality patient-specific data in accordance with the local regulatory landscape. Every step of the WGS pipeline, which includes DNA extraction, library preparation, sequencing, bioinformatics analysis, and data storage, is considered with respect to its logistics, necessities, potential pitfalls, and the required quality management. WGS is likely to drive clinical diagnostics and patient care forward, if requirements and challenges of the technique are recognized and met.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.SEMCANCER.2021.06.018
Abstract: Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected in three recent FDA tissue agnostic cancer drug approvals. In addition, there is increasing evidence from studies that interrogate the entire genome by whole-genome sequencing that acquired global and complex genomic aberrations including those in non-coding regions of the genome might also reflect clinical outcome. After addressing technical, logistical, financial and ethical challenges, national initiatives now aim to introduce clinical whole-genome sequencing into real-world diagnostics as a rational and potentially cost-effective tool for response prediction in cancer and to identify patients who would benefit most from 'expensive' targeted therapies and recruitment into clinical trials. However, so far, this has not been accompanied by a systematic and prospective evaluation of the clinical utility of whole-genome sequencing within clinical trials of uniformly treated patients of defined clinical outcome. This approach would also greatly facilitate novel predictive biomarker discovery and validation, ultimately reducing size and duration of clinical trials and cost of drug development. This manuscript is the third in a series of three to review and critically appraise the potential and challenges of clinical whole-genome sequencing in solid tumors and hematological malignancies.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2018
Abstract: Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose r up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10 −4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD 10 −4 was achieved in this high-risk population.
Publisher: Massachusetts Medical Society
Date: 17-12-2015
Publisher: Massachusetts Medical Society
Date: 17-07-2014
Publisher: American Society of Hematology
Date: 21-08-2019
DOI: 10.1182/BLOODADVANCES.2019000237
Abstract: Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can sub ide early-stage patients into naive B-cell–like CLL (n-CLL), memory B-cell–like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46 95% confidence interval [CI], 0.24-0.87 P = .018) in CLL4, and for progression-free survival (HR, 0.25 95% CI, 0.10-0.57 P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Publisher: Springer Science and Business Media LLC
Date: 20-05-2016
DOI: 10.1038/LEU.2016.134
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for schuh Anna.