1. Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer
- Author
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Caroline S. Verbeke, Katrin Stecker, Johannes Matthias Löhr, Markus Maeurer, Henrik Grönberg, Stephan Brock, Masoud Karimi, Linnéa Malgerud, Johan Lindberg, Rainer Heuchel, Maria Gustafsson-Liljefors, Marco Del Chiaro, Lars Engstrand, Carolin Huelsewig, Martin Stein, Regina Bohnert, Stephan L. Haas, Valtteri Wirta, Johan Permert, David B. Jackson, Alexander Picker, and Carlos Fernández Moro
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,pancreatic cancer ,medicine.disease_cause ,Bioinformatics ,Targeted therapy ,0302 clinical medicine ,Prospective Studies ,Precision Medicine ,Research Articles ,Aged, 80 and over ,education.field_of_study ,High-Throughput Nucleotide Sequencing ,bioinformatics ,evidence‐based ,Genomics ,General Medicine ,Middle Aged ,Oncology ,NGS ,030220 oncology & carcinogenesis ,Molecular Medicine ,KRAS ,Research Article ,Carcinoma, Pancreatic Ductal ,Adult ,Population ,Antineoplastic Agents ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Germline mutation ,Pancreatic cancer ,Genetics ,medicine ,Humans ,education ,Germ-Line Mutation ,Aged ,business.industry ,Cancer ,Precision medicine ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Pharmacogenomics ,Mutation ,drug–drug interactions ,Feasibility Studies ,Tumor Suppressor Protein p53 ,business ,Software - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence-based software, could be conducted within a 2-week period, thus being feasible for clinical routine. Therapy recommendations were principally off-label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome-associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software-analysis of NGS data provides evidence-based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.
- Published
- 2017