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Mol Oncol. 2017 Oct;11(10):1413-1429. doi: 10.1002/1878-0261.12108. Epub 2017 Aug 8.

Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer.

Author information

1
Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
2
Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
3
Department of Medical Epidemiology & Biostatistics (MEB), Karolinska Institutet, Stockholm, Sweden.
4
Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
5
Department of Oncology at Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
6
Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
7
Molecular Health GmbH, Heidelberg, Germany.
8
Innovation Office, Karolinska University Hospital, Stockholm, Sweden.
9
Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.

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.

KEYWORDS:

NGS ; bioinformatics; drug-drug interactions; evidence-based; pancreatic cancer

PMID:
28675654
PMCID:
PMC5623817
DOI:
10.1002/1878-0261.12108
[Indexed for MEDLINE]
Free PMC Article

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