Complexities of Next-Generation Sequencing in Solid Tumors: Case Studies

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  • 1 Department of Medicine, University of Washington;
  • 2 Clinical Research Division, Fred Hutchinson Cancer Research Center;
  • 3 VA Puget Sound Health Care System; and
  • 4 Department of Laboratory Medicine, University of Washington, Seattle, Washington.
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With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.

Submitted September 1, 2019; accepted for publication March 31, 2020.

Disclosures: Dr. Yu has disclosed that he receives consulting fees from Amgen, AstraZeneca, Bayer, Dendreon, Janssen, Merck, Pharmacyclics, and Seattle Genetics, and grant/research support from Bayer, Dendreon, Merck, and Seattle Genetics. Dr. Cheng has disclosed that she receives grant/research support from Clovis Oncology, Janssen, Medivation, Sanofi, and Astellas. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This study was supported by generous funding from the Institute for Prostate Cancer Research, the Prostate Cancer Foundation, the National Cancer Institute (T32 CA009515, Training in Cancer Biology and Transplantation; CA097186, Pacific Northwest Prostate Cancer SPORE; Cancer Center Support Grant P30 CA015704), and the Congressional Designated Medical Research Program (PC131820).

Correspondence: Heather H. Cheng, MD, PhD, Department of Medicine, University of Washington, 825 Eastlake Avenue East, Seattle, WA 98109. Email: hhcheng@uw.edu
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