Clinical Application of Targeted Deep Sequencing in Solid-Cancer Patients and Utility for Biomarker-Selected Clinical Trials

Abstract

Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase.

Implications for practice: This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase.

Trial registration: ClinicalTrials.gov NCT02141152.

Keywords: Clinical trials; Metastatic cancer; Molecular screening; Next‐generation sequencing.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

© AlphaMed Press 2017.

Figures

Figure 1.

Overall scheme of the NEXT‐1 molecular‐screening program. (A): Quality control test for molecular tests. (B): Patients for analysis: pancreatic/biliary tract cancer included 28 pancreatic adenocarcinoma patients (*), 11 gall bladder cancer patients, 13 biliary tract cancer patients, and 10 ampulla of Vater cancer patients; others included 21 sarcoma patients, 21 melanoma patients, 4 gastrointestinal stromal tumor patients, 2 duodenal cancer patients, 1 anal squamous cell cancer patient, 1 adenocortical carcinoma patient, 3 patients with metastases of unknown origin, 1 anaplastic astrocytoma patient, 2 small‐bowel cancer patients, and 9 neuroendocrine carcinoma patients (**). Abbreviations: QC, quality control; FFPE, formalin‐fixed paraffin‐embedded.

Figure 2.

Mutations in key genes and pathways. Variants are shown in association with the RAF/MEK, PI3K/AKT/mTOR, and DNA damage and repair pathways, as well as others. The upper panel shows patients guided toward matched therapy (blue) or conventional chemotherapy (olive green) and their responses. The right panel indicates a frequency of the variants in each gene.

Figure 3.

Therapy distribution for 418 patients and the recurrently mutated genes. (A): The inner circle represents the patients undergoing different therapies, and the outer circle shows mutation‐variant distributions: potentially treatable variants (blue), any variants (light blue), and no variants (grey) among the three groups. The right panel shows frequently detected genes representing (B) key genes in the matched‐therapy group and (C) genes with potentially treatable variants in all three groups. The number of patients is indicated in brackets. Abbreviations: CRC, colorectal cancer; GC, gastric cancer; GUC, genitourinary cancer; PC/BTC, pancreatic/biliary tract cancer.