In patients with advanced cancer, abnormalities often proliferate beyond the reach of initial therapies, even the newer, targeted therapies, which typically work against single abnormalities. And so the ability to identify additional disease pathways—and therapeutic targets—is much desired. With the publication of a pilot study’s results, this ability is starting to look more feasible. This study, which focused on a small number of patients with advanced cancer, describes the use of whole-genome sequencing (WGS) and whole transcriptome sequencing (WTS) to identify genomic events and associated expression changes.
During the course of the study, which was led by the Translational Genomics Research Institute (TGen) and the Virginia G. Piper Cancer Center, both encouraging signs and challenges became clear, even though just nine patients were enrolled. For all nine patients, WGS was used to compare their germline DNA from white blood cells to the DNA from their tumor cells. For six of these patients, researchers also used WTS to sequence their total RNA isolated from the tumor, and compare that to total RNA from nonpatient controls. Ultimately, the researchers evaluated transcriptomic changes and performed integrated genomics analyses with WGS data to identify potential druggable targets.
According to Glen Weiss, M.D., the study’s lead author, “We demonstrate the feasibility of using NGS in advanced cancer patients so that treatments for patients with progressing tumors may be improved.” Besides this general assessment, the study produced a fairly dramatic outcome: one patient’s treatment was based on targets and pathways identified by next-generation sequencing, and the patient had a short-lived PET/CT response with a significant reduction in his tumor-related pain.
The study, which was published October 30 in PLOS ONE, is entitled “A Pilot Study Using Next-Generation Sequencing in Advanced Cancers: Feasibility and Challenges.” It had two main objectives: 1) identify as many genomic changes as possible; 2) develop a workflow process from tumor biopsy to treatment.
According to the study, a total of 18 targets were identified, with 5 targets appearing in one patient. With respect to workflow, and its implications for treatment, the study noted, “This process must occur in a short enough timeframe in order for patient to benefit from this additional information in developing a treatment plan.”
Some of the challenges highlighted by the study include NGS reporting delays, communication of results to out-of-state participants and their treating oncologists, and chain-of-custody handling from fresh biopsy samples for CLIA (Clinical Laboratory Improvement Amendments) target validation.
“With improved efficiencies that decrease the time to get NGS results and at reasonable costs, we can envision how NGS might be applied more globally to advanced cancer patients,” said John Carpten, Ph.D., TGen deputy director and also a senior author of the study. “Even during the relatively short time that this study was enrolling, we observed significant improvements in sequencing analyses and lower costs.”
The study also showed that WGS and WTS both have advantages, and that newer technological strategies may capture the best of both: “The integration of epigenomics analysis could also factor as another layer towards facilitating identification of druggable targets with existing therapies.”