A Pilot Study Shows Next-Generation Sequencing Feasibility in Patients with Advanced Cancers

Faster analysis of genetic variations should uncover new drug targets and pathways even as cancers mutate beyond initial therapies

A pilot study led by the Translational Genomics Research Institute (TGen) and the Virginia G. Piper Cancer Center at Scottsdale Healthcare shows that, even for patients with advanced and rapidly transforming cancer, next generation sequencing is feasible. While the initial effort was a slower process than anticipated due to a variety of issues, treatments for patients with progressing tumours may be improved.

Better optics and faster computers, which are the hallmarks of today's Next Generation Sequencing (NGS), are leading to genomic analysis that enables development of new drugs that target specific genetic mutations. However, because patients' tumours often contain multiple abnormalities, their cancer often progresses beyond initial targeted therapies.

In an exploratory study, researches showed that the most cutting-edge NGS — whole genome sequencing (WGS), and even more advanced whole transcriptome sequencing (WTS) — can reveal larger numbers of targets in an individual's tumour, and that these "could be addressed using specific therapeutic agents, and perhaps reduce the chance of progression," according to the pilot study published on 30 October 2013 in the scientific journal PLOS ONE.

The study reported results on nine patients evaluated at the Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, a partnership of Scottsdale Healthcare and TGen. Patients with advanced cancer often exhaust treatment options and targeting a single abnormality is not sufficient to prevent progression, according to Dr Glen Weiss, an Associate Professor in TGen's Cancer and Cell Biology Division and the study's lead author. He was previously affiliated with Scottsdale Healthcare, and now is affiliated with Cancer Treatment Centers of America Western Regional Medical Center in Arizona.

For all nine patients, WGS was used to compare their germline DNA to the DNA from their tumour cells. For six of these patients, researchers also used WTS to sequence their total RNA isolated from the tumour, and compare that to total RNA from non-patient controls.

The researchers found that it is feasible to perform these advanced NGS technologies for patients in a clinical trial situation.  One patient's treatment was based on targets and pathways identified by NGS and the patient had a short-lived PET/CT response with a significant reduction in his tumour-related pain.

In addition to identifying as many genomic changes as possible, a secondary objective of this pilot study was to develop a workflow process from tumour biopsy to treatment. "This process must occur in a short enough timeframe in order for patient to benefit from this additional information in developing a treatment plan," the authors wrote.

To design treatment plans based on information garnered from NGS, several challenges were encountered: 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.

The study also showed that WGS and WTS both have advantages, and that newer technological strategies may capture the best of both.

"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 Dr John Carpten, 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 was funded by the National Foundation for Cancer Research and the Lee T. Hanley Fund for Pancreatic Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Reference:

Weiss GJ, Liang WS, Demeure MJ, et al. (2013) A Pilot Study Using Next-Generation Sequencing in Advanced Cancers: Feasibility and Challenges. PLoS ONE 8(10): e76438. doi:10.1371/journal.pone.0076438

The authors have declared that no competing interests exist.