Next-generation sequencing could emerge as new standard of testing in cancer research and care – analysis from BioPharm Insight

Need for more trained biostatisticians to understand genetic data
CUSTOM study is first completed prospective trial using genetic analysis alone to assign cancer treatment
TGen conducting advanced melanoma study evaluating genomic-sequencing guided treatment and outcomes

BioPharm InsightProprietary Intelligence

by Kimberly Ha in Chicago
(Republished with permission from BioPharm Insight.  All rights reserved.)

Next-generation sequencing (NGS) still has room for improvement, but could eventually replace current sequencing techniques that are less sensitive in cancer research and clinical utility, experts told this news service at the American Society of Clinical Oncology meeting in Chicago.
Illumina (NYSE:ILMN), Roche (VTX:ROG) and Life Technologies (NASDAQ:LIFE) are major players in this space.

CUSTOM is the first completed prospective clinical trial that used genetic analysis alone to assign cancer treatment for patients with one of three different cancers. Patients diagnosed with advanced stage non-small-cell lung cancer, small-cell lung cancer or thymic cancer were enrolled in this study.

Researchers used NGS to evaluate almost 200 genes, and patients were assigned to different treatment groups based on genetic mutations or amplification. Extensive genetic testing on the tumour biopsy took two weeks to complete, according to Dr Giuseppe Giaccone, lead study investigator, and director of the lung cancer program at Georgetown Lombardi Comprehensive Cancer Center, Washington DC.

“We thought it would take seven years, but we actually enrolled almost 700 patients in two years,” Giaccone said. The study utilized fluorescence in situ hybridization (FISH) analysis and then added NGS to detect 197 cancer genes. Tissue samples were obtained from patients in the study for three biopsies: FISH, NGS and frozen tissue for validation testing.

Illumina’s MiSeq personal sequencer – one of the fastest in the industry – was used in the CUSTOM study, said Giaccone. Life Technologies’ Ion Torrent is another sequencer with similar speeds, he added. The sequencing run only takes a day now, but the critical limitation is a biostatistician is needed to decipher the data, he said. “NGS still takes too long to make treatment decisions, but we proved we can do this using a small amount of tissue,” he said.

Many hospital centers are now setting up NGS for screening, and the technology is now more widely available, he said. Yet NGS is still in the exploratory stages, in terms of using this data alone to drive treatment decisions, Giaccone said. Although this data is interesting, he said he was not sure if the data generated from NGS alone would be sufficient to make a treatment decision.

“NGS is probably going to replace sequencing methods which are less sensitive in the future, but we need to speed up the time taken to [perform these assay tests and] get results,” said Giaccone. “The timing is critical, as some patients only have months.”

In addition, not every cancer is driven by a mutation, and there are also parallel pathways in action, Giaccone said. But NGS can certainly help us understand the underlying molecular basis of certain types of cancers better, to help identify better targets and therapies, he noted.

Search is on for more targeted therapies

Dr Karen Reckamp, co-chair of the Lung Cancer and Thoracic Oncology Program, City of Hope, California, said targeted agents in lung cancer have increased overall survival to an average of 36 months for some patients who harbor driver mutations.

“The number of patients who can receive targeted therapies in lung cancer is still a small percentage, and that’s why the five-year overall survival rate really hasn’t improved that much,” she explained.

A disappointment with the CUSTOM study was it was expected some patients would have more mutations, Giaccone said. Some mutations, such as P13K and Her-2, are really rare, and only occur in 1-2% of the overall patient pool in certain diseases, he noted. An issue is a lack of approved therapies to treat certain patients that harbor these mutations, he added.

Dr Nathan Pennell, an oncologist at Cleveland Clinic, Ohio, discussed a study at a session called “Molecular Testing in Lung Cancer: How Soon is Now?” that showed 37% out of 1007 patients with adenocarcinoma of the lung reported no detectable mutations after genomic testing. The major mutations identified in this study were KRAS (25%), EGFR (15%), ALK (8%), and EGFR-other (6%).

In another study, NGS of 386 lung cancer cases showed that 85% of tumours harboured at least one actionable genomic alternation, Pennell noted in the poster discussion session.

“The cost of NGS is approaching current molecular testing, but it’s not sensitive enough yet to replace tissue testing,” Pennell said. There needs to be more research conducted to improve the yield of tissue samples, he added at the poster session. There also needs to be an establishment of a nationwide testing and trial network of this genetics data and this should be a discussion between NCI-sponsored cooperative groups, international groups and the pharmaceutical industry, Pennell said.

Cost is a consideration for NGS, as well as how to interpret and use these results, Reckamp said. “Most of this work is still done at academic centers, and the next step will be how to disseminate this technology to the general public,” she said.

Meanwhile, a team led by Dr Jeffery Trent, president and research director at TGen, a translational genomics research institute in Phoenix, Arizona, will be enrolling the first patients this summer in a study that evaluates personalized therapy identification in patients with BRAF wild-type metastatic melanoma.

The study is funded by the SU2C-MRA Melanoma Dream Team Translational Cancer Research Grant. It is the first study of its kind, as nine pharmaceutical companies have agreed to give patients access to their targeted therapies on-site during the clinical trial.

The study plans to enroll 200 patients and will assess both genetic and genomic sequencing and the utility of personalized therapy in this specific type of melanoma. “This is a remarkably exciting time in medicine,” noted Trent, who is also former deputy director of the Human Genome Project.
“People are excited about the power of genomics, but we also have to realize there are multiple components that propagate cancer,” said Mace Rothenberg, senior vice president, Pfizer Oncology. Genomic sequencing has made tremendous progress against resistant cancers, such as in pancreatic cancer, he added.

NGS is not so cost-prohibitive anymore, but the major issue is who can interpret this genomics data, said Trent.


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