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Sequencing-Based Gene Panels Help Diagnose, Guide Treatment, AACC Presenters Say

ATLANTA (GenomeWeb) – Gene panel testing is enabling clinicians to classify cancer patients' disease and identify potential treatment courses, according to presenters at the American Association for Clinical Chemistry meeting, held here this week.

As more gene variants are linked to various forms of cancer and more drugs are targeted to those specific forms of disease, clinicians need a way to identify patients whose tumors harbor these mutations and who may benefit from targeted therapies.

"The goal of a gene panel test," said Yale University School of Medicine's John Howe, "is to uncover actionable genes."

An actionable gene mutation, he added, could be one that is associated with a US Food and Drug Administration-approved therapy for that tumor type or even for another tumor type, or it could be one that would enable a patient to take part in a clinical trial.

Next-generation sequencing-based gene panels, Howe and other speakers said during a session here, offer a way to examine multiple genes using one test with relatively quick turnaround time and costs comparable to other assays. For cancer, gene panel tests typically include between 50 and 500 genes.

A number of companies — including Foundation Medicine, Genoptix, and ARUP, as well as Illumina, Thermo Fisher Ion Torrent, and Qiagen, among others — offer gene panel tests, the speakers noted, but developing in-house tests enable clinicians and laboratorians to focus on particular genes of interest and update the panel quickly.

Speakers recounted their development of NGS-based gene panel tests for both blood and solid cancers.

Howe, for instance, has developed an acute myeloid leukemia/myelodysplastic syndrome gene panel based on the Ion Torrent PGM platform. This panel of 25 genes, he noted, includes genes clinicians he works with are interested in that are not always all found together on one commercial test.

Weill Cornell Medical College's Helen Fernandes, meanwhile, has developed both a small pan-cancer panel of about 50 genes for solid tumors and a larger panel of some 300 genes. The small panel, she noted, is suitable for finding mutations in certain hotspots to inform patient diagnosis and treatment, as well as gauging prognosis, while the larger panel has greater utility for clinical trials.

Results from gene panel testing often fall into a few broad categories, and aren't always definitive, the speakers noted. Fernandes reports findings as belonging to one of three tiers. Tier one results, she said, are actionable variants that have therapeutic, diagnostic, or prognostic significance. Tier two results, meanwhile, have been linked to cancer in academic studies or might be associated with a clinical trial. And tier three results include mutations that are broadly linked to cancer, like TP53 mutations.

Howe similarly reports three possible mutation categories: actionable mutations, mutations uncovered in another tumor type, and mutations whose significance isn’t clear.

Still, such gene panel tests have enabled Fernandes to both classify one patient's disease and uncover a clinical trial for another to participate in.

Fernandes recounted the case of a 77-year-old woman with two thyroid nodules. Gene panel testing found that one nodule was a papillary thyroid carcinoma that harbored a BRAF V600E mutation, while the other was a follicular variant with a NRAS Q61R mutation. She and her colleagues confirmed these findings using Sanger sequencing.

In thyroid cancer, Fernandes noted that the BRAF mutation is associated with poor outcomes, while the NRAS mutation is not. This finding, she said, is "very relevant for follow up because thyroid surgery can be pretty bloody."

Meanwhile, NGS gene panel testing of a 71-year-man who presented with abdominal pain, jaundice, and weight loss  — he had a hepatic mass — enabled Fernandes to uncover a trio of mutations in that tumor.

Through the panel, Fernandes found that the man had an IDH1 R132H mutation, as well as TP53 and KIT mutations. The latter two, she noted, are so-called frequent flyer mutations, with the former mutation typically found in gliomas.

However, by searching through COSMIC and The Cancer Genome Atlas databases she found that such mutations are also prevalent in liver cancers.  This patient, she added, has since been enrolled in a clinical trial and is doing better on a treatment targeted at IDH1.

These, she added, are examples of how to use next-generation sequencing in the clinic, noting that challenges of variant interpretation, uncertain regulatory environment, reimbursement, and more remain.