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Gene Profiling Uncovers Actionable Mutations in More Than Half of Non-Small Cell Lung Cancers

NEW YORK (GenomeWeb) – Targeted sequencing matched mutations to therapeutic options in more than half of the non-small cell lung cancer patients analyzed in a new study.

NSCLC accounts for 85 percent to 90 percent of the approximately 222,500 new lung cancer cases in the US each year. Recent studies have uncovered a number of genes that are frequently mutated in NSCLC and guidelines from the National Comprehensive Cancer Network (NCCN) recommend testing for seven genes in NSCLC patients to match them to targeted therapies.

In a new study, researchers from the Icahn School of Medicine at Mount Sinai used a gene-sequencing panel to analyze 932 samples from NSCLC patients to see whether they harbored mutations in those NCCN genes or other genes associated with targeted therapies. As they reported in Genome Medicine, Mount Sinai's Fei Ye and her colleagues found that the majority of patients did harbor such mutations. They additionally found mutations among a portion of NSCLC patients that could indicate that they are sensitive to JAK inhibitor therapy and anti-PD1 immunotherapy.

"The current study demonstrated the clinical utility of NGS-based cancer gene profiling in NSCLCs," the researchers wrote.

Ye and her colleagues performed targeted next-generation sequencing using the Ion AmpliSeq Cancer Hotspot panel assay on 932 samples obtained from NSCLC patients. The cancer assay covered 50 cancer-linked genes such as ALK, CDKN2A, JAK2, and PIK3CA. Using that, the researchers reached a mean sequencing depth of 2,129X and uncovered nearly 3,000 mutations among the tumor samples they analyzed.

The researchers first focused on examining mutations in the genes covered by the NCCN guidelines: EGFR, ALK, ROS1, RET, BRAF, MET, and HER2.

They uncovered EGFR mutations within 231 of the samples, including 188 activating mutations that indicated that these patients might benefit from gefitinib, erlotinib, or afatinib treatment. They likewise found BRAF mutations in 34 samples, 19 of which were activating mutations that could be targeted with vemurafenib or dabrafenib and nine that indicated that dasatinib therapy might work.

Ye and her colleagues also looked to see if the patients in their samples harbored mutations in genes for which targeted therapies are currently under investigation for use in NSCLC. They found KRAS, HRAS, and NRAS mutations within a respective 292, two, and five cases, suggesting that the patients might consider enrolling in MEK inhibitor trials. Similarly, they uncovered CDKN2A mutations in 38 patients that could consider entering a cell cycle inhibitor trial.

All together, they reported that 65 percent of the patients in their study had an actionable mutation. However, they noted that they did not have data from the patients' oncologists to see what treatments they actually underwent.

At the same time, the researchers searched for potentially actionable mutations that haven't been catalogued extensively in NSCLC. They found nine samples, or about 1 percent, with a JAK2 p.V617F activating mutation that's commonly found in myeloproliferative disorders. Ye and her colleagues noted that ruxolitinib, which inhibits the JAK1 and JAK2 kinases, has been approved in the US for myelofibrosis and polycythemia vera.

To gauge whether lung cancer cells might be sensitive to JAK2 inhibition, they examined the Genomics of Drug Sensitivity in Cancer database. They found that lung cancer cell lines that expressed higher levels of JAK2 had increased sensitivity to fedratinib.

The researchers noted that JAK2 gains were linked to elevated PD-L1 expression, while loss of it was linked to lower PD-L1 levels, suggesting that JAK2 activating mutations could sensitize tumors to anti PD-1 immunotherapy.

They also uncovered 62 samples with germline JAK3 activating mutations that might also benefit from such treatment.