Next-Generation Sequencing in NSCLC Reveals Mutations With Therapeutic Implications

11/09/17

A recent study showed that after performing next-generation sequencing of non-small cell lung cancer (NSCLC) gene panels, actionable mutations were identifiable in 65% of cases with available targeted therapeutic options.

A few recent studies have identified numerous genes that are often mutated in NSCLC. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend testing for seven genes in patients with NSCLC to match them to targeted therapies.

A group of researchers from the Icahn School of Medicine at Mount Sinai (New York, NY) performed targeted next-generation sequencing on clinical cases of NSCLC (n = 932) using the Ion AmpliSeq Cancer Hotspot panel assay, which covers 50 cancer-linked genes such as ALK, CDKN2A, JAK2, and PIK3CA. Using the assay, researchers found almost 3000 mutations among the tumor samples.

Results of the study were published in Genome Medicine (online October 30, 2017; doi:10.1186/s13073-017-0478-1).

After the assay was utilized, researchers found that actionable mutations were identifiable in 65% of cases with available targeted therapeutic options, including 26% of the patients with mutations in NCCN guideline genes. The most notable mutation discovered was JAK2 p.V617F, which is commonly found in myeloproliferative disorders (1%; n = 9/932).

An analysis of cancer cell line pharmacogenomics data revealed that a high level of JAK2 expression is associated with increased sensitivity to a selective JAK2 inhibitor. Further analysis showed that JAK2 gain or loss due to genetic alterations in NSCLC samples are associated with elevated or reduced PD-L1 expression. This finding suggests that activating JAK2 p.V617F could translate to sensitivity to both JAK inhibitors and anti-PD1 immunotherapies.

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Researchers also noted that they detected JAK3 germline activating mutations in 6.7% of patients (n = 62) who may benefit from anti-PD1 therapy.

Researchers concluded that the study “demonstrated the clinical utility of targeted next-generation sequencing with a focus hotspot cancer gene panel in NSCLCs and identified activating mutations in JAK2 and JAK3 with clinical implications.” The relationship between JAK2/JAK3 mutations and JAK kinases or anti-PD1 therapy warrants further investigation, they wrote.—Zachary Bessette