Adenocarcinoma is the most common type of lung cancer with 64% of these patients harboring one or more actionable oncogenic drivers.¹ Through tumor genotyping, lung cancer patients with actionable oncogenic drivers can be treated with genotype-directed targeted therapy to improve their median overall survival (OS) to 3.5 years versus 2.4 years for those who did not receive targeted therapy (propensity score-adjusted HR=0.69; 95% CI: 0.53-0.90; p=0.006).¹ However, targeted therapy is not applicable to all patients with advanced non-small cell lung carcinoma (NSCLC). Whereas the targeted drug gefitinib can improve the progression-free survival (PFS) of patients with epidermal growth factor receptor (EGFR) gene mutation when compared to carboplatin plus paclitaxel (HR=0.48; 95% CI: 0.36-0.64; p<0.001), the targeted therapy can also increase the mortality rate of NSCLC patients with wild-type EGFR (HR=2.85; 95% CI: 2.05-3.98; p<0.001).²

As the response to targeted therapy is highly dependent on mutational status, Dr. Dara Aisner, Associate Professor of the University of Colorado Cancer Center, United States, strongly recommended panel-based testing for NSCLC patients unless the quantity of tissue samples is insufficient or there is high non-tumor content. Indeed, NSCLC patients with EGFR, ALK and ROS1 positive tumors typically respond optimally to targeted therapy, and the prescription of first-line immunotherapy could be detrimental to these patients with actionable oncogenic drivers. As such, point mutations of the EGFR and BRAF loci in addition to the rearrangement of ALK, RET, ROS1 and NTRK1/2/3 genes should be investigated. Immunohistochemistry of programmed death-ligand 1 (PD-L1) should also be performed to confirm the presence of actionable oncogenic drivers.

Currently, oncogene mutations could be detected by either DNAor RNA-based next generation sequencing (NGS) platforms. However, DNA-based NGS may provide false-negative signals when encountering repetitive introns or complex genomic events in the tumor cells. To clarify the NGS results, Dr. Aisner advised repeating testing with RNA-based NGS which is capable of bypassing introns during nucleotide sequencing. Notably, 15.5% of DNA-based NGS negative results can turn positive in one of the oncogene loci upon retesting by the RNA-based NGS platform.³ In this connection, the National Comprehensive Cancer Network (NCCN) guidelines now recommend patients with unidentifiable oncogene mutations to be retested with RNA-based NGS to maximize the detection of gene fusion events.

Aside from invasive procedures, circulating tumor cell DNA (ctDNA) can also be isolated directly from the peripheral blood to evaluate the presence of actionable oncogenic drivers.⁴ As ctDNA are shed by tumor cells, Dr. Aisner noted that liquid biopsy can be used to complement conventional invasive biopsy testing especially when negative NGS results are obtained. With multiple options available to confirm the presence of oncogenic driver mutations for NSCLC, Dr. Aisner emphasized the importance of directing first-line NSCLC treatment based on molecular testing results. “When any of these [driver oncogenes] is positive, targeted therapy is the preferred firstline treatment,” Dr. Aisner commented, “Where a known driver mutation is absent, the laboratory finding should be considered as uninformative…passenger mutation (a mutation in the oncogene loci but do not confer oncogenesis) should not be counted.”