Dr Watson on the Use of Oncogene Analysis to Determine Clinically Relevant HER2, KRAS and MET Copy-Number Gain in NSCLC

"We were seeing which copy number gain genes coexisted with driver mutations that were more traditionally defined. We found that for all 3 genes—in the MET group in particular—there was frequent co-amplification and mutation. We saw the same gene alterations at an increased frequency than would be expected. This has been previously defined as a phenomenon, but not as generalized and not quantified in the way that this investigation allowed us to…"

Alec Watson, MD, second-year fellow, Division of Medical Oncology, School of Medicine, University of Colorado Anschutz, discusses findings from a retrospective analysis of oncogene overlap to potentially identify clinically relevant thresholds for HER2, KRAS, and MET gene copy number gain (CNG) in non–small cell lung cancer (NSCLC).

Watson and colleagues retrospectively analyzed DNA/RNA from 13,702 NSCLC adenocarcinoma samples, and subsequently examined the correlation between CNG of HER2, KRAS, and MET oncogenes and overall survival (OS). Gene CNG is a continuous variable, and the relevant cutpoints for HER2, KRAS, and MET CNG in NSCLC remain uncertain. The analysis aimed to identify CNG thresholds by using oncogene overlap analysis to better understand their clinical relevance, Watson explains.

The thresholds for HER2 and KRAS was determined to be as a CNG of 6; MET CNG was considered amplified at a threshold of 4. These thresholds were used to categorize subgroups with altered genetic profiles and reduced survival outcomes, he says The investigation also examined which driver mutations coexisted with highly amplified HER2, KRAS, and MET genes, considering the principle of mutual exclusivity in oncogenes. Some mutations were more likely to coexist with amplified genes, suggesting that specific oncogenes may be synergistic for cancer growth, Watson adds.

Particularly in the MET amplification group, co-occurrence of MET mutations was observed at a higher frequency than would be expected, he reports. This phenomenon was more frequently seen in the MET group than in the other amplified genes, which supports the idea that cancers with MET amplification may be more reliant on this pathway. Additionally, in cases of acquired resistance to therapies, MET amplification is often associated with resistance to EGFR-targeted treatments, as MET signaling can serve as an alternative pathway for tumor survival, Watson emphasizes. In these cases, combining MET-targeted therapy with EGFR inhibitors may restore objective response rates in previously resistant tumors.

Overall, this NGS investigation, which allowed for concurrent analysis of gene mutations and CNG in the same cohort, provides a more comprehensive understanding of the genetic landscape in NSCLC, he expands. The results emphasize the importance of considering the co-occurrence of mutations and amplifications in personalized treatment strategies. Further prospective research is needed to evaluate the benefits of targeted therapies in these genetically defined subgroups, Watson concludes.