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Updated: Apr 23, 2026
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
The minority report: targeting the rare oncogenes in NSCLC
Caroline E McCoach1, Robert C Doebele
1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, 12801 E. 17th Avenue, Aurora, CO, 80045, USA.
Opinion Statement:
Lung cancer is still responsible for the highest number of cancer deaths worldwide. Despite this fact, significant progress has been made in the treatment of non-small cell lung cancer (NSCLC). Specifically, efforts to identify and treat genetic alterations (gene mutations, gene fusions, gene amplification events, etc.) that result in oncogenic drivers are now standard of care (EGFR and ALK) or an intense area of research. The most prevalent oncogenic drivers have likely already been identified; thus, there is now a focus on subgroups of tumors with less common genetic alterations. Interestingly, as we explore these less common mutations, we are discovering that many occur across other tumor types (i.e., non-lung cancer), further justifying their study. Furthermore, many studies have demonstrated that by searching broadly for multiple genetic alterations in large subsets of patients they are able to identify potentially targetable alterations in the majority of patients. Although individually, the rare oncogenic drivers subgroups may seem to occur too infrequently to justify their exploration, the fact that the majority of patients with NSCLC harbor a potentially actionable driver mutation within their tumors and the fact that different types of cancers often have the same oncogenic driver justifies this approach.
Insights
Identifying rare genetic alterations in non-small cell lung cancer (NSCLC) is crucial. These less common oncogenic drivers, often found across various cancer types, are actionable targets for a majority of NSCLC patients.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally.
- Advances in targeted therapies focus on identifying and treating specific genetic alterations driving cancer growth.
- Established targets like EGFR and ALK are standard, but research now explores less common mutations.
Purpose of the Study:
- To investigate the significance of rare genetic alterations in NSCLC.
- To highlight the potential of targeting less prevalent oncogenic drivers.
- To underscore the value of broad genetic profiling in identifying actionable mutations.
Main Methods:
- Analysis of genetic alterations in NSCLC tumors.
- Focus on identifying subgroups with less common mutations.
- Cross-tumor type analysis of genetic drivers.
Main Results:
- Many rare mutations in NSCLC are also found in other cancer types.
- Broad screening for multiple genetic alterations can identify actionable targets in most NSCLC patients.
- Individually rare drivers collectively represent a significant therapeutic opportunity.
Conclusions:
- Exploring rare oncogenic drivers in NSCLC is justified due to their prevalence across diverse cancers.
- Targeting these less common alterations offers potential therapeutic strategies for a majority of NSCLC patients.
- Comprehensive genetic profiling is essential for maximizing treatment opportunities in NSCLC.
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