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Updated: May 9, 2026
Ultra-Fast Amplicon-Based Next-Generation Sequencing in Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
A clinical model for identifying radiosensitive tumor genotypes in non-small cell lung cancer
Kimberly L Johung1, Xiaopan Yao, Fangyong Li
1Authors' Affiliations: Departments of Therapeutic Radiology, Medical Oncology, Neurosurgery, Yale University School of Medicine; and Yale Center for Analytic Sciences, Yale University School of Public Health, New Haven, Connecticut.
Purpose:
Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes.
Experimental Design:
Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments.
Results:
In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment.
Conclusions:
This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.
Insights
Tumors with EGFR mutations or ALK translocations show increased radiosensitivity in non-small cell lung cancer (NSCLC) brain metastases. This finding helps identify radiosensitive NSCLC genotypes for improved treatment outcomes.
Area of Science:
- Oncology
- Radiotherapy
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) exhibits variable responses to radiation therapy.
- Molecular drivers of radiosensitivity in NSCLC remain largely undefined.
- Gamma Knife radiotherapy offers a model to investigate tumor genotype-specific radiation responses.
Purpose of the Study:
- To evaluate clinical outcomes following Gamma Knife radiotherapy for NSCLC intracranial metastases.
- To determine if specific tumor genotypes (EGFR, ALK, KRAS) correlate with radiosensitivity.
- To establish a model for identifying radiosensitive NSCLC subtypes.
Main Methods:
- Prospective enrollment of 239 NSCLC patients in a Gamma Knife data repository (2005-2012).
- Analysis of molecular pathology (EGFR, ALK, KRAS mutations) in 81 patients.
- Evaluation of local and distant brain control for 469 metastases in 79 patients using modified Cox proportional hazards models.
Main Results:
- No in-field recurrence observed in metastases with EGFR mutations (0/164) or ALK translocations (0/61).
- In-field recurrence rates were 19% for tumors without these mutations and 18% for KRAS-mutant tumors.
- Superior local control was predicted for EGFR-mutant and ALK-translocated tumors; distant recurrence rates were similar across genotypes.
Conclusions:
- EGFR kinase domain mutations and EML4-ALK translocations identify radiosensitive NSCLC genotypes.
- These genetic alterations are associated with significantly better local control after Gamma Knife radiotherapy.
- A novel model is proposed for identifying radiosensitive NSCLC subtypes based on molecular markers.
