Related Experiment Video
Updated: Dec 6, 2025
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Inter- and Intratumor Heterogeneity of EGFR Compound Mutations in Non-Small Cell Lung Cancers: Analysis of Five Cases
Kenichi Suda1, Kazuko Sakai2, Keiko Obata1
1Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Background:
Several clinical and preclinical studies suggest that non-small cell lung cancers (NSCLCs) with EGFR compound mutations were associated with lower efficacies of first-generation EGFR inhibitors than tumors with single EGFR mutation. Some researchers hypothesize that EGFR mutation status is heterogeneous in such tumors and that second-generation EGFR inhibitors may eliminate cancer cells with uncommon EGFR mutations from tumors with EGFR compound mutations. However, this hypothesis is currently unproven; therefore, we performed the current study to determine if tumor cells with EGFR compound mutations are present in heterogeneous or homogeneous manners.
Patients And Methods:
Multiregion analysis was performed for surgically resected primary NSCLC tumors with EGFR compound mutations to examine the intratumor heterogeneity of EGFR compound mutations. In addition, we evaluated the intertumor heterogeneity of EGFR compound mutations using 2 pleural disseminations obtained from a patient with NSCLC at exploratory thoracotomy and 9 primary or metastatic lesions obtained from 2 autopsied NSCLC patients. Digital polymerase chain reaction, target sequencing, or direct sequencing were used to detect EGFR mutations.
Results:
This study included 5 NSCLC cases; their compound mutations were L858R+S768I, G719X+S768I, G719A+R776H, L858R+E709G, and L858R+I759M. Noncancerous pulmonary tissues from each patient did not harbor EGFR mutations, which revealed that all mutations were somatic. We did not detect any intra- or intertumor heterogeneity in these EGFR compound mutations.
Conclusion:
No intra- or intertumor heterogeneity was observed for EGFR compound mutations. Our results indicate that both EGFR mutations were truncal and selective elimination of cancer cells with uncommon EGFR mutations is unrealistic.
Insights
Tumors with multiple EGFR mutations in non-small cell lung cancer (NSCLC) show no heterogeneity. This suggests that targeting uncommon EGFR mutations with therapies is unlikely to be effective in NSCLC treatment.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) with multiple EGFR mutations often shows reduced sensitivity to first-generation EGFR inhibitors.
- A hypothesis suggests intratumor heterogeneity in these NSCLCs, where second-generation inhibitors could target uncommon EGFR mutations.
- This hypothesis remains unproven, necessitating investigation into the mutation distribution within tumors.
Purpose of the Study:
- To investigate the presence and distribution of tumor cells with compound epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer.
- To determine if EGFR compound mutations exhibit intratumor or intertumor heterogeneity.
Main Methods:
- Multiregion analysis of surgically resected primary NSCLC tumors with EGFR compound mutations.
- Evaluation of intertumor heterogeneity using pleural and autopsy specimens from NSCLC patients.
- Detection of EGFR mutations via digital PCR, target sequencing, and direct sequencing.
Main Results:
- Five NSCLC cases with specific compound EGFR mutations (L858R+S768I, G719X+S768I, G719A+R776H, L858R+E709G, L858R+I759M) were analyzed.
- All analyzed mutations were confirmed as somatic, as they were absent in noncancerous lung tissues.
- No evidence of intratumor or intertumor heterogeneity was found for the investigated EGFR compound mutations.
Conclusions:
- EGFR compound mutations in NSCLC do not display intra- or intertumor heterogeneity.
- Both identified EGFR mutations are likely 'truncal', originating early in tumor development.
- Selective elimination of cancer cells with uncommon EGFR mutations is not a feasible therapeutic strategy for these NSCLCs.
