Difference in Radiosensitivity Depending on the Presence and Absence of EGFR Mutations: Clinical and In Vitro Analyses

Abstract

For stage IV non-small cell lung cancer (NSCLC), the treatment drug is selected based on the gene mutation status. However, the dose or field of radiation therapy is not change based on the genetic status. We evaluated both clinical and in vitro data, showing that the presence or absence of epidermal growth factor receptor (EGFR) mutations affects radiosensitivity in patients with brain metastases (BM) from NSCLC. Patients with BM from NSCLC who received whole brain radiotherapy (WBRT) were enrolled in this study. Patient characteristics are shown in the Table. EGFR mutations were observed in 13 (31.0%) patients. The prescribed dose was 30 Gy in 10 fractions (85.7%). The A549, VMRC-LCD, NCI-H1975, and HCC4006 cell lines were used for the in vitro study. EGFR mutation was negative in A549 and VMRC-LCD and positive in NCI-H1975 (exon21) and HCC4006 (exon19). After irradiation of these cell lines with 0, 2, 4, and 8 Gy, a colony formation assay was performed. DNA double-strand breaks (DSBs) were assessed 30 min and 24 h after 4 Gy irradiation using γH2AX. The median follow-up period was 4 months (range, 1-35). Intracranial recurrence was observed in 14 (33.3%) patients during the follow-up period. Thirty-nine (92.9%) patients died during the follow-up period. Patients with EGFR mutation-positive tumors had significantly better intracranial control rates than those with EGFR mutation-negative tumors (p = 0.0213). A similar tendency was observed in the analysis conducted, except for the cases in which tyrosine kinase inhibitor (TKI) was administered after WBRT. In the EGFR mutation-positive group, no significant difference was observed between patients who received TKI after WBRT and those who did not (p = 0.527). In the colony formation assay, EGFR mutation-positive cell lines showed a significantly lower number of colonies formed after irradiation with 2 and 4 Gy than mutation-negative cell lines (p = 0.00018 and 0.0000291, respectively). EGFR mutation-positive cell lines had significantly more DNA-DSBs remaining 24 h after irradiation than mutation-negative cell lines (p = 0.0000000312). Our data suggest that patients with EGFR mutation-positive NSCLC are more radiosensitive than those with negative EGFR mutations.