This work presents the first thorough examination of epidermal growth factor receptor (EGFR) mutation prevalence in Kurdish patients with non-small cell lung cancer (NSCLC), identifying unique molecular and epidemiological traits. We found an overall EGFR mutation rate of 18.2% among 149 metastatic non-squamous NSCLC cases, which is comparable to Middle Eastern cohorts but much lower than rates reported in East Asian populations (47.2%–64.2%). Significant gender differences were found, with females (55.6%) having EGFR mutations at a significantly higher rate than males (44.4%, *p* = 0.0056). For Exon 19 deletions, this difference was especially noticeable (73.3% in females versus 66.7% in males). EGFR positivity was significantly higher in non-smokers (70.4%) than in smokers (29.6%, *p* < 0.0001), indicating a strong correlation between smoking status and mutation frequency. Significant variations in the distribution of mutations according to smoking status were found by subtype-specific analyses: L858R (4 versus 1 case, *p* = 0.04) and Exon 19 deletions (13 versus 6 cases, *p* = 0.001) were more common in non-smokers, while Exon 20 insertions showed no significant association (1 female case, *p* = 0.7147). According to available data, rare G719X/S768I variants (2.0%) may benefit from Afatinib, but Exon 19 deletions were the most common subtype in clinical settings (70.4% of EGFR-positive cases), indicating the use of first-line Osimertinib. By establishing that Kurdish NSCLC patients having a unique molecular subgroup, these findings highlight the significance of population-specific genomic profiling in precision oncology and cast doubt on long-held beliefs regarding the epidemiology of EGFR mutations in Asian populations. However, the study's retrospective design and small sample sizes for uncommon mutation subtypes are among its limitations, which call for additional prospective validation in larger cohorts. These findings highlight the need for specialised diagnostic and treatment approaches in underrepresented populations and advance our understanding of the heterogeneity of EGFR mutations across ethnic groups.
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