Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer

Abstract

Purpose: EGFR mutation is a predictor of epidermal growth factor receptor-tyrosine kinase inhibitor treatment response in patients with non-small-cell lung cancer (NSCLC). However, it remains unclear whether chemotherapy affects EGFR mutation status in NSCLC. We investigated the influence of chemotherapy on EGFR mutations in plasma and tumor tissues from patients with NSCLC.

Patients and methods: Samples were derived from three cohorts: one, 264 patients with advanced NSCLC who received first-line chemotherapy with matched pre- and postchemotherapy blood samples; two, 63 patients with stages IIb to IIIb disease with pre- and post-neoadjuvant chemotherapy tumor tissues; and three, 79 patients with advanced NSCLC who underwent palliative surgery. EGFR mutation status was determined and analyzed to reveal potential impact of chemotherapy.

Results: In the first cohort, EGFR mutations were detected in 34.5% of the prechemotherapy plasma samples (91 of 264) but in only 23.1% of the postchemotherapy plasma samples (61 of 264). The decrease in EGFR mutation rate was statistically significant (P < .001). Patients whose EGFR mutations switched from positive to negative after chemotherapy had a better partial response (PR) than patients with a reverse change (P = .037). A similar decrease in EGFR mutation rate was observed in tissues after neoadjuvant chemotherapy in the second cohort (34.9% [22 of 63] v 19.0% [12 of 63]; P = .013). In the third cohort, 38.0% of the tumors (30 of 79) showed an intratumor heterogeneity of EGFR mutation, whereas 62.0% (49 of 79) were homogeneous, either with EGFR mutation or no mutation.

Conclusion: Our results suggest that chemotherapy may reduce EGFR mutation frequency in patients with NSCLC, likely the result of a preferential response of subclones with EGFR mutations in tumors with heterogeneous tumor cell populations.

Fig 1.

Response outcome between different subgroups of mutation change in cohort one. The x-axis indicates percentage of different response group; the y-axis indicates three groups according to EGFR mutation variation. PD, progressive disease; PR, partial response; SD, stable disease.

Fig 2.

Multiple foci microdissection and analysis of intratumor genetic heterogeneity on EGFR mutation. Blue circles in hematoxylin and eosin staining tissue (10 × 10) represent microdissected foci; DHPLC graph represents corresponding tumor foci mutation status. (A) Tissue with homogeneity of wild-type EGFR; (B) tissue with heterogeneity of EGFR mutation; (C) tissue with homogeneity of mutant EGFR.