Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)

Sun Min Lim, Hye Ryun Kim, Eun Kyung Cho, Young Joo Min, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Byoung Chul Cho, Ji-Hyun Lee, Hye Cheol Jeong, Eun Kyung Kim, Joo-Hang Kim, Sun Min Lim, Hye Ryun Kim, Eun Kyung Cho, Young Joo Min, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Byoung Chul Cho, Ji-Hyun Lee, Hye Cheol Jeong, Eun Kyung Kim, Joo-Hang Kim

Abstract

Background: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients.

Patients and methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies).

Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P<0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders.

Conclusions: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163).

Keywords: epidermal growth factor; next-generation sequencing; primary resistance; tyrosine kinase inhibitor.

Conflict of interest statement

The authors have no potential conflicts of interest to disclose.

Figures

Figure 1. Kaplan-Meier curve showing
Figure 1. Kaplan-Meier curve showing
A. median progression-free survival and B. median overall survival among responders and non-responders to gefitinib.
Figure 2. Landscape genomic profile of patients
Figure 2. Landscape genomic profile of patients
Samples are grouped by response to gefitinib.
Figure 3. Kaplan-Meier curve showing
Figure 3. Kaplan-Meier curve showing
A. median progression-free survival and B. median overall survival among patients with or without PI3K/Akt/mTOR pathway alterations.

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