Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Abstract

Purpose To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. Patients and Methods Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS). After resistance to osimertinib treatment, tumor tissue was collected by core needle biopsy. DNA was extracted from 15 × 5 um sliced section of formalin-fixed paraffin-embedded (FFPE) material and NGS was done. The genetic changes were analyzed. Results A total of 9 Chinese patients were studied, 5 females and 4 males, age 51–89 years. After progression with osimertinib treatment, core needle biopsy was performed and next-generation sequencing was performed. Nine patients had harboring 62 point mutations, 2 altered gene copies, 2 amplifications, and 1 EML4-ALK gene fusion. No MET or HER2 amplification was found in this cohort study. Nine patients still maintained initial EGFR 19 del or L858R activating mutations, while 7 of them kept EGFR T790M mutations. Among the 7 patients, 5 had secondary EGFR C797S and/or C797G mutations, which all happened in the same allele with T790M mutation. All patients were treated with targets therapies, chemotherapy, or best supportive care (BSC) in accordance with NGS genetic results and patients' performance status; 7 of them are still alive and 2 of them died of disease progression at last follow-up. Conclusions EGFR C797S/G mutation and the same one presented on the same allele with EGFR T790M mutation were the most common mutation feature and played a key role in resistance to osimertinib in Chinese patients with NSCLC. Tumor cells losing T790M mutation and maintaining EGFR activating mutation might benefit from first-generation EGFR-TKI treatment.

Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment inEGFR-Mutant Non–Small Cell Lung Cancer Cells

“…In addition to EGFR C797S mutation, there are reports of genomic alterations in patient samples that have been sequenced after progression. For instance, BRAF V600E mutation (39,40), KRAS mutations (22,41,42), PIK3CA mutations (41,42), ALK gene fusion (43), etc. are reported.…”

The Status of the EGFR T790M Mutation is associated with the Clinical Benefits of Osimertinib Treatment in Non-small Cell Lung Cancer Patients: A Meta-Analysis

“…Complex mechanisms that mediate resistance to Osimertinib have been demonstrated, such as the acquisition of tertiary EGFR mutations (e.g. EGFR 797S, L718Q mutations), HER2 or MET amplification, BRAF mutations, and the histologic changes to small cell transformation [10]. It is worth noting that even though the mechanisms of Osimertinib resistance are heterogeneous, they can be conceptualized as binary variables: some patients lose secondary T790M mutations when they acquire Osimertinib resistance, while some patients remain a T790M positive status [11].…”

Bevacizumab Combined with Icotinib Overcomes Osimertinib Resistance in a Patient of Non-Small-Cell Lung Cancer

“…The C797S/G mutation appears to be a leading resistant mechanism to the third-generation EGFR TKIs. 12 The structure of EGFR T790M mutation and C797S/G mutation happened more in cis than in trans. 12,[21][22][23] MET amplification, EGFR T790M loss, HER-2 or alternative kinase activation, SCLC or squamous cell transformation, and EML4-ALK rearrangement were also reported after resistance to Osimertinib.…”

“…12 The structure of EGFR T790M mutation and C797S/G mutation happened more in cis than in trans. 12,[21][22][23] MET amplification, EGFR T790M loss, HER-2 or alternative kinase activation, SCLC or squamous cell transformation, and EML4-ALK rearrangement were also reported after resistance to Osimertinib. 24 Currently most studies focus on overcoming EGFR C797S/G mutation and alternative kinase activation by using combination therapy.…”

“…[9][10][11] Among them, EGFR C797S/G mutation happened in 20%-60% patients. 12 So Re-biopsy to study the resistance mechanisms at the time of disease progression is necessary to direct therapeutic regimens for patients with Osimertinib resistance. 13,14 Currently, no drug or therapeutic strategies has been approved for the treatment of Osimertinib resistant patients, especially for patients who are T790M negative or lost.…”