Coexistence of sensitive and resistant epidermal growth factor receptor (EGFR) mutations in pretreatment non-small cell lung cancer (NSCLC) patients: First or third generation tyrosine kinase inhibitors (TKIs)?
Introduction
Lung cancer is increasing in frequency among malignant diseases both in China and worldwide [[1], [2]]. Molecular biological studies of non-small cell lung cancer (NSCLC) have contributed to the development of targeted anticancer agents, representing a major breakthrough in NSCLC management. Activating mutations in the epidermal growth factor receptor (EGFR) involve one of the most common genetic alterations in NSCLC. These mutations can be detected in 15% of Caucasians and 40%–50% of East Asians with advanced NSCLC [3]. It has been well established that active EGFR mutations confer sensitivity to first generation tyrosine kinase inhibitors (TKIs), which provide survival benefits compared with conventional chemotherapy [[4], [5], [6]]. Among the mutations, single classical mutations, including a deletion in exon 19 (Del-19) and a point mutation in exon 21 (21 L858R), are the most robust positive predictors of clinical response.
In addition to Del-19 and 21L858R, substitution of threonine with methionine in exon 20 (T790M mutation) and insertion in exon 20 have been identified and associated with drug resistance [7]. Previously, the presence of the T790M mutation was regarded as a second hit mutation due to TKIs exposure [8]. However, several studies suggested that the T790M mutation can be detected in TKI-naïve patients, and a de novo T790M mutation predicts a poorer objective response rate (ORR) and progression–free survival (PFS) when treated with gefitinib [[9], [10], [11]].
Sensitive and resistant mutations can also be concomitantly detected within a single tumor sample by routine clinical molecular testing in TKIs-naïve patients. These clinical findings may cause a dilemma for the treating physicians concerning whether and which TKIs should be recommended. In this study, we summarized the clinical data of TKI–naïve advanced NSCLC patients harboring compound mutations with drug–resistant patterns detected by routine molecular methods (e.g., 20T790M+19del/21L858R mutations) and analyzed the therapeutic efficacy of first and third generation TKIs.
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Patients
Between January 2011 and January 2017, consecutive advanced stage NSCLC patients with concurrent sensitive (Del-19, 21L858R and other atypical mutations) and drug–resistant mutations (20T790M or 20 insertion) were identified from molecular pathology reports based on our registration system. The inclusion criteria were as follows: a) NSCLC confirmed pathologically or cytologically, b) positron emission tomography/computed tomography (PET/CT) or other radiological evaluation was performed to
Frequency and characteristics of patients harboring complex mutations with de novo drug-resistant patterns
During the study period, a total of 16,842 patients were screened with 5900 positive individuals. Mutation types were as follows: 2633 in the exon 19 deletion, 2637 in the 21 L858R point mutation, 311 with single atypical mutations in exons 18–21, and 147 with complex mutations but without drug–resistant patterns (e.g., 18G719X+20S768I or 20S768I+21L861Q). Among the remaining 172 cases, 111 individuals were excluded because T790M mutation was a result of TKI exposures. Finally, the coexistence
Discussion
Our study showed that baseline coexistence of resistant and sensitive mutations were rare, accounting for 1.0% of the entire EGFR mutation spectrum when analyzed by routine clinical detection methods. First generation TKIs, including gefitinib, erlotinib, and icotinib, are ineffective even with the presence of sensitive mutations, while osimertinib carries survival benefits for those patients, and thus should be considered during the whole clinical management period.
The T790M mutation was
Conflict of interest statement
None.
Disclosure of funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements
We would like to acknowledge all the patients and their families for their contributions to this study. No writing assistance was received.
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2022, Biochemical PharmacologyCitation Excerpt :Apparently, EGFR harbouring mutations in codons 792, 796 and 797 are most commonly found to exhibit resistance to all current EGFR-TKIs [30]. A study showed that the two emerging EGFR mutations, L792H and G796R, disrupt osimertinib binding in silico, while concomitant mutations of L858R/T790M/L792H and L858R/T790M/G796R conferred resistance to osimertinib in vitro [31]. These findings indicate that using osimertinib as the first line of treatment would be challenging and suggest that the sensitivity to TKIs was determined by the combination of de novo and acquired mutations.
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Bo Zhang and Jianlin Xu contributed equally to this work.