|Ahead of print publication
Rare mutations of epidermal growth factor receptor in epidermal growth factor receptor-tyrosine kinase inhibitor-naive non-small cell lung carcinoma and the response to erlotinib therapy
Murat Sari, Adnan Aydiner
Department of Medical Oncology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
|Date of Submission||16-Sep-2019|
|Date of Decision||20-Nov-2019|
|Date of Acceptance||07-Jan-2020|
|Date of Web Publication||10-Feb-2020|
Department of Medical Oncology, Istanbul Medical Faculty, Istanbul University, Capa, Fatih, Istanbul 34093
Source of Support: None, Conflict of Interest: None
Context: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered to be effective treatments for advanced NSCLC patients with sensitizing EGFR mutations. There are many complex and rare mutations in the EGFR gene. The efficacy of the first-generation EGFR-TKI (erlotinib) is unknown for tumors harboring rare EGFR mutations.
Aims: The purpose of this study was to investigate the clinical significance of rare EGFR mutations in EGFR-TKI-naive patients and the efficacy of erlotinib.
Settings and Design: Istanbul University, Istanbul Medical Faculty, Department of Medical Oncology, Istanbul/Turkey, and retrospective observational study.
Subjects and Methods: We retrospectively analyzed 117 non-small cell lung cancer (NSCLC) patients with EGFR mutations who had not previously used EGFR-TKIs. Exons 18–21 of EGFR were analyzed by polymerase chain reaction and subjected to direct sequencing methods.
Statistical Analysis Used: Survival estimates were calculated by the Kaplan–Meier method using SPSS 25 software (IBM SPSS, Chicago, USA).
Results: Of 117 patients who had EGFR mutations, 23 patients had rare and complex EGFR mutations. Only 9 of them were treated with erlotinib. Three patients (3.5%) with exon 20 mutations received erlotinib. Two with EGFR-p. Q787Q (SNP ID, rs10251977; c.2361G>A) synonymous mutation in exon 20 were responsive to erlotinib therapy in the second-line setting after first-line chemotherapy. To the best of our knowledge, the present two cases are the first to be reported with lung adenocarcinoma with EGFR-p. Q787Q synonymous mutation responding to erlotinib.
Conclusion: NSCLC patients harboring rare EGFR mutations generally did not show consistent or favorable responses to EGFR-TKI. We suggest that this rare synonymous mutation (EGFR-p. Q787Q) is a sensitive EGFR mutation in NSCLC.
Keywords: Epidermal growth factor receptor mutation, epidermal growth factor receptor-p.Q787Q, erlotinib, G719C/A, L861Q, non-small cell lung cancer, S768I
|How to cite this URL:|
Sari M, Aydiner A. Rare mutations of epidermal growth factor receptor in epidermal growth factor receptor-tyrosine kinase inhibitor-naive non-small cell lung carcinoma and the response to erlotinib therapy. J Can Res Ther [Epub ahead of print] [cited 2020 Feb 24]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=278079
| > Introduction|| |
Lung cancer is the leading cause of cancer-related death among men and women. It is estimated that there are 1.6 million deaths worldwide due to lung cancer each year. The treatment of patients with lung cancer depends on the cell type (non-small cell lung cancer [NSCLC] vs. small cell lung cancer), molecular characteristics, tumor stage, and an assessment of the patient's overall medical condition. NSCLCs are the most prevalent form of this disease.
As a result of a better understanding of the molecular pathways leading to malignancy in NSCLC, agents targeting these pathways in malignant cells have been developed. Therapy can then be individualized based on the specific abnormality, if any, present in a given patient. In particular, mutations in the epidermal growth factor receptor (EGFR) gene and translocations involving the anaplastic lymphoma kinase or the ROS1 genes play a pivotal role in carcinogenesis of some lung cancers. Alterations in these actionable kinases predict the clinical effectiveness of tyrosine kinase inhibitors (TKIs) that target these aberrant oncogenes. Advanced NSCLCs that contain characteristic mutations in EGFR are highly sensitive to EGFR-TKIs. Analysis for the presence or absence of a driver mutation in EGFR is the standard approach to decide whether or not to use an EGFR-TKI for the initial treatment of a patient with advanced NSCLC.
Mutations in the EGFR tyrosine kinase are observed in approximately 15% of NSCLC adenocarcinoma in the United States (US) and occur more frequently in women and nonsmokers. In Asian populations, the incidence of EGFR mutations is substantially higher. In advanced NSCLC, the presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR-TKIs such erlotinib, gefitinib, afatinib, and osimertinib. The most frequent and clinically significant mutations include in-frame deletions involving amino acids LeuArgGluAla motifs (LREA residues 746–750) of exon 19 and the Leu858Arg (L858R) substitution in exon 21. Together, these classic mutations account for almost 85% of all EGFR mutations. The response rate to EGFR-TKI is around 70%–80%, and progression-free survival (PFS) reaches approximately 10 months for 1st generation TKIs. And also, PFS is 11–14 mo for afatinib and 19 mo for osimertinib.
Other EGFR mutations have also been associated with enhanced effects of EGFR-TKIs. These include the less-prevalent EGFR 2155G>T (G719C) and EGFR 2156G>C (G719A) mutations (both of them ~3% of reported EGFR mutations), EGFR 2582T>A (L861Q ~2% of all EGFR mutations), and the EGFR 2303G>T (S768I 1%–2% of all EGFR mutations).
Other EGFR mutations and tumors with multiple EGFR mutations have not been completely characterized. Not all EGFR mutations are alike, and the sensitivity of the less common mutations to EGFR-TKIs is often not well defined. Their predictive value is often not clear. Documenting the sensitivity or resistance of these minor mutations is critical for guiding treatment decisions. The purpose of this study was to investigate the clinical significance of rare exon 20 mutations in EGFR-TKI-naive patients, and the efficacy of erlotinib.
| > Subjects and Methods|| |
One hundred and seventeen patients with a diagnosis of metastatic NSCLC with nonsquamous histology and whose tumor specimens were obtained during diagnostic or surgical procedures and genotyped for EGFR mutations between 2009 and 2017 were identified. All patients had stage IV disease with visceral and/or nonvisceral metastases. EGFR mutation analysis was performed using standard DNA sequencing techniques with direct sequencing of exons 18–21 of EGFR. In brief, DNA was isolated from the sample, quantified and amplified by polymerase chain reaction (PCR) using primers to exons 18–21 of EGFR. PCR products were analyzed by bidirectional direct DNA sequencing. Tumor genotype was performed in baseline diagnostic specimens before patient exposure to EGFR-TKIs. Patients in this study could only use the first-generation EGFR-TKI (erlotinib). In addition, since erlotinib was not licensed and not reimbursed for the treatment of NSCLC with a rare EGFR mutation in the first line in our country, our patients were able to take erlotinib in the second or further lines of treatment. Afatinib, a second-generation EGFR-TKI has been approved by the FDA for the treatment of NSCLC with rare EGFR mutations recently. Unfortunately, when these patients applied for treatment, afatinib was not licensed for use in our country and was not reimbursed.
Data collection and statistics
We reviewed our institution's patient medical records and radiographic studies to obtain clinical and pathologic information such as EGFR mutation status and response to EGFR-TKIs retrospectively. Treatment response was assessed after 12 weeks of treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines for measuring solid tumors, combined with a subjective physician's medical judgment of the treatment benefit in each patient. Patients with progression according to RECIST criteria or patients with rapid clinical deterioration according to subjective medical decisions before 12th week evaluation were considered as progressive disease (PD). Overall survival (OS) was determined from the start of treatment until the date of death for any cause or last follow-up. The study was closed in May 2019 and as of this date statistical analyses were performed. Survival estimates were calculated by the Kaplan–Meier method using SPSS 25 software (IBM SPSS, Chicago, USA). The reporting of parameters involving clinical, pathologic, radiographic, response data, and tumor genotypes used descriptive methods. Signed informed consents for tyrosine kinase inhibitor treatment and genotyping for EGFR mutations from tumor specimens were obtained from all patients before treatment. Signed informed consents for tyrosine kinase inhibitor treatment and genotyping for EGFR mutations from tumor specimens were obtained from all patients before treatment. This study protocol was reviewed and approved by the Institutional Review Board of Istanbul University, Institute of Oncology (IRB registration June 27, 2019-127820) and conducted in accordance with the precepts established by the Helsinki Declaration.
| > Results|| |
We evaluated 117 patients who underwent EGFR mutation testing and had a positive test result. The number of male and female patients was equal. Only 23 of the EGFR mutant patients had a rare and/or complex EGFR mutation. All of the patients had stage IV disease at the time of diagnosis, and the median age of the patients was 60 (35–80) years. The vast majority of patients with rare EGFR mutations were active or ex-smokers. Only four patients with rare mutation never smoked and the remaining patients (19 patients) were heavy smokers with a median of 33 packs/year (12–80 pack/year) and only 4 out of 19 patients stopped smoking after lung cancer diagnosis. Our EGFR mutant patients (classic and rare) also have a high rate of smoking history. However, in general, the rate of EGFR positivity in NSCLC patients is 5%–10% in our center and also in our society. All of the patients were diagnosed with nonsquamous NSCLC. [Table 1] shows the frequency of EGFR mutations identified during the clinical genotyping of tumor specimens.
|Table 1: The frequency of different epidermal growth factor receptor mutations of Exons 18-21 of epidermal growth factor receptor|
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Single mutations in exon 19 and exon 21 were the most prevalent mutation types. Single mutations involving G719C and S768I were less common. Rare single mutations comprised 19.6% of all mutations, and complex mutations were found in 3.4% of the patients. Twenty-three patients had rare single mutations. Ten had exon 18 G719C/X, ten had exon 21 L861Q, and three had exon 20 mutations (two of them were EGFR-p. Q787Q (SNP ID, rs10251977; c. 2361G>A)). Nine of 23 patients harboring rare mutations were treated with erlotinib (150 mg/day) [Table 2]. Patients harboring classical mutation were treated with erlotinib as second line when progression developed, but the majority of patients with rare mutations used erlotinib as fourth-line or later during progression.
|Table 2: Clinical, pathologic, molecular characteristics, and response to erlotinib of non-small cell lung carcinoma with rare and compound epidermal growth factor receptor mutations|
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Response to epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib
Of the 23 patients with a tumor genotype revealing a rare EGFR mutation, 9 received an EGFR-TKI during their clinical course. The median follow-up time was 21 (3, 5–64) months. Five of the 9 patients died during the follow-up, and the median OS time was 33 months (26, 6–39, 3 months). Of the 14 patients with rare EGFR mutations who did not receive erlotinib, 12 died during the follow-up and the median OS time was 20 months (13, 6–26, 3 months). There was not a significant difference between the two groups in terms of OS according to erlotinib use [P = 0.43; [Figure 1].
|Figure 1: Kaplan–Meier curves for overall survival of patients with rare epidermal growth factor receptor mutations on the basis of erlotinib treatment|
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Five patients with exon 18 mutations received erlotinib therapy, and one of them had a complex mutation. The patient whose tumor had an S768I+G719A complex mutation experienced a rapid disease progression during erlotinib treatment and died within 1 month after starting erlotinib [Table 2]. While one patient with exon 18 G719A mutation had a partial response to erlotinib, the other two patients with G719A had PD and died shortly after starting erlotinib. One patient with the G719C mutation has been still using erlotinib as first-line therapy since 2017, and she has had a partial response. Two of the 10 patients with the exon 21 L861Q mutation received erlotinib after progression during chemotherapy; one had a complete response, and the other had a partial response to erlotinib treatment. These two patients have been using erlotinib since 2016 and 2017, respectively. Of the 6 patients with a tumor genotype revealing an exon 20 EGFR mutation, 3 received erlotinib (2 patients with a rare exon 20 [EGFR-p. Q787Q] and one with a complex S768I+G719A mutation).
Interestingly, two cases with EGFR-p. Q787Q polymorphism of exon 20 showed very impressive treatment responses with erlotinib. One patient still had a near-complete response [Figure 2], and the other patients had a partial response to erlotinib and progressed after 7 months. In both cases, targeted EGFR sequencing did not reveal “activating” mutations or amplification. However, in both patients, we identified a synonymous heterozygous single-nucleotide variant at coding position 2361 (G/A instead of the wild-type G/G) in EGFR exon 20. This variant had been previously described in HNSCC cell lines, in which increased gefitinib sensitivity was observed in cells with the heterozygous G/A versus G/G (wild-type) genotype at this position.
|Figure 2: (a) The graph shows tumor marker (carcinoma embryonic antigen) levels in the patient's serum, and (b) computed tomography scan images show response of mediastinal and lung lesions in the corresponding patient to erlotinib treatment. Red arrows indicate the location of lung and mediastinal metastases that subsequently responded to treatment|
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| > Discussion|| |
NSCLC harboring an EGFR gene mutation, responds well to EGFR-TKIs. Other than the two classical EGFR mutations, there are many rare mutations in EGFR exons 18–21. Polymorphisms of the EGFR gene have also been reported.
In this retrospective study, rare single mutations comprised 19.6% of all mutations, and complex mutations were found in 3.4% of the patients; we also identified some novel rare mutations. In this study, the frequency of rare mutations was consistent with the literature of retrospective studies showing 8.1%–18.2% frequency.,,,,, As our hospital is a reference center, these patients with rare mutations were generally sent to our hospital for treatment. Wu et al. reported that mutations on G719 and L861Q represented a major portion of rare mutations and were associated with the favorable effectiveness of EGFR-TKIs. In our cohort, 20 of 117 patients had these uncommon mutations as well as major rare mutations. The frequency of complex mutations has been reported to range from 3.4% to 6.9%.,,, The frequency in our study was 3.4%, similar to previous studies.,,,
There is inconclusive data on first-generation TKI response of rare EGFR mutations; therefore, the clinical importance of these mutations is uncertain. In our study, it was shown that patients with rare mutations and who used erlotinib at any stage of the treatment process had longer survival than those who did not, but this difference was not statistically significant. However, as the number of patients were low in both groups, this result should be approached with suspicion. We reviewed reports in the literature evaluating the effectiveness of EGFR-TKIs in rare EGFR mutant NSCLC patients [Table 3].
|Table 3: Reports in the literature of epidermal growth factor receptor - tyrosine kinase inhibitor in rare epidermal growth factor receptor mutant non-small cell lung carcinoma patients|
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In our study, one patient with a complex S768I+G719A mutation received erlotinib, and progression occurred. In the literature, the EGFR S768I point mutation occurs in 1%–2% of EGFR mutant lung cancers. The sensitivity to EGFR-TKIs has been controversial, while some reports have shown relative resistance, one prior clinical case of an EGFR S768I mutant lung adenocarcinoma patient showed sensitivity to gefitinib. In the literature, six patients with the S768I+G719X mutation showed a partial response during their clinical course.,,,
Mutations with G719C, G719A, and L861Q are generally accepted as moderately sensitive to EGFR-TKIs, especially in high doses. In our study, three patients with rare exon 18 G719A single mutation and one G719C single mutation had used erlotinib. One of three patients with exon 18 G719A and one patient with G719C had a partial response [Table 2].
Exon 21 L861Q (~2% of all EGFR mutations) has also been associated with enhanced effects of EGFR-TKIs. The L861Q mutation has been described to have response rates that exceed 50% and PFSs of more than 5 months in gefitinib/erlotinib-treated patients. L861Q mutations can be a single mutation or a part of complex mutations. In our study, we observed single mutations in 10 (8.5%) cases. One patient had a complete response, and the other patient had a partial response to erlotinib treatment.
In addition to rare and complex mutations, the EGFR-p. Q787Q polymorphism of exon 20 was detected in two patients and was associated with a good response and prolonged PFS. To the best of our knowledge, these two EGFR c.2361G>A, EGFR-p. Q787Q heterozygous synonymous mutations are the first to be reported with lung adenocarcinoma that responds well to erlotinib treatment. There are two studies in the literature on EGFR gene polymorphism, EGFR-p. Q787Q and anti-EGFR treatment efficacy. In the first one, EGFR-p. Q787Q was showed in a metastatic colorectal carcinoma with a better clinical outcome after anti-EGFR treatment independently of RAS mutational status. And in the second one, this synonymous mutation in two patients with head and neck squamous cell carcinoma responding gefitinib unexpectedly very well were identified. Reports like ours support our thesis that EGFR-p. Q787Q causes increased sensitivity to anti-EGFR treatment.
Sensitivity to erlotinib treatment may have occurred as a result of a mechanism, as stated by Tan et al., in our two cases with EGFR-p. Q787Q synonymous mutations. In the study of Tan et al., they showed that loss of stability of EGFR-AS1 long noncoding RNA resulted in a decrease in the levels. As a result, reduced EGFR-AS1 levels shifted towards splicing EGFR isoform D, leading to ligand-mediated pathway activation. Thus, they showed a 70-fold increased sensitivity to EGFR-TKIs with this synonymous mutation. This may explain the erlotinib sensitivity in our cases.
Our study has some limitations that need to be acknowledged. First, this was a retrospective observational study (many items are not defined from a predefined study protocol). The sample size was relatively small, and this was an exploratory study and not a confirmatory one. Second, subjective bias may have had some impact on the results. Finally, our patients could only use the first-generation EGFR-TKI (Erlotinib) not a second-generation, potent and approved TKI Afatinib due to reimbursement problems in our country.
With the help of studies such as ours and others, we can conclude that EGFR-TKIs may be effective in NSCLC patients harboring rare and complex mutations, and these data can support clinicians in their determination of the use of EGFR-TKIs in this subset of patients. Reporting of the genotype-response pattern of NSCLCs with complex and other rare mutations of EGFR will help to define the complete spectrum of how the EGFR genotype affects the response of NSCLCs to EGFR-TKIs.
| > Conclusion|| |
Rare EGFR mutations showed a heterogeneous composition. NSCLC patients harboring rare EGFR mutations may show consistent and favorable responses to EGFR-TKI. Our two cases add to the evidence that the EGFR-p. Q787Q (single-nucleotide polymorphism of exon 20) causes sensitivity to TKI therapy. These cases continue to highlight the importance of publishing treatment response data for cases of rare EGFR mutations to guide clinical decision-making.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]