Unarranged territory in uncommon EGFR mutations.
Ontology highlight
ABSTRACT:
SUBMITTER: Fujii H
PROVIDER: S-EPMC9359962 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
Publications
Unarranged territory in uncommon <i>EGFR</i> mutations.
Fujii Hiroyuki H Okuma Yusuke Y
Translational lung cancer research 20220701 7
Similar Datasets
Project description: Not available
| S-EPMC11225339 | biostudies-literature
Project description:Frequent mutations in the GNAQ, MMP8, Akt3, EGFR, and PIK3R1 genes have been reported in human cancers but mostly have not been well examined in thyroid cancer. Selected exons of GNAQ, MMP8, AKT3, EGFR, and PIK3R1 genes were sequenced in various thyroid cancers. We found a G2203A EGFR mutation, resulting in a G735S amino acid change, in one of 21 (5%) papillary thyroid cancer samples. We did not find any mutation in the MMP8 gene, but observed a frequent SNP A259G (K87E) genotype switch in various types of thyroid cancer samples. We did not find any mutation in the GNAQ, AKT3, and PIK3R1 genes in various types of thyroid cancer. No mutation in these genes was found in 12 cell lines derived from various types of thyroid cancer. Therefore, unlike in other cancers, mutations in these genes are uncommon in thyroid cancer.
| S-EPMC3133631 | biostudies-literature
Project description: Not available
| S-EPMC5395747 | biostudies-literature
Project description:Lung cancer is the most common cancer and the leading cause of cancer death. Non-small cell lung cancer (NSCLC) represents over 85% of all lung cancers, and up to 50% of Asian NSCLC patients harboring epidermal growth factor receptor (EGFR) gene mutations. A number of studies have consistently demonstrated that uncommon EGFR-mutated NSCLC patients treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can achieve better survival outcomes. However, because uncommon EGFR mutations are generally associated with reduced sensitivity to EGFR-TKIs, which will bring a negative impact on the result of the study, the majority of clinical trials investigating the efficacy of EGFR-TKIs have included only patients with common EGFR mutations. In addition, uncommon EGFR mutations are rare in themselves, leading to the small number of such patients enrolled in these trials. Due to the small number and highly heterogeneous sensitivity of uncommon EGFR mutations, the efficacy of EGFR-TKIs in patients harboring uncommon EGFR mutations remains elusive. This article reviews the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations, and give some reasonable advice about the selection of treatments for patients with NSCLC who harbor uncommon EGFR mutations.
| S-EPMC6754574 | biostudies-literature
Project description: Not available
| S-EPMC11912071 | biostudies-literature
Project description:The optimal management of advanced non-small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment-related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR-G719A mutation treated with afatinib (at an off-label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off-target pan-EGFR inhibitor (including osimertinib)-resistant KRAS mutation and not by acquisition of EGFR-T790M. We further present the current state of evidence in the literature behind use of first-, second-, and third-generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations. KEY POINTS: Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non-small cell lung cancer (NSCLC). Afatinib is the only currently U.S. Food and Drug Administration-approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X). Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.
| S-EPMC8018319 | biostudies-literature
Project description:Approximately 10% of the epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are uncommon EGFR mutations. Although the efficacy of second (2G) or third generation (3G) EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon EGFR mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon EGFR mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon EGFR mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon EGFR mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major EGFR mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8-13.5), 11.7 months (95% CI: 6.6-16.7), 7.7 months (95% CI: 4.9-17.4), and 5.0 months (95% CI: 3.7-6.1) for major uncommon EGFR mutation (G719X, L861Q), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9-34.2), 28.8 (95% CI: 24.4-33.4), 13.5 months (95% CI: 7.4-27.8), and 9.4 months (95% CI: 3.4-10.5) for major uncommon EGFR mutation (G719X), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6-16.9), and 37.5 months (95% CI: 35.4-39.6) for common EGFR mutation-positive NSCLC. After failing 1L EGFR-TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G EGFR-TKI after failing the first-line EGFR-TKI, the ORR and PFS for 3G EGFR-TKI were 80% and 8.9 months (95% CI: 8.0-9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8-39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.
| S-EPMC7600176 | biostudies-literature
Project description:BackgroundEGFR mutant non-small cell lung cancer (NSCLC) is a heterogeneous disease. The treatment for frequent EGFR mutations relies on tyrosine kinase inhibitors (TKIs); the clinical and therapeutic significance of uncommon EGFR mutations is uncertain.MethodsThis is a single-center retrospective study of patients with EGFR-mutant lung cancer (2009-2017). Molecular analyses of EGFR exons 18-21 were performed. Only patients with uncommon mutations were included (p.Glu709X, p.Gly719X, p.Ala767_Val769 dup, p.Ser768Ile, and p.Leu861Gln).ResultsAmong 6,747 tumor samples, 95 out 820 patients (11.6%) harbored 113 uncommon EGFR mutations. There were 50 metastatic NSCLC patients for whom the median OS was 18.0 months (95% CI: 15, 32). In this population, the p.Leu861Gln uncommon exon 21 EGFR mutation was associated with poor prognosis (HR: 2.96, 95% CI: 1.39, 6.31; P=0.003). Among those harboring a single uncommon EGFR mutation, median OS was 27.6 months (95% CI: 10.8, not attained) in patients who were treated by chemotherapy only (n=13) versus 6.0 months (95% CI: 2.4, not attained) in patients exclusively treated with a first or second-EGFR-TKI (n=9; HR: 0.27, 95% CI: 0.09, 0.78; P=0.01. In patients with a single uncommon EGFR mutation, first-line chemotherapy was associated with a better overall survival than TKIs (HR: 0.31, 95% CI: 0.15, 0.68; P=0.002). In patients who received first or second-EGFR-TKI as first-line treatment (n=26), OS was significantly better for those with two uncommon EGFR mutations than those with a single uncommon mutation (HR: 0.07, 95% CI: 0.009, 0.54; P=0.001).ConclusionsIn conclusion, uncommon EGFR mutations may be associated with a poor outcome and the data challenge the use of first-generation TKI in such patients, however first-line TKI is more effective in cases of double uncommon mutations and such patients should be treated accordingly.
| S-EPMC7578497 | biostudies-literature
Project description:BackgroundThe best management for rare epidermal growth factor receptor (EGFR) mutations in advanced non-small cell lung carcinoma (NSCLC) remains uncertain. The literature indicates that response to usual treatment could differ in certain subgroups such as exon 20 insertion/duplication (E20ID), other single uncommon mutation (OSUM), and EGFR complex mutation (ECM).MethodsIn this observational, regional, multi-center, retrospective study, we gathered data on uncommon EGFR mutations in NSCLC from 2007 to 2021. We analyzed patient characteristics, prognostic factors and treatment outcomes [objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS)].ResultsAmong 119 patients with an uncommon EGFR mutant, 34 harbored E20ID, 23 ECM, and 62 OSUM. There were significantly more non-smokers in E20ID. Female gender and performance status <2 were associated with a better prognosis. Among the 97 metastatic patients with available data for 1st line treatment, median estimated OS was 21 months (95% CI: 18-31 months), with better non-significant OS for ECM. Median estimated PFS was 7 months (95% CI: 4-9 months). We found significant differences in ORR, DCR and PFS favoring 1st line chemotherapy for E20ID, whereas the outcomes for OSUM and ECM were more favorable for tyrosine kinase inhibitor (TKI) (mainly 2nd and 3rd generation).ConclusionsThere were variations in treatment outcomes among subgroups in our cohort. Exon 20 insertions showed better ORR and PFS with 1st line chemotherapy compared to TKI. Conversely, other rare EGFR mutations including ECM had better ORR and PFS with TKI than chemotherapy. There was no significant difference in OS among treatment groups overall or within rare mutation subgroups.
| S-EPMC9264085 | biostudies-literature
Project description:Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%-20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.
| S-EPMC10326255 | biostudies-literature