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Concurrent gene alterations with EGFR mutation and treatment efficacy of EGFR-TKIs in Chinese patients with non-small cell lung cancer.

ABSTRACT: We investigated the frequency of concurrent genes in EGFR-mutant non-small cell lung cancer patients and determined its value in predicting the efficacy of EGFR-TKIs treatment.Three hundred and twenty patients, who harbored EGFR activating mutations and received EGFR-TKIs treatment, were examined for another eight genes including KRAS, NRAS, PIK3CA, BRAF, and HER2 mutations and ALK, ROS1, and RET fusion genes based on reverse transcription PCR. Progression-free survival and overall survival with EGFR-TKIs treatment were evaluated using Kaplan-Meier methods and compared between different patients using log-rank tests.Twenty-one (6.6%) of 320 EGFR mutant samples with additional gene alterations were identified. The most common concurrent gene was PIK3CA mutation (n = 9), followed by EML4-ALK rearrangement (n = 6), HER2 mutation (n = 3), RET rearrangement (n = 1), ROS1 rearrangement (n = 1) and KRAS mutation (n = 1). Patients with single EGFR mutation had a significantly longer progression-free survival than those with concurrent genes (10.9 vs. 6.0 months, P = 0.002). Among the 21 cases, patients with PIK3CA mutation had the longest median progression-free survival (7.6 months), followed by ALK rearrangement (5.0 months) and other gene types (1.2 months). No overall survival difference was found between patients with single EGFR mutation and concurrent gene alterations (21.0 vs.17.6 months, P = 0.17).We demonstrated that concurrent gene alterations occurred in some patients with EGFR mutations. Concurrent gene alterations decreased the efficacy of EGFR-TKIs.

SUBMITTER: Hu W

PROVIDER: S-EPMC5421908 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Concurrent gene alterations with EGFR mutation and treatment efficacy of EGFR-TKIs in Chinese patients with non-small cell lung cancer.

Hu Wentao W Liu Yahui Y Chen Jian J

Oncotarget 20170401 15

<h4>Purpose</h4>We investigated the frequency of concurrent genes in EGFR-mutant non-small cell lung cancer patients and determined its value in predicting the efficacy of EGFR-TKIs treatment.<h4>Methods</h4>Three hundred and twenty patients, who harbored EGFR activating mutations and received EGFR-TKIs treatment, were examined for another eight genes including KRAS, NRAS, PIK3CA, BRAF, and HER2 mutations and ALK, ROS1, and RET fusion genes based on reverse transcription PCR. Progression-free su ...[more]

PMID: 28212572

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Project description:IntroductionEpidermal growth factor receptor (EGFR) 19del and L858R mutation are known as "common mutations" in non-small cell lung cancer (NSCLC) and predict sensitivities to EGFR tyrosine kinase inhibitors (TKIs), whereas 20ins and T790M mutations confer drug-resistance to EGFR-TKIs. The role of the remaining uncommon EGFR mutations remains elusive.MethodsWe retrospectively screened a group of NSCLC patients with uncommon EGFR mutations other than 20ins and T790M. The mutation patterns, use of different generations of EGFR-TKIs, and concurrent genetic alterations were analyzed. Meanwhile, a cohort of patients with single 19del or L858R were included for comparison.ResultsA total of 180/1,300 (13.8%) patients were identified. There were 102 patients with advanced or recurrent NSCLC that received first-line therapy of gefitinib/erlotinib/icotinib and afatinib and were eligible for analysis. The therapeutic outcomes among patients with common mutations (EGFRcm, n = 97), uncommon mutation plus common mutations (EGFRum+EGFRcm, n = 52), complex uncommon mutations (complex EGFRum, n = 22), and single uncommon mutations (single EGFRum, n = 28) were significantly different (ORRs: 76.3%, 61.5%, 54.5%, and 50.0%, respectively, p = 0.023; and mPFS: 13.3, 14.7, 8.1, and 6.0 months, respectively, p = 0.004). Afatinib showed superior efficacy over gefitinib/erlotinib/icotinib in EGFRcm (ORR: 81.0% vs. 75.0%, p = 0.773; mPFS: 19.1 vs. 12.0m, p = 0.036), EGFRum+EGFRcm (ORR: 100% vs. 54.5%, p = 0.017; mPFS: NE vs. 13.6m, p = 0.032), and single EGFRum (ORR: 78.6% vs. 21.4%, p = 0.007; mPFS: 10.1 vs. 3.0m, p = 0.025) groups. Comprehensive genomic profiling by Next Generation Sequencing encompassing multiple cancer-related genes was performed on 51/102 patients; the mPFS of patients without co-mutation (n = 16) and with co-mutations of tumor-suppressor genes (n = 31) and driver oncogenes (n = 4) were 31.1, 9.2, and 12.4 months, respectively (p = 0.046). TP53 mutation was the most common co-alteration and showed significantly shorter mPFS than TP53 wild-type patients (7.0 vs. 31.1m, p < 0.001). Multivariate analysis revealed that concurrent 19del/L858R and tumor-suppressor gene alterations independently predicted better and worse prognosis in patients with uncommon mutations, respectively.ConclusionsUncommon EGFR mutations constitute a highly heterogeneous subgroup of NSCLC that confer different sensitivities to EGFR-TKIs with regard to the mutation patterns. Afatinib may be a better choice for most uncommon EGFR mutations. Concurrent 19del/L858R and tumor-suppressor gene alterations, especially TP53, can be established as prognostic biomarkers.

Project description:BACKGROUND:The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non-small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments. METHODS:Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS:In total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR?=?1.88, 95%CI: 1.59-2.23, p <?0.001, I2 =?0.0%, P =?0.792) and overall survival (OS) (HR?=?1.92, 95%CI: 1.55-2.38, p <?0.001, I2 =?0.0%, P =?0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P <?0.001, I2 =?0.0%, P =?0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P <?0.001, I2 =?0.0%, P =?0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study. CONCLUSIONS:This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

Project description:BackgroundWhile prospective clinical studies on immunotherapy in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) are ongoing, this study aimed to investigate the outcomes of immunotherapy combinations in such a population in a real-world setting.MethodsThe clinical data of pretreated EGFR-mutated NSCLC patients who acquired EGFR-TKI resistance and received immunotherapy were retrospectively analyzed in this study. Progression-free survival (PFS) was assessed using the Kaplan-Meier log-rank test, and univariate and multivariate analysis were performed.ResultsA total of 31 patients were analyzed in this study. A total of 25 (80.6%) patients received combination immunotherapy. In the univariate analysis, patients who received combination immunotherapy seemingly acquired longer PFS than those who received monotherapy, although there was no significant difference (3.42 months vs. 1.61; P = 0.078; hazard ratio (HR) 0.43, 95% CI: 0.16-1.13). Patients who received antiangiogenic drugs prior to immunotherapy acquired better PFS (3.42 months vs. 1.58; P = 0.027; HR 0.37, 95% CI: 0.15-0.93), while patients with liver metastasis had inferior PFS (2.04 months vs. 3.42; P = 0.031; HR 2.83, 95% CI: 1.05-7.60). Furthermore, multivariate analysis confirmed that the above three factors had independent prognostic value.ConclusionsThe study revealed that immunotherapy combinations are better choices than single-agent regimens in previously treated and EGFR-mutant NSCLC patients with progressive disease. In addition, antiangiogenic drugs administered before immunotherapy might be a favorable prognostic factor, while liver metastasis was associated with a short PFS in this setting. In future, more robust and prospective clinical trial results are expected to guide clinical practice.Key pointsSignificant study findings Immunotherapy-based combination therapies are better choices than single-agent regimens in heavily treated EGFR-mutant NSCLC patients. What this study adds Patients without liver metastasis and with prior antiangiogenic drugs obtained more benefit from immunotherapy in this setting.

Project description:Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) significantly improve prognosis of advanced NSCLC patients harboring EGFR sensitizing mutation. However, acquired resistance to EGFR-TKIs limits the good outcomes. Chinese herbal medicine (CHM) has been used for NSCLC patients receiving EGFR-TKIs for more than 10°years as an adjuvant treatment. Methods: Studies were searched from China BioMedical Literature, Chinese National Knowledge Infrastructure, Cqvip Database, Wanfang Database, MEDLINE (PubMed), EMBASE (Ovid), Google Scholar, and Cochrane Library from inception to March, 2021. Randomized controlled clinical trials (RCT) comparing EGFR-TKIs + CHM (TKIs + CHM) versus EGFR-TKIs with/without placebo (TKIs ± placebo) in participants with advanced NSCLC harboring EGFR sensitizing mutation were included in this study. Two authors screened all references, assessed the risk of bias and extracted data independently. Data were summarized using hazard ratio (HR) and risk ratios (RR), with 95% confidence intervals (CI) for binary outcomes. Meta-analysis was performed using random effects model. Overall quality of evidence was assessed using GRADE. Results: A total of 9 RCTs (1137 participants, 581 in the TKIs + CHM group and 556 in the TKIs ± placebo group) were included in this review. Only first-generation EGFR-TKIs were included. Most trials included used oral CHM preparations to tonify Qi and/or Yin. Treatment lasted from enrollment until disease progression (PD) or intolerable adverse events (AE). Combination of CHM with EGFR-TKIs improved median progression-free survival (mPFS) (HR,0.59; 95% CI, 0.52-0.68; P < 0.00001) and objective response rate (ORR) (RR, 1.23; 95% CI, 1.13-1.34; P < 0.00001) compared with used of EGFR-TKIs ± placebo. CHM reduced AE associated with EGFR-TKIs such as cutaneous toxicity (RR, 0.58; 95% CI, 0.46-0.73; P < 0.00001) and diarrhea (RR, 0.43; 95% CI, 0.30-0.60; P < 0.00001). Conclusion: Combination therapy of CHM and EGFR-TKIs significantly delays acquired resistance while improving ORR to EGFR-TKIs. Furthermore, CHM reduces AE induced by EGFR-TKIs. More international multi-centered, double-blinded, placebo-controlled, well-designed clinical trials are needed in future research.

Project description:BackgroundIdentification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations.MethodsWe retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS.ResultsAmong the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72-10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22-3.13), MET FISH + (HR = 2.83,95% CI = 1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor.ConclusionsWe determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.

Dataset Information

Concurrent gene alterations with EGFR mutation and treatment efficacy of EGFR-TKIs in Chinese patients with non-small cell lung cancer.

Publications

Concurrent gene alterations with EGFR mutation and treatment efficacy of EGFR-TKIs in Chinese patients with non-small cell lung cancer.

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