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Targeted Next-Generation Sequencing Analysis Predicts the Recurrence in Resected Lung Adenocarcinoma Harboring EGFR Mutations.

ABSTRACT: Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected EGFR-mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of stage I-IIIA EGFR-mutated lung adenocarcinoma were analyzed by targeted NGS for 207 cancer-related genes. Recurrence free survival (RFS) was estimated according to genetic alterations using the Kaplan-Meier method and Cox proportional regression analysis. The relapse rate was 25.2% (33/131). Five-year RFS of stages IA, IB, II, and IIIA were 82%, 75%, 35%, and 0%, respectively (p < 0.001). RFS decreased with the number of co-mutations (p = 0.025). Among co-mutations, the CTNNB1 mutation was associated with short RFS in a multivariate analysis (hazard ratio: 5.4, 95% confidence interval: 2.1-14.4; p = 0.001). TP53 mutations were associated with short RFS in stage IB-IIIA (p = 0.01). RFS was shorter with EGFR exon 19 deletion (19-del) than with mutation 21-L858R in stage IB-IIIA tumors (p = 0.008). Among 19-del subtypes, pL747_P753delinS (6/56, 8.9%) had shorter RFS than pE746_A750del (39/56, 69.6%), the most frequent subtype (p = 0.004).

SUBMITTER: Kim IA

PROVIDER: S-EPMC8306820 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Targeted Next-Generation Sequencing Analysis Predicts the Recurrence in Resected Lung Adenocarcinoma Harboring EGFR Mutations.

Kim In Ae IA Hur Jae Young JY Kim Hee Joung HJ Lee Song Am SA Hwang Jae Joon JJ Kim Wan Seop WS Lee Kye Young KY

Cancers 20210720 14

Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected EGFR-mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of stage I-IIIA EGFR-mutated lung adenocarcinoma were analyzed by targeted NGS for 207 cancer-related genes. Recurrence free survival (RFS) was estimated according to genetic altera ...[more]

PMID: 34298845

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Project description:BackgroundThe efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co-mutations in resected epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment.Materials and methodsMutation profiling of 416 cancer-relevant genes was conducted for 139 resected stage I-IIIa lung ADCs with EGFR mutations using targeted next-generation sequencing. Co-mutation profiles were systematically analyzed.ResultsRare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first-generation TKIs. Ninety-one percent of patients harbored at least one co-mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II-III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty-four percent of patients with EGFR TKI-sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1.ConclusionOperable lung ADCs with EGFR TKI-sensitizing mutations are associated with a high proportion of co-mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy.Implications for practiceThe efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next-generation sequencing of 416 cancer-relevant genes in 139 resected lung cancers revealed the co-mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI-resistant mutations in 34.71% of patients with a drug-sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.

Project description:BackgroundEpidermal growth factor receptor (EGFR) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in tumorigenesis and development. However, EGFR expression alone has limited clinical and prognostic significance. Recently, the cross-talk between EGFR and G-protein-coupled chemokine receptor CXCR4 has become increasingly recognized.MethodsIn the present study, immunohistochemical staining of EGFR and CXCR4 was performed on paraffin-embedded specimens from 131 patients with surgically resected PDAC. Subsequently, the associations between EGFR expression, CXCR4 expression, EGFR/CXCR4 coexpression and clinicopathologic factors were assessed, and survival analyses were performed.ResultsIn total, 64 (48.9%) patients expressed EGFR, 68 (51.9%) expressed CXCR4, and 33 (25.2%) coexpressed EGFR and CXCR4. No significant association between EGFR and CXCR4 expression was observed (P = 0.938). EGFR expression significantly correlated with tumor differentiation (P = 0.031), whereas CXCR4 expression significantly correlated with lymph node metastasis (P = 0.001). EGFR/CXCR4 coexpression was significantly associated with lymph node metastasis (P = 0.026), TNM stage (P = 0.048), and poor tumor differentiation (P = 0.004). By univariate survival analysis, both CXCR4 expression and EGFR/CXCR4 coexpression were significant prognostic factors for poor disease-free survival (DFS) and overall survival (OS). Moreover, EGFR/CXCR4 coexpression significantly increased the hazard ratio for both recurrence and death compared with EGFR or CXCR4 protein expression alone. Multivariate survival analysis demonstrated that EGFR/CXCR4 coexpression was an independent prognostic factor for DFS (HR = 2.33, P<0.001) and OS (HR = 2.48, P = 0.001).ConclusionsIn conclusion, our data indicate that although EGFR expression alone has limited clinical and prognostic significance, EGFR/CXCR4 coexpression identified a subset of PDAC patients with more aggressive tumor characteristics and a significantly worse prognosis. Our results suggest a potentially important "cross-talk" between CXCR4 and EGFR intracellular pathways and indicate that the simultaneous inhibition of these pathways might be an attractive therapeutic strategy for PDAC.

Project description:Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFR (L858R) and EGFR (Del19), in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFR (T790M) mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFR (T790M), and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFR (T790M) resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFR (T790M) and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFR (T790M) resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/HER-TKI afatinib have been approved for use as the first-line treatment of metastatic NSCLC with actEGFRm. This review will summarize and evaluate a broad range of evidence of recent development of EGFR/HER-TKIs, with a focus on the second- and third-generation EGFR/HER-TKIs, in the treatment of patients with NSCLC harboring EGFR mutations.

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Targeted Next-Generation Sequencing Analysis Predicts the Recurrence in Resected Lung Adenocarcinoma Harboring EGFR Mutations.

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Targeted Next-Generation Sequencing Analysis Predicts the Recurrence in Resected Lung Adenocarcinoma Harboring <i>EGFR</i> Mutations.

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