Dataset Information

Quantification of epidermal growth factor receptor (EGFR) mutation may be a predictor of EGFR-tyrosine kinase inhibitor treatment response.

ABSTRACT:

Background

Epidermal growth factor receptor (EGFR) gene mutation is a reliable predictive factor for response to EGFR-tyrosine kinase inhibitors (TKIs). The quantified EGFR value may also predict response and survival within an EGFR mutated group.

Methods

We conducted a retrospective study of 836 lung cancer patients. The patient sample was divided into two groups based on the mean delta cycle threshold (?Ct) value. EGFR mutation tests using peptide nucleic acid (PNA)-mediated clamping polymerase chain reaction (PCR) were performed. The efficiency of PCR clamping was determined by measuring the Ct value and EGFR quantification was determined by the corrected ?Ct value.

Results

EGFR mutation positivity was 30.1% and there were 235 single activating mutations. In this mutation group, the higher corrected ?Ct value (? mean value) group showed better objective response (70.9% vs. 54.9%, P?=?0.022) and clinical benefit rates (86.4% vs. 68.3%, P?=?0.003) than the lower group. In addition, corrected ?Ct values were significantly and inversely correlated with disease response (r?=?-0.184, P?=?0.017). In multivariate analysis, both female gender (P?=?0.014) and higher corrected ?Ct value (P?=?0.012) were independent predictive factors for better clinical benefit rate. The higher corrected ?Ct value group had a tendency for longer progression-free survival than the lower group (P?=?0.050).

Conclusion

The corrected ?Ct value, which refers to EGFR quantification by PNA-mediated PCR clamping, can predict better clinical response to EGFR-TKI therapy. However, further study is warranted to determine its value as a biomarker to reflect survival.

SUBMITTER: Park HY

PROVIDER: S-EPMC5093171 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

Quantification of epidermal growth factor receptor (EGFR) mutation may be a predictor of EGFR-tyrosine kinase inhibitor treatment response.

Park Ha Young HY Oh Hyung Joo HJ Kim Ki-Hyun KH Kim Tae-Ok TO Park Cheol-Kyu CK Shin Hong-Jun HJ Lim Jung-Hwan JH Kwon Yong-Soo YS Oh In-Jae IJ Kim Yu-Il YI Lim Sung-Chul SC Kim Young-Chul YC Choi Yoo-Duk YD

Thoracic cancer 20160901 6

<h4>Background</h4>Epidermal growth factor receptor (EGFR) gene mutation is a reliable predictive factor for response to EGFR-tyrosine kinase inhibitors (TKIs). The quantified EGFR value may also predict response and survival within an EGFR mutated group.<h4>Methods</h4>We conducted a retrospective study of 836 lung cancer patients. The patient sample was divided into two groups based on the mean delta cycle threshold (∆Ct) value. EGFR mutation tests using peptide nucleic acid (PNA)-mediated cla ...[more]

PMID: 27755804

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Project description:The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis and the meta-analysis of individual participant data reported by non-small cell lung cancer (NSCLC) Meta-analysis Collaborative Group in neo-adjuvant setting validated respectively that adjuvant and neoadjuvant chemotherapy would significantly improve overall survival (OS) and recurrence-free survival for resectable NSCLC. However, chemotherapy has reached a therapeutic plateau. It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeting therapy provides a dramatic response to patients with advanced EGFR-mutation positive NSCLC. Researchers have paid more attention to exploring applications of TKIs to early resectable NSCLCs. Several studies on adjuvant TKI treatment concluded its safety and feasibility. But there existed certain limitations of these studies as inference factors to interpret data accurately: the BR19 study recruited patients among which almost 52% had stage IB and only 15 (3.0%, 15/503) had been confirmed with EGFR-mutant type; retrospective studies performed at Memorial Sloan Kettering Cancer Center (MSKCC) selected EGFR mutant-type NSCLC patients but couldn't avoid inherent defects inside retrospective researches; the RADIANT study revised endpoints from targeting at EGFR immunohistochemistry (IHC)+ and/or fluorescence in situ hybridization (FISH)+ mutation to only EGFR IHC+ mutation, leading to selective bias; despite that the SELECT study validated efficacy of adjuvant TKI and second round of TKI after resistance occurred, a single-arm clinical trial is not that persuasive in the absence of comparison with chemotherapy. Taking all these limitations into account, CTONG1104 in China and IMPACT in Japan have been conducted and recruiting patients to offer higher level of evidences to explore efficacy of preoperative TKI therapy for early resectable EGFR mutation positive NSCLC patients (confirmed by pathological results of tumor tissue or lymph node biopsy). On the other hand, case reports and several phase II clinical trials with small sample size tried to elbow their way on respect of preoperative TKI treatment and advised that TKI tended to improve response rate. However, no data on survival rate was present. The first phase II study of biomarker-guided neoadjuvant therapy for stage IIIA-N2 NSCLC patients stratified by EGFR mutation status, sponsored by CSLC0702, showed erlotinib tended to improve response rate, but failed to show benefits of disease-free survival (DFS) or OS. Subsequently, CTONG1103 was designed to investigate efficacy of erlotinib vs. combination of gemcitabine/cisplatin (GC) as neoadjuvant treatment in stage IIIA-N2 NSCLC with sensitizing EGFR mutation in exon 19 or 21. All these ongoing trials should be worthy of our expect to provide convincing evidences for customized therapy for patients with resectable NSCLC.

Project description:Mutations in the Epidermal growth factor receptor (EGFR) kinase domain, such as the L858R missense mutation and deletions spanning the conserved sequence 747LREA750, are sensitive to tyrosine kinase inhibitors (TKIs). The gatekeeper site residue mutation, T790M accounts for around 60% of acquired resistance to EGFR TKIs. The first generation EGFR TKIs, erlotinib and gefitinib, and the second generation inhibitor, afatinib are FDA approved for initial treatment of EGFR mutated lung adenocarcinoma. The predominant biomarker of EGFR TKI responsiveness is the presence of EGFR TKI-sensitizing mutations. However, 30-40% of patients with EGFR mutations exhibit primary resistance to these TKIs, underscoring the unmet need of identifying additional biomarkers of treatment response. Here, we sought to characterize the dynamics of tyrosine phosphorylation upon EGFR TKI treatment of mutant EGFR-driven human lung adenocarcinoma cell lines with varying sensitivity to EGFR TKIs, erlotinib and afatinib. We employed stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative mass spectrometry to identify and quantify tyrosine phosphorylated peptides. The proportion of tyrosine phosphorylated sites that had reduced phosphorylation upon erlotinib or afatinib treatment correlated with the degree of TKI-sensitivity. Afatinib, an irreversible EGFR TKI, more effectively inhibited tyrosine phosphorylation of a majority of the substrates. The phosphosites with phosphorylation SILAC ratios that correlated with the TKI-sensitivity of the cell lines include sites on kinases, such as EGFR-Y1197 and MAPK7-Y221, and adaptor proteins, such as SHC1-Y349/350, ERRFI1-Y394, GAB1-Y689, STAT5A-Y694, DLG3-Y705, and DAPP1-Y139, suggesting these are potential biomarkers of TKI sensitivity. DAPP1, is a novel target of mutant EGFR signaling and Y-139 is the major site of DAPP1 tyrosine phosphorylation. We also uncovered several off-target effects of these TKIs, such as MST1R-Y1238/Y1239 and MET-Y1252/1253. This study provides unique insight into the TKI-mediated modulation of mutant EGFR signaling, which can be applied to the development of biomarkers of EGFR TKI response.

Dataset Information

Quantification of epidermal growth factor receptor (EGFR) mutation may be a predictor of EGFR-tyrosine kinase inhibitor treatment response.

Background

Methods

Results

Conclusion

Publications

Quantification of epidermal growth factor receptor (EGFR) mutation may be a predictor of EGFR-tyrosine kinase inhibitor treatment response.

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