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The percentage of Epidermal Growth Factor Receptor (EGFR)-mutated neoplastic cells correlates to response to tyrosine kinase inhibitors in lung adenocarcinoma.

ABSTRACT: BACKGROUND:Epidermal Growth Factor Receptor (EGFR) molecular analysis is performed to assess the responsiveness to Tyrosine Kinase Inhibitors (TKIs) in patients with Non-Small Cell Lung Cancer (NSCLC). The existence of molecular intra-tumoral heterogeneity has been observed in lung cancers. The aim of the present study is to investigate if the percentage of mutated neoplastic cells within the tumor sample might influence the responsiveness to TKIs treatment. MATERIAL AND METHODS:A total of 931 cases of NSCLC were analyzed for EGFR mutational status (exon 18, 19, 20, 21) using Next Generation Sequencer. The percentage of mutated neoplastic cells was calculated after normalizing the percentage of mutated alleles obtained after next generation sequencer analysis with the percentage of neoplastic cells in each tumor. RESULTS:Next generation sequencing revealed an EGFR mutation in 167 samples (17.9%), mainly deletions in exon 19. In 18 patients treated with TKIs and with available follow-up, there was a significant correlation between the percentage of mutated neoplastic cells and the clinical response (P = 0.017). Patients with a percentage of mutated neoplastic cells greater than 56%, have a statistical trend (P = 0.081) for higher Overall Survival (26.3 months) when compared to those with a rate of mutated neoplastic cells lower than 56% (8.2 months). CONCLUSIONS:The percentage of EGFR-mutated neoplastic cells in the tumor is associated with response to TKIs. A "quantitative result" of EGFR mutational status might provide useful information in order to recognize those patients which might have the greatest benefit from TKIs.

SUBMITTER: de Biase D

PROVIDER: S-EPMC5433779 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The percentage of Epidermal Growth Factor Receptor (EGFR)-mutated neoplastic cells correlates to response to tyrosine kinase inhibitors in lung adenocarcinoma.

de Biase Dario D Genestreti Giovenzio G Visani Michela M Acquaviva Giorgia G Di Battista Monica M Cavallo Giovanna G Paccapelo Alexandro A Cancellieri Alessandra A Trisolini Rocco R Degli Esposti Roberta R Bartolini Stefania S Pession Annalisa A Tallini Giovanni G Brandes Alba A AA

PloS one 20170516 5

<h4>Background</h4>Epidermal Growth Factor Receptor (EGFR) molecular analysis is performed to assess the responsiveness to Tyrosine Kinase Inhibitors (TKIs) in patients with Non-Small Cell Lung Cancer (NSCLC). The existence of molecular intra-tumoral heterogeneity has been observed in lung cancers. The aim of the present study is to investigate if the percentage of mutated neoplastic cells within the tumor sample might influence the responsiveness to TKIs treatment.<h4>Material and methods</h4>A ...[more]

PMID: 28520821

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Project description:Importance:Metformin hydrochloride is emerging as a repurposed anticancer drug. Preclinical and retrospective studies have shown that it improves outcomes across a wide variety of neoplasms, including lung cancer. Particularly, evidence is accumulating regarding the synergistic association between metformin and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Objective:To assess the progression-free survival (PFS) in patients with advanced lung adenocarcinoma who received treatment with EGFR-TKIs plus metformin compared with those who received EGFR-TKIs alone. Design, Setting, and Participants:Open-label, randomized, phase 2 trial conducted at the Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. Eligible patients were 18 years or older, had histologically confirmed stage IIIB-IV lung adenocarcinoma with an activating EGFR mutation. Interventions:Patients were randomly allocated to receive EGFR-TKIs (erlotinib hydrochloride, afatinib dimaleate, or gefitinib at standard dosage) plus metformin hydrochloride (500 mg twice a day) or EGFR-TKIs alone. Treatment was continued until occurrence of intolerable toxic effects or withdrawal of consent. Main Outcomes and Measures:The primary outcome was PFS in the intent-to-treat population. Secondary outcomes included objective response rate, disease control rate, overall survival (OS), and safety. Results:Between March 31, 2016, and December 31, 2017, a total of 139 patients (mean [SD] age, 59.4 [12.0] years; 65.5% female) were randomly assigned to receive EGFR-TKIs (n?=?70) or EGFR-TKIs plus metformin (n?=?69). The median PFS was significantly longer in the EGFR-TKIs plus metformin group (13.1; 95% CI, 9.8-16.3 months) compared with the EGFR-TKIs group (9.9; 95% CI, 7.5-12.2 months) (hazard ratio, 0.60; 95% CI, 0.40-0.94; P?=?.03). The median OS was also significantly longer for patients receiving the combination therapy (31.7; 95% CI, 20.5-42.8 vs 17.5; 95% CI, 11.4-23.7 months; P?=?.02). Conclusions and Relevance:To our knowledge, this is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS. These results justify the design of a phase 3, placebo-controlled study. Trial Registration:ClinicalTrials.gov identifier: NCT03071705.

Dataset Information

The percentage of Epidermal Growth Factor Receptor (EGFR)-mutated neoplastic cells correlates to response to tyrosine kinase inhibitors in lung adenocarcinoma.

Publications

The percentage of Epidermal Growth Factor Receptor (EGFR)-mutated neoplastic cells correlates to response to tyrosine kinase inhibitors in lung adenocarcinoma.

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