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      The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study

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          Abstract

          Objectives

          Owing to novel therapy strategies in epidermal growth factor receptor (EGFR)-mutated patients, molecular analysis of the EGFR and KRAS genome has become crucial for routine diagnostics. Till date these data have been derived mostly from clinical trials, and thus collected in pre-selected populations. We therefore screened ‘allcomers’ with a newly diagnosed non-small cell lung carcinoma (NSCLC) for the frequencies of these mutations.

          Design

          A cohort study.

          Setting

          Lung cancer centre in a tertiary care hospital.

          Participants

          Within 15 months, a total of 552 cases with NSCLC were eligible for analysis.

          Primary and secondary outcome measures

          Frequency of scrutinising exons 18, 19 and 21 for the presence of activating EGFR mutation and secondary codon 12 and 13 for activating KRAS mutations.

          Results

          Of the 552 patients, 27 (4.9%) showed a mutation of EGFR. 19 of these patients (70%) had deletion E746-A750 in codon 19 or deletion L858R in codon 21. Adenocarcinoma (ACA) was the most frequent histology among patients with EGFR mutations (ACA, 22/254 (8.7%) vs non-ACA, 5/298 (1.7%); p<0.001). Regarding only ACA, the percentage of EGFR mutations was higher in women (16/116 (14%) women vs 6/138 (4.3%) men; p=0.008). Tumours with an activating EGFR mutation were more likely to be from non-smokers (18/27; 67%) rather than smoker (9/27; 33%).

          KRAS mutation was present in 85 (15%) of all cases. In 73 patients (86%), the mutation was found in exon 12 and in 12 cases (14%) in exon 13. Similarly, ACA had a higher frequency of KRAS mutations than non-ACA (67/254 (26%) vs 18/298 (6.0%); p<0.001).

          Conclusions

          We found a lower frequency for EGFR and KRAS mutations in an unselected Caucasian patient cohort as previously published. Taking our results into account, clinical trials may overestimate the mutation frequency for EGFR and KRAS in NSCLC due to important selection biases.

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          Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.

          David Eberhard, Bruce Johnson, Lukas Amler … (2005)
          Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described. Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses. EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients. EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.
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            KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.

            Erminia Massarelli, Marileila Varella-Garcia, Ximing Tang … (2007)
            EGFR gene mutations and increased EGFR copy number have been associated with favorable response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small-cell lung cancer (NSCLC). In contrast, KRAS mutation has been shown to predict poor response to such therapy. We tested the utility of combinations of these three markers in predicting response and survival in patients with NSCLC treated with EGFR-TKIs. Patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. EGFR and KRAS mutations were analyzed using PCR-based sequencing. EGFR copy number was analyzed using fluorescence in situ hybridization. The study included 73 patients, 59 of whom had all three potential markers successfully analyzed. EGFR mutation was detected in 7 of 71 patients (9.8%), increased EGFR copy number in 32 of 59 (54.2%), and KRAS mutation in 16 of 70 (22.8%). EGFR mutation (P 99.7% chance of objective response, whereas patients with KRAS mutation with or without increased EGFR copy number had a >96.5% chance of disease progression. KRAS mutation should be included as indicator of resistance in the panel of markers used to predict response to EGFR-TKIs in NSCLC.
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              Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial.

              Jean-Yves Douillard, Frances A Shepherd, Vera Hirsh … (2010)
              PURPOSE In the phase III INTEREST trial, 1,466 pretreated patients with advanced non-small cell lung cancer (NSCLC) were randomly assigned to receive gefitinib or docetaxel. As a preplanned analysis, we prospectively analyzed available tumor biopsies to investigate the relationship between biomarkers and clinical outcomes. METHODS Biomarkers included epidermal growth factor receptor (EGFR) copy number by fluorescent in situ hybridization (374 assessable samples), EGFR protein expression by immunohistochemistry (n = 380), and EGFR (n = 297) and KRAS (n = 275) mutations. Results For all biomarker subgroups analyzed, survival was similar for gefitinib and docetaxel, with no statistically significant differences between treatments and no significant treatment by biomarker status interaction tests. EGFR mutation-positive patients had longer progression-free survival (PFS; hazard ratio [HR], 0.16; 95% CI, 0.05 to 0.49; P = .001) and higher objective response rate (ORR; 42.1% v 21.1%; P = .04), and patients with high EGFR copy number had higher ORR (13.0% v 7.4%; P = .04) with gefitinib versus docetaxel. CONCLUSION These biomarkers do not appear to be predictive factors for differential survival between gefitinib and docetaxel in this setting of previously treated patients; however, subsequent treatments may have influenced the survival results. For secondary end points of PFS and ORR, some advantages for gefitinib over docetaxel were seen in EGFR mutation-positive and high EGFR copy number patients. There was no statistically significant difference between gefitinib and docetaxel in biomarker-negative patients. This suggests gefitinib can provide similar overall survival to docetaxel in patients across a broad range of clinical subgroups and that EGFR biomarkers such as mutation status may additionally identify which patients are likely to gain greatest PFS and ORR benefit from gefitinib.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMJ Open
                Journal ID (iso-abbrev): BMJ Open
                Journal ID (hwp): bmjopen
                Journal ID (publisher-id): bmjopen
                Title: BMJ Open
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2044-6055
                Publication date Collection: 2013
                Publication date (Electronic): 3 April 2013
                Volume: 3
                Issue: 4
                Electronic Location Identifier: e002560
                Affiliations
                [1 ]Klinik für Pneumologie, Lungenklinik Heckeshorn, HELIOS Klinikum Emil von Behring , Berlin, Berlin, Germany
                [2 ]HELIOS Klinikum Emil von Behring, Institut für Gewebediagnostik , Berlin, Berlin, Germany
                [3 ]Klinik für Pneumologie, HELIOS Klinikum Schwerin, Berlin, Berlin , Germany
                Author notes
                [Correspondence to ] Professor Torsten Thomas Bauer; torsten.bauer@ 123456helios-kliniken.de
                Article
                Publisher ID: bmjopen-2013-002560
                DOI: 10.1136/bmjopen-2013-002560
                PMC ID: 3641502
                PubMed ID: 23558737
                SO-VID: 9404a190-adc3-44f4-a2fd-1d02939f0e82
                Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

                History
                Date received : 10 January 2013
                Date revision received : 17 February 2013
                Date accepted : 22 February 2013
                Categories
                Subject: Oncology
                Subject: Research
                Subject: 1506
                Subject: 1717
                Subject: 1731
                Subject: 1697

                ScienceOpen disciplines: Medicine
                Keywords: lung cancer,non smal cell lung cancer,egfr
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: lung cancer, non smal cell lung cancer, egfr

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