Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas

Feinberg School of Medicine, Northwestern University, The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois. .
Cancer (Impact Factor: 4.89). 01/2013; 119(2). DOI: 10.1002/cncr.27730
Source: PubMed


Lung adenocarcinomas can be distinguished by identifying mutated driver oncogenes, including epidermal growth factor receptor (EGFR) and KRAS. Mutations in EGFR are associated with both improved survival as well as response to treatment with erlotinib and gefitinib. However, the prognostic significance of KRAS has not been evaluated in large numbers of patients and remains controversial. For the current report, the authors examined the association of EGFR and KRAS mutations with survival among patients with advanced lung adenocarcinomas.

Data were analyzed from patients with advanced lung adenocarcinomas who had known EGFR and KRAS mutation status evaluated between 2002 and 2009. The collected clinical variables included age, sex, Karnofsky performance status, smoking history, and treatment history. Overall survival from the diagnosis of advanced disease was analyzed using Kaplan-Meier and Cox proportional hazard methods.

In total, 1036 patients were evaluated, including 610 women (59%) and 344 never-smokers (33%). The median patient age was 65 years (range, 25-92 years), and the majority of patients (81%) had a Karnofsky performance status ≥80%. In multivariate analysis, EGFR mutations were associated with longer overall survival (hazard ratio, 0.6; P < .001), and KRAS mutations were associated with shorter survival (hazard ratio, 1.21; P = .048).

KRAS mutations predicted shorter survival for patients with advanced lung adenocarcinomas. The presence of EGFR and KRAS mutations define distinct subsets of patients with lung adenocarcinomas and should be determined in patients when they are diagnosed with advanced disease. Clinical trial reports should include EGFR and KRAS mutation status along with other prognostic factors.

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    • "In non-small-cell lung cancer (NSCLC), KRAS is the most frequently mutated oncogene, accounting for 26% and 11% of adenocarcinoma tumours in Western and Asian patients, respectively (Dearden et al, 2013). Although some studies have shown KRAS mutations in NSCLC are associated with poor prognosis, including a meta-analysis of 28 studies (Mascaux et al, 2005; Johnson et al, 2013), conflicting results from other studies (recently reviewed in Martin et al, 2013) mean the prognostic impact of KRAS mutations in NSCLC remains unclear. Recently, with a number of agents in clinical development targeting KRAS mutant NSCLC, such as MEK inhibitors (Martin et al, 2013), it is important to discern the prognostic and predictive role of KRAS mutations. "
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    ABSTRACT: Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.British Journal of Cancer advance online publication, 30 June 2015; doi:10.1038/bjc.2015.215
    Full-text · Article · Jun 2015 · British Journal of Cancer
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    • "However, we did find that patients with the EGFR mutation responded better to first-line chemotherapy (46.2% versus 20.8%, P=0.043) and a longer progression-free survival (7.0 months versus 4.6 months, P=0.042) than those without EGFR mutation in KRAS wild-type patients. Earlier research18 showed that patients with the KRAS mutation had shorter survival than their KRAS wild-type counterparts, suggesting that KRAS mutation and EGFR mutation might have opposing effects. Both the EGFR and KRAS genes predict the prognosis of NSCLC.19,20 "
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    ABSTRACT: Background The purpose of this research was to investigate the relationship between epidermal growth factor receptor (EGFR) mutations and the response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Methods A total of 266 patients with stage IIIB or IV NSCLC who received platinum-based doublet therapies as first-line chemotherapy were investigated retrospectively, and their clinical data were assessed according to EGFR mutation. Results EGFR mutations were identified in 45.5% of patients. There was no significant difference in response rate between EGFR mutation carriers and EGFR wild-type carriers (P=0.484). Among the patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type, however, those with EGFR mutations responded better to treatment than EGFR wild-type patients (46.2% versus 20.8%, P=0.043). The disease control rate associated with pemetrexed-based treatments was higher than for vinorelbine-based therapies in EGFR mutation patients (P=0.001). EGFR mutation was found in patients with longer progression-free survival and median survival time, and improved 1-year and 2-year overall survival when compared with EGFR wild-type patients (6.1 versus 5.0 months, P=0.004; 18.9 versus 13.8 months, P=0.001; 81.0% versus 63.4%, P=0.002; and 33.9% versus 22.8% P=0.044, respectively). Patients with the EGFR exon 19 mutation had longer progression-free survival than those with EGFR exon 21 mutation (P=0.007). Multivariate analysis showed that the response to first-line chemotherapy and the presence of EGFR mutations were independent prognostic factors in patients with advanced NSCLC. Conclusion Our data showed that the presence of EGFR mutations meant longer survival times for patients with advanced NSCLC who received platinum-based doublet first-line chemotherapy, especially in those with the exon 19 deletion mutation. Among KRAS wild-type patients, those with EGFR mutation responded better to first-line chemotherapy than EGFR wild-type patients.
    Full-text · Article · Jul 2014 · OncoTargets and Therapy
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    • "Metastatic non-small cell lung cancer (mNSCLC) patients with activating epidermal growth factor receptor mutations (EGFR+) have, compared to KRAS mutated (KRAS+) or EGFR/KRAS wildtype (WT) patients, a longer progression free survival (PFS) and overall survival (OS) when treated with EGFR-tyrosine kinase inhibitors (TKI) [1] [2] [3]. Differences in tumor biology may also reflect metastatic pattern. "
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    ABSTRACT: Objectives Both bone and brain are frequent sites of metastasis in non-small cell lung cancer (NSCLC). Conflicting data exist whether EGFR mutant (+) patients are more prone to develop brain metastases or have a better outcome with brain metastases compared to EGFR/KRAS wild type (WT) or KRAS+ patients. For bone metastases this has not been studied. Methods In this retrospective case-control study all EGFR+ (exon 19 and 21) patients diagnosed at two pathology departments were selected (2004/2008 to 2012). For every EGFR+ patient a consecutive KRAS+ and WT patient with metastatic NSCLC (mNSCLC) was identified. Patients with another malignancy within 2 years of mNSCLC diagnosis were excluded. Data regarding age, gender, performance score, histology, treatment, bone/brain metastases diagnosis, skeletal related events (SRE) and subsequent survival were collected. Results 189 patients were included: 62 EGFR+, 65 KRAS+, 62 WT. 32%, 35% and 40% respectively had brain metastases (p = 0.645). Mean time to brain metastases was 20.8 [±12.0], 10.8 [±9.8], 16.4 [±10.2] months (EGFR + -KRAS+ p = 0.020, EGFR + -WT p = 0.321). Median post brain metastases survival was 12.1 [5.0-19.1], 7.6 [1.2-14.0], 10.7 [1.5-19.8] months (p = 0.674). 60%, 52% and 50% had metastatic bone disease (p = 0.528). Mean time to development of metastatic bone disease was 13.4 [±10.6], 23.3 [±19.4], 16.4 [±9.6] months (p = 0.201). Median post metastatic bone disease survival was 15.0 [10.6-20.3], 9.0 [5.2-12.9], 3.2 [0.0-6.9] months (p = 0.010). Time to 1st SRE was not significantly different. Conclusions Incidence of brain and bone metastases was not different between EGFR+, KRAS+ and WT patients. Post brain metastases survival, time from mNSCLC diagnosis to metastatic bone disease and 1st SRE did not differ either. Post metastatic bone disease survival was significantly longer in EGFR+ patients. Although prevention of SRE's is important for all patients, the latter finding calls for a separate study for SRE preventing agents in EGFR+ patients.
    Full-text · Article · Apr 2014 · Lung cancer (Amsterdam, Netherlands)
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