Original studyClinical Outcome With Platinum-Based Chemotherapy in Patients With Advanced Nonsquamous EGFR Wild-Type Non–Small-Cell Lung Cancer Segregated According to KRAS Mutation Status
Introduction
In the era of personalized cancer treatments for non–small-cell lung cancer (NSCLC), current research is primarily focusing on trying to pinpoint the molecular alterations that may predict increased sensitivity to anticancer therapies. In this context, the discovery of activating mutations of the epidermal growth factor receptor (EGFR) gene and, more recently, of anaplastic lymphoma kinase (ALK) gene rearrangements, have dramatically changed our approach to patients with advanced disease.1, 2 That is because highly effective biological therapies have become available for these molecularly selected subsets of patients, namely, the EGFR tyrosine kinase inhibitors (TKIs) and the ALK TKIs, respectively.1, 3
Nevertheless, as many as 70% to 85% of unselected patients with advanced NSCLC (depending on ethnicity) carry an EGFR wild type (WT) phenotype,1 for whom small clinical benefit, if any, has been observed with treatment using a reversible EGFR TKI (gefitinib or erlotinib).4, 5, 6, 7 As a result, given that only few of the patients with EGFR WT will test positive for ALK gene rearrangement, platinum-based chemotherapy still represents the best first-line treatment option for the majority of patients with EGFR WT. Against this background, it seems crucial to identify biomarkers of sensitivity to chemotherapy in EGFR WT disease.
Importantly, molecular aberrations may also act as negative predictors of sensitivity to treatment. Several reports now suggest that mutations in the Kirsten rat sarcoma viral oncogene (KRAS), which result in a constitutively activated guanosine triphosphate–binding protein, may predispose to resistance to gefitinib or erlotinib, most likely because of the deregulation of signaling pathways downstream of EGFR.7, 8 Of note, this negative prediction of KRAS mutation is very relevant in clinical practice, owing to the fact that KRAS is the most commonly mutated oncogene in lung adenocarcinomas, in which it is found in approximately 20% of cases.9
Remarkably, KRAS and EGFR mutations are mutually exclusive, which, coupled with the notion that NSCLCs may harbor KRAS mutations as a single specific mutated oncogene, corroborates the fact that KRAS acts as the primary genetic “driver” leading to cancer in these particular patients. If this is the case, the poor treatment sensitivity of patients with KRAS mutations may not be confined to EGFR TKIs alone, being potentially observed in the presence of cytotoxic chemotherapy also. Recent data consistently suggest that patients with KRAS mutations may have poor sensitivity to various cytotoxic agents or chemotherapy combination regimens, or both.10, 11, 12, 13, 14 On this basis, we undertook a retrospective analysis to assess the clinical outcomes of patients with advanced nonsquamous EGFR WT NSCLC who received first-line platinum-based chemotherapy and to evaluate the impact of the presence and type of specific KRAS mutations on treatment outcome.
Section snippets
Study Design
Patients were eligible for this study if they had a histologic diagnosis of stage IIIB or IV (either de novo or relapsed) nonsquamous NSCLC with a documented EGFR WT genotype and were treated with first-line platinum-based chemotherapy. An EGFR mutation test has been available at our institution on physician request since January 2006. However, after the approval of gefitinib by the European Medicines Agency for the first-line treatment of EGFR-mutant NSCLC (July 2009), this test was routinely
Patient Characteristics
Of the 272 patients with advanced EGFR WT NSCLC seen at our institution between January 2006 and November 2012, 204 were included in the analysis. Reasons for patient exclusion were squamous histologic type (n = 13), unassessable KRAS status (n = 2), ALK positivity (n = 10), no administration of first-line platinum-based chemotherapy because of rapid worsening of clinical conditions (n = 18), first-line treatment with single-agent chemotherapy (n = 8) or with a reversible EGFR TKI (n = 10), and
Discussion
In the present study, we evaluated the clinical impact of KRAS mutation in a population of patients with advanced nonsquamous EGFR WT NSCLC treated with first-line platinum-based chemotherapy and found a statistically significant worse clinical outcome for patients with KRAS mutations in terms of response rate, disease control rate, and PFS. Specifically, the HR of PFS for patients with KRAS mutations vs. patients with EGFR WT/KRAS WT was 1.35. Interestingly, the multivariate analysis showed
Conclusion
Our data suggest that KRAS mutation is associated with a poorer PFS in patients treated with first-line platinum-based chemotherapy compared with patients with EGFR WT/KRAS WT, which may have important therapeutic implications given the emerging clinical role of agents aimed at targeting tumors with a hyperactivated Ras/Raf/MEK/ERK pathway. Also, our initial observation that patients with codon 13 mutations could perform poorly while receiving platinum-based chemotherapy may suggest the
Acknowledgments
This work was supported by the Italian Association for Cancer Research (AIRC).
References (37)
- et al.
A phase II trial of erlotinib monotherapy in pretreated patients with advanced non-small cell lung cancer who do not possess active EGFR mutations: Okayama Lung Cancer Study Group trial 0705
J Thorac Oncol
(2010) - et al.
Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial
Lancet Oncol
(2013) - et al.
Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype
Lung Cancer
(2012) - et al.
KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies
Lung Cancer
(2010) - et al.
Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers
J Thorac Oncol
(2013) - et al.
Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study
Lancet Oncol
(2013) - et al.
The 2004 World Health Organization classification of lung tumors
Semin Roentgenol
(2005) - et al.
Molecular pathology of lung cancer: key to personalized medicine
Mod Pathol
(2012) - et al.
Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization
J Thorac Oncol
(2011) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009)
Clinical and molecular features in patients with advanced non-small-cell lung carcinoma refractory to first-line platinum-based chemotherapy
Lung Cancer
Clinical outcome of patients with non-small cell lung cancer receiving front-line chemotherapy according to EGFR and K-RAS mutation status
Lung Cancer
Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice
Ann Oncol
Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer
Ann Oncol
Conformational states of human rat sarcoma (Ras) protein complexed with its natural ligand GTP and their role for effector interaction and GTP hydrolysis
J Biol Chem
Advances on EGFR mutation for lung cancer
Transl Lung Cancer Res
Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment
Clin Cancer Res
The role of anaplastic lymphoma kinase inhibitors in the treatment of advanced nonsmall cell lung cancer
Curr Opin Oncol
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2018, Clinical Lung CancerCitation Excerpt :Mellema et al,17 in a larger multi-center cohort study in the Netherlands on 464 patients, showed a higher ORR in G12V patients treated with taxanes. In contrast, Metro et al,20 in a retrospective cohort study based on 77 KRAS mutant patients, did not observe any difference according to amino acid substitution. However, all were relatively small cohort studies, limiting their level of evidence.
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2016, Clinical Lung CancerCitation Excerpt :For these reasons, it is important to determine EGFR mutations and EML4-ALK translocation before any treatment decision is made. Finally, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are present in approximately 25% of patients with NS-NSCLC11,12; data on their ability to predict response to TKIs are conflicting and their correlation with resistance to therapy (TKIs and chemotherapy), has not been unequivocally defined.13-15 In general, EML4-ALK translocation and EGFR and KRAS mutations are considered to be mutually exclusive, as reported in several studies.16-18
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2016, Clinical Lung CancerCitation Excerpt :This pathway converges at MEK1/2, for which the only known substrate is ERK1/2. There are no targeted therapies specifically approved for patients with KRAS-mutant (KRASm) NSCLC,4 and this patient population derives less clinical benefit from chemotherapy than the overall NSCLC population.5,6 Selumetinib (AZD6244, ARRY-142886) is an oral, potent and selective, allosteric MEK1/2 inhibitor7 with a short half-life of 5.33 hours.8,9
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2016, Lung CancerCitation Excerpt :Similarly, multiple studies have concluded the presence of a KRAS tumor mutation is not predictive of worse progression-free or overall survival in advanced NSCLC patients treated with platinum-based chemotherapy in the first or second line settings [18–21]. However, the data from these analyses contrast to the study by Metro and colleagues in which patients with KRAS mutations were shown to have a decreased PFS and OS in response to first line platinum-based chemotherapy [22]. With the current conflicting evidence regarding treatment prognosis in patients with KRAS-mutant NSCLC, we sought to determine if there is a correlation between KRAS mutation status and response to first-line cytotoxic chemotherapy in patients with metastatic or recurrent NSCLC within our single institution cohort.
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