Elsevier

Clinical Lung Cancer

Volume 15, Issue 1, January 2014, Pages 86-92
Clinical Lung Cancer

Original study
Clinical Outcome With Platinum-Based Chemotherapy in Patients With Advanced Nonsquamous EGFR Wild-Type Non–Small-Cell Lung Cancer Segregated According to KRAS Mutation Status

This work was presented in abstract form at the European Society of Medical Oncology 2012 Congress; September 28-October 2, 2012; Vienna, Austria.
https://doi.org/10.1016/j.cllc.2013.08.002Get rights and content

Abstract

Background

We hypothesized that KRAS mutations function as a marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type (WT) non–small-cell lung cancer (NSCLC).

Patients and Methods

Consecutive advanced nonsquamous EGFR WT NSCLCs treated at the Medical Oncology of Perugia with simultaneous assessment of KRAS mutation status were eligible. Anaplastic lymphoma kinase (ALK) gene status was known in roughly half of the patients who had KRAS WT.

Results

Two hundred four patients were included. Among them, the 77 individuals carrying a KRAS-mutant phenotype experienced a significantly inferior outcome in terms of response rate (P = .04), disease control rate (P = .05), and progression-free survival (PFS) (P = .05) compared with the EGFR WT/KRAS WT population. The association between KRAS mutation and shorter PFS remained statistically significant at multivariate analysis (hazard ratio [HR], 1.45). In addition, patients with KRAS mutations reported a significantly shorter overall survival (OS) compared with patients with EGFR WT/KRAS WT/ALK negativity (n = 64) (P = .02). Among patients with KRAS mutations, those harboring a mutation at codon 13 (n = 12) performed worse than those with a mutation at codon 12 (n = 62) in terms of both PFS and OS (P = .09 for both).

Conclusion

KRAS mutation appears to negatively affect sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR WT NSCLC. Studies on larger case series are needed to address differences in clinical outcome according to the type of mutation.

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).

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