Elsevier

The Lancet Oncology

Volume 9, Issue 10, October 2008, Pages 962-972
The Lancet Oncology

Fast track — Articles
Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer

https://doi.org/10.1016/S1470-2045(08)70206-7Get rights and content

Summary

Background

Somatic mutations of the k-RAS oncogene have been assessed as a mechanism of de-novo resistance to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibition in patients with non-small-cell lung cancer (NSCLC), and to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). The aim of this systematic review and meta-analysis was to assess if k-RAS mutations represent a candidate predictive biomarker for anti-EGFR-targeted therapeutic strategies in mCRC and NSCLC.

Methods

We systematically identified articles pertaining to k-RAS mutational status in patients with NSCLC treated with tyrosine-kinase inhibitors (TKI), and patients with mCRC treated with any anti-EGFR-based regimens. Eligible studies had to report complete responses (CR) and partial responses (PR), stratified by k-RAS mutational status. Potential between-study heterogeneity was accommodated by use of random-effects models for bivariable meta-analysis of sensitivity and specificity (the primary endpoints). The positive and negative likelihood ratios (+LR and −LR, respectively) of k-RAS mutations for predicting an absence of response were considered as secondary endpoints and were calculated by use of pooled estimates for sensitivity and specificity.

Findings

Of 252 retrieved manuscripts, 17 were deemed eligible for the NSCLC meta-analysis (165 of 1008 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to TKIs (sensitivity=0·21 [95% CI 0·16–0·28], specificity=0·94 [0·89–0·97]; +LR=3·52; −LR=0·84). Of 68 retrieved manuscripts reporting on anti-EGFR monoclonal-antibody-based treatment of mCRC, eight studies were deemed eligible for the final analysis (306 of 817 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments (sensitivity=0·47 [0·43–0·52]; specificity=0·93 [0·83–0·97]; +LR=6·82; −LR=0·57).

Interpretation

This analysis provides empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR TKIs in advanced NSCLC; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with mCRC. The low sensitivity and relatively high −LR of k-RAS mutations for determining non-responsiveness clearly shows that additional mechanisms of resistance to EGFR inhibitors exist.

Funding

None.

Introduction

The concept of inhibiting activation of the epidermal growth factor receptor (EGFR) has been implemented in the therapeutic armamentarium for patients with epithelial malignancies, such as lung and colorectal cancer. Since the mid-1960s, when the EGFR protein was first isolated and characterised, it has been regarded as a suitable antineoplastic target.1, 2 EGFR is expressed in many tumours, including non-small-cell lung cancer (NSCLC) and colorectal cancer, where it is regarded as a poor prognostic factor correlating with aggressive disease and decreased survival.3, 4 Prevention of ligand binding by use of monoclonal antibodies, or blockade of intracellular receptor phosphorylation by tyrosine-kinase inhibitors (TKIs), dampen signal transduction through pathways such as the RAS/RAF/MAPK and PI3K/AKT cascades, which promote cell growth, proliferation, invasion, angiogenesis, and metastasis.5, 6

Nowadays, there are a series of agents targeting EGFR that are already in clinical use or under clinical investigation, with several more in development (preclinical).7, 8 Two different anti-EGFR targeting strategies are currently clinically available: monoclonal antibodies that target the extracellular domain of the receptor, thereby inhibiting dimerisation and subsequent signal transduction (eg, cetuximab and panitumumab),9, 10, 11 and small-molecule inhibitors of the intracellular phosphotyrosine-kinase domain (eg, the 4-anilinoquinazoline TKIs gefitinib and erlotinib).12, 13, 14 Although both drug classes have been assessed in various cancer types, much of our current understanding of EGFR and its role in therapeutic decision making stems from studies of TKIs in NSCLC. Initial studies of single-agent TKIs in NSCLC, showed moderate overall responses of between 9–18%;15, 16, 17, 18 however, a subgroup of patients showed substantial long-lasting responses. In view of these mixed findings, investigators were spurred on into addressing ways of identifying potential responders. First indications arose from data correlating clinical responses to TKIs with the clinicopathological factors of adenocarcinoma histology, smoking history, sex, and ethnicity in NSCLC.19 Subsequently, patients responding to TKIs were shown to harbour somatic mutations in EGFR. The presence of these “sensitivity-conferring” mutations correlated with the aforementioned clinicopathological factors of adenocarcinoma (including those with BAC or BAC-like component).19, 20, 21, 22 In addition to the identification of a potential molecular marker of response, the presence of somatic mutations in the k-RAS oncogene was proposed as a marker of non-responsiveness (de-novo resistance).23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49

A similar story unfolded in metastatic colorectal cancer (mCRC). After the development of cetuximab and panitumumab, clinical assessments showed responses for these agents of between 10–30% (single agent monoclonal antibody and plus chemotherapy, respectively) in chemorefractory patients with mCRC.8 Once again, this low response prompted investigators to identify mechanisms that might assist in improving the likelihood of response, if only in a subset of patients with mCRC. In view of the fact that k-RAS mutations occur in a substantial proportion of mCRC (30–50%) and are negative prognostic factors,50, 51 they were assessed as potential markers for the response of individuals to anti-EGFR agents.7 Therefore, the hypothesis that mCRC tumours show some form of primary, de-novo, or acquired resistance to anti-EGFR agents capitalised on knowledge of both tumour biology50, 52, 53, 54 and previous data from NSCLC.23

Panitumumab was originally approved as single-agent therapy for patients with progressive EGFR-positive mCRC, who are chemorefractory to fluoropyrimidines, irinotecan, and oxaliplatin-based regimens. The recent amendment of the panitumumab licensing for the treatment of patients with EGFR-positive chemorefractory mCRC only if they have wildtype k-RAS, has resulted in a dramatic (and rapid) change in our clinical perception of mCRC.55 Following on from data concerning panitumumab licensing, the other clinically available anti-EGFR monoclonal antibody, cetuximab, has come under scrutiny for potential response enrichment by stratifying patients with mCRC on the basis of k-RAS mutational status.9, 56, 57, 58, 59, 60, 61, 62, 63, 64

Herein, we present the findings of a systematic review and meta-analysis, attempting to assess the predictive value of k-RAS mutations in two solid tumours, NSCLC and mCRC. We aim to show that k-RAS mutations might represent a key mechanism of de-novo non-responsiveness (ie, resistance), applicable with respect to this particular signalling pathway, with the potential to offer patient enrichment for anti-EGFR-targeted therapeutic strategies in various cancer types.

Section snippets

Study eligibility and identification

We did systematic computerised searches of the PubMed and Medline databases (up to June 5, 2008) and the Cochrane library (Issue 2, 2008), to identify all published articles reporting on anti-EGFR targeted agents for NSCLC and mCRC. For the NSCLC search, we used a previously reported search strategy.19 For mCRC, we used combinations of the following search terms: “erlotinib”, “gefitinib”, “tarceva”, “iressa”, “colorectal cancer”, “rectal cancer”, “ABX”, “EGFR”, “RAS”, “epidermal growth factor

Results

Our initial search yielded 3240 studies for NSCLC and 333 studies for mCRC. As shown in the NSCLC flow chart (figure 1), 17 studies were included in the final meta-analysis, reporting on 1008 patients, of whom 165 had k-RAS mutations. The characteristics of eligible studies are summarised in table 1. Ten studies that were initially deemed eligible were subsequently excluded from the NSCLC analysis; five did not report (detect) any k-RAS mutations,40, 41, 45, 47, 49 two were updated by

Discussion

The present systematic review of the literature and meta-analyses were done to assess the potential use of k-RAS mutations as predictive factors of non-responsiveness (ie, resistance) to EGFR-targeted agents. Overall, we found substantial evidence that in both mCRC and NSCLC, k-RAS mutations are appropriate markers for identifying a subgroup of patients (representing about 40% of patients with mCRC and 20% of patients with NSCLC) that have an extremely limited probability of responding to

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