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02-06-2013 | Genetics | Article

KRAS gene mutation fails to predict NSCLC chemotherapy success

Abstract

Free abstract

medwireNews: Research casts doubt on the ability of the KRAS mutation to aid the selection of patients with non-small-cell lung cancer (NSCLC) to receive adjuvant chemotherapy (ACT).

"Overall, [KRAS] is not significantly predictive of a differential benefit from ACT, particularly in patients with adenocarcinoma, and at this time, it cannot be recommended as a tool to select patients for ACT," report Frances Shepherd (Princess Margaret Hospital, Toronto, Ontario, Canada) and co-authors.

They pooled data for 1543 participants of four clinical trials of chemotherapy after surgery and found no significant difference in the overall or progression-free survival (PFS) over a median of 5.5 years of patients with codon 12 (n=275), 13 (n=24), or 14 (n=1) KRAS mutations compared with patients with the wild-type gene (n=1243).

Nor did KRAS status predict the overall survival or PFS of the 763 patients who were randomly assigned to receive observation rather than ACT, or the outcome of patients with adenocarcinoma histology, after adjusting for trial, age, gender, performance status, tumor stage, node, or histology.

Furthermore, there was no significant difference in the risk for death in patients with wild-type or mutant KRAS regardless of whether they received ACT or underwent observation.

However, further analysis indicates that while patients whose tumors had the codon 12 mutation experienced no significant benefit from ACT compared with observation, those with the codon 13 mutant had significantly poorer overall survival with ACT than with observation (hazard ratio [HR]=5.78).

Furthermore, the impact of ACT in patients with codon 12 mutations was dependent on the amino acid substitution. The HR for overall survival was 0.66 for patients with G12A or G12R compared with 0.94 for patients with G12C or G12A, and 1.39 for those with G12D or G12S, although the differences did not reach statistical significance.

"Although our results suggest a potentially detrimental effect from chemotherapy in patients with codon 13 mutations, validation studies will be critical," Shepherd et al comment in the Journal of Clinical Oncology.

They emphasize that large international collaborations are necessary to determine the impact of codon 13 mutations and amino acid substitutions on ACT efficacy.

Finding that patients with a KRAS mutation were a significant 2.76 times more likely to develop a second primary tumor than those without, but significantly less likely to do so if they received ACT (HR=0.66), the team suggests guidelines on postoperative imaging follow up of patients are required.

"KRAS mutation status may identify a cohort of patients who, in the absence of ACT, may be at particularly high risk of developing second primary cancers and who potentially might benefit from more intense follow-up," they add.

medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

By Lynda Williams, Senior medwireNews Reporter