O13. Subtype-specific KRAS mutations in advanced lung adenocarcinoma

Background: So far there is no strong evidence for the predictive effects of KRAS mutations on the clinical outcome of platinum-based chemotherapy in advanced lung adenocarcinoma. However, most of the studies did not take into account the subtype-specific mutations in the KRAS gene.

Methods: For this very reason we studied a cohort of 505 unresectable stage III-IV lung adenocarcinoma patients with known KRAS mutational status. Formalin fixed paraffin embedded histological samples were subjected to restriction fragment length-based KRAS codon 12 and 13 mutation screen. All mutant cases then were analyzed by direct sequencing. Next, the correlation of various subtype-specific mutations with the clinicopathological characteristics including smoking status, progression-free survival (PFS), overall survival (OS) and response rate (RR) to platinum-based treatment was analyzed.

Results: In our cohort, 338 non-KRAS mutant (67%), 147 codon 12 mutant (29%) and 20 codon 13 mutant (4%) patients had been identified. We found no significant differences among the different KRAS mutation groups in PFS or in OS. Importantly, we found that the G12V subtype of KRAS codon 12 mutation was significantly more frequent in never-smoker than in ever-smoker patients (26% vs. 6%, P=0.023). Furthermore, patients with G12V mutations had a non-significantly higher RR when compared to other patients presenting with other codon 12 mutation subtypes (G12×) (66% vs. 47%, respectively; P=0.072). There was also a non-significant increase in the median PFS in the G12V mutant cohort (7.8 vs. 5.8 months in the G12× group, P=0.145).

Conclusions: KRAS mutation status per se is neither prognostic nor predictive in advanced lung adenocarcinoma. However, subtype-specific analysis may reveal clinically relevant subgroups.

Keywords: Non-small cell lung cancer (NSCLC); adenocarcinoma; KRAS; mutation