Abstract
Current guidelines lack comprehensive information on the metastatic site-specific role of KRAS mutation in lung adenocarcinoma (LADC). We investigated the effect of KRAS mutation on overall survival (OS) in this setting. In our retrospective study, 500 consecutive Caucasian metastatic LADC patients with known KRAS mutational status were analyzed after excluding 32 patients with EGFR mutations. KRAS mutation incidence was 28.6%. The most frequent metastatic sites were lung (45.6%), bone (26.2%), adrenal gland (17.4%), brain (16.8%), pleura (15.6%) and liver (11%). Patients with intrapulmonary metastasis had significantly increased KRAS mutation frequency compared to those with extrapulmonary metastases (35% vs 26.5%, p = 0.0125). In contrast, pleural dissemination and liver involvement were associated with significantly decreased KRAS mutation incidence (vs all other metastatic sites; 17% (p < 0.001) and 16% (p = 0.02) vs 33%, respectively). Strikingly, we found a significant prognostic effect of KRAS status only in the bone metastatic subcohort (KRAS-wild-type vs KRAS-mutant; median OS 9.7 v 3.7 months; HR, 0.49; 95% CI, 0.31 to 0.79; p = 0.003). Our study suggests that KRAS mutation frequency in LADC patients shows a metastatic site dependent variation and, moreover, that the presence of KRAS mutation is associated with significantly worse outcome in bone metastatic cases.
Highlights
While extensive data is available on the predictive and prognostic significance of Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation in colorectal carcinoma (CRC), we have ambiguous information on its prognostic role in lung cancer
There is very limited comprehensive data available regarding the influence of KRAS mutation on the organ specificity of lung adenocarcinoma metastases[37]
This observation further supports the proposal that non-small cell lung cancer (NSCLC) staging should take into account the number and site of metastases since tumors with a single metastasis in a single organ had significantly better prognosis than those with multiple metastases in one or several organs[39]
Summary
While extensive data is available on the predictive and prognostic significance of KRAS mutation in colorectal carcinoma (CRC), we have ambiguous information on its prognostic role in lung cancer. KRAS mutation has been reported to be a potential negative prognostic factor in patients with liver metastatic colorectal cancer in various treatment modalities[14,15,16]. A meta-analysis including 1677 advanced NSCLC patients revealed that patients with KRAS mutations had significantly lower ORR and potentially lower PFS after first-line chemotherapy[23]. The presence of KRAS mutations had a mild negative impact on OS in advanced NSCLC patients treated with first-line chemotherapy in 52 Italian institutions[24]. A retrospective analysis of 484 Asian advanced NSCLC patients showed only limited predictive role of KRAS mutation[25]. The aim of our study was to investigate the metastatic site-specific prognostic value of KRAS mutation in LADC patients
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