KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis

Zoltan Lohinai, Thomas Klikovits, Judit Moldvay, Gyula Ostoros, Erzsebet Raso, Jozsef Timar, Katalin Fabian, Ilona Kovalszky, István Kenessey, Clemens Aigner, Ferenc Renyi-Vamos, Walter Klepetko, Balazs Dome, Balazs Hegedus, Zoltan Lohinai, Thomas Klikovits, Judit Moldvay, Gyula Ostoros, Erzsebet Raso, Jozsef Timar, Katalin Fabian, Ilona Kovalszky, István Kenessey, Clemens Aigner, Ferenc Renyi-Vamos, Walter Klepetko, Balazs Dome, Balazs Hegedus

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.

Figures

Figure 1. Metastatic site-specific variation of KRAS…
Figure 1. Metastatic site-specific variation of KRAS status.
(A) Patients with multiple-organ metastases showed a non-significant increase in the percentage of KRAS mutant cases (vs single-organ spread, 32% v 27%). (B) In the organ-specific analysis, patients with brain, bone or adrenal gland metastases demonstrated similar KRAS mutation frequencies (29%, 28% and 33%, respectively). However, pulmonary metastatic cases demonstrated increased KRAS mutation frequency when compared to those with extrapulmonary metastases (35% and 26.5%; p = 0.0125). In contrast, pleural dissemination and liver metastasis associated with decreased KRAS mutation incidence (17% (p < 0.001) and 16% (p = 0.0023), respectively).
Figure 2. Kaplan-Meier curves for the OS…
Figure 2. Kaplan-Meier curves for the OS of lung adenocarcinoma patients according to metastatic sites and KRAS mutation status.
(A) Patients with multiple-organ metastases had significantly decreased median overall survival (OS) compared to those with single-organ metastasis (6.8 vs 11.6 months; HR, 0.62; 95% CI, 0.498 to 0.788; p < 0.001). (B) In the comparison of single-organ sites, patients presented with single-organ metastasis to the pleura demonstrated significantly decreased median OS when compared to those with lung (7.5 vs 15.6 months; HR, 0.460; 95% CI, 0.255 to 0.646; p < 0.001) or adrenal spread (7.5 vs 14.4 months; HR, 1.896; 95% CI, 1.154 to 3.114; p = 0.011). Furthermore, patients with brain metastasis showed significantly decreased OS when compared to patients presented with lung metastasis (median OS, 10.3 vs 15.6 months, respectively; HR, 1.5; 95% CI, 1.004 to 2.117; p = 0.04). We found no statistically significant information in any other organ specific comparison. KRAS mutation had no significant prognostic effect (C) in the full cohort of metastatic stage patients at diagnosis or according to (D) patients with single or multiple-organ spreads.
Figure 3
Figure 3
Kaplan-Meier curves for the OS of metastatic lung adenocarcinoma patients according to KRAS mutation status in patients with (A) lung, (B) bone, (C) adrenal, (D) brain, (E) pleura, and (F) liver spread. Both single- and multiple-organ metastatic cases were included in these analyses. We found a clinically relevant and also significant decrease in OS in patients presented with KRAS mutant bone metastasis (vs KRAS wild-type, median OS 3.7 v 9.7 months; HR, 0.49; 95% CI, 0.31 to 0.79; p = 0.003). Importantly, we found no statistically significant information in any other organ-specific comparison.

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