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. 2017 May;32(3):514-522.
doi: 10.3904/kjim.2015.299. Epub 2017 Apr 14.

KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancer

Sehhoon Park  1 , Ji-Yeon Kim  1 , Se-Hoon Lee  1 , Beomseok Suh  2 , Bhumsuk Keam  1 , Tae Min Kim  1 , Dong-Wan Kim  1 , Dae Seog Heo  1
Affiliations

KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancer

Sehhoon Park et al. Korean J Intern Med. 2017 May.

Abstract

Background/aims: The predictive and prognostic value of KRAS mutation and its type of mutations in non-small cell lung cancer (NSCLC) are controversial. This clinical study was designed to investigate the predictive value of KRAS mutations and its mutation types to pemetrexed and gemcitabine based treatment.

Methods: Advanced NSCLC patients tested for KRAS mutation (n = 334) were retrospectively reviewed and 252 patients with wild type epidermal growth factor receptor and no anaplastic lymphoma kinase fusion were enrolled for the analysis. KRAS mutations were observed in 45 subjects with mutation type as followed: G12C (n = 13), G12D (n = 12), G12V (n = 12), other (n = 8). Response rate (RR), progression-free survival (PFS), and overall survival (OS) of pemetrexed singlet and gemcitabine based chemotherapy were analysis.

Results: Age, sex, performance status were well balanced between subjects with or without KRAS mutations. No difference was observed in RR. Hazard ratio (HR) of PFS for pemetrexed treated subjects with G12C mutation compared to subjects with KRAS wild type was 1.96 (95% confidential interval [CI], 1.01 to 3.79; p = 0.045), but other mutations failed to show clinical significance. By analysis done by PFS, compared to the subjects with transition mutation, HR was 1.48 (95% CI, 0.64 to 3.40; p = 0.360) for subjects with transversion mutation on pemetrexed treatment and 0.41 (95% CI, 0.19 to 0.87; p = 0.020) for subjects treated with gemcitabine based chemotherapy. No difference was observed in OS.

Conclusions: In this study, different drug sensitivity was observed according to the type of KRAS mutation. NSCLC subpopulations with different KRAS mutation type should be considered as different subgroups and optimal chemotherapy regimens should be searched in further confirmative studies.

Keywords: Carcinoma, non-small-cell lung; Gemcitabine; KRAS; Pemetrexed.

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Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Figure 1.
Figure 1.
Flow chart of patients selection. NSCLC, nonsmall cell lung cancer; MT, mutation; WT, wild type; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; CTx, cytotoxic chemotherapy.
Figure 2.
Figure 2.
Kaplan-Meier curves of progression-free survival (PFS). PFS curve plotted by subjects treated by pemetrexed singlet. (A) Subjects with KRAS wild type (WT) and G12C mutations (MTs) ([median PFS, 2.9 months; 95% confidential interval (CI), 2.3 to 4.0] vs. [median PFS, 1.6 months; 95% CI, 0.6 to 3.4], p = 0.040); PFS curve plotted by subjects treated by gemcitabine based chemotherapy. (B) Subjects with KRAS wild type and G12C mutations ([median PFS, 4.8 months; 95% CI, 4.2 to 5.2] vs. [median PFS, 5.0 months; 95% CI, 4.0 to 5.3], p = 0.761).
Figure 3.
Figure 3.
Kaplan-Meier curves of progression-free survival (PFS). (A, B) PFS curve plotted by each type of KRAS mutation (MT): (A) subjects with pemetrexed singlet treated; (B) subjects with gemcitabine based chemotherapy treated. (C, D) PFS curve plotted by transition mutation or transverse mutation: (C) subjects with pemetrexed singlet treatment; (D) subjects with gemcitabine based chemotherapy treatment.
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