Abstract 2398: KRAS mutation status is a strong prognostic factor in some but not all subtypes of non-small cell lung cancer.
Authors: Brustugun Odd Terje , Lund-Iversen Marius , Bjaanæs Maria M. , Halvorsen Ann Rita , Skrede Martina L. , Jørgensen Lars H. , Kure Elin H. , Helland Åslaug 
Published: August 2014

Non-small cell lung cancer is cancer killer #1, and consists of a variety of histological subtypes of which adenocarcinoma, squamous cell carcinoma and large cell carcinoma are most frequent. Genetic aberrations are regarded both prognostic and predicitive in NSCLC, and are found with various frequency and different significance in the subtypes. Mutation in the KRAS gene is a well-known factor in NSCLC, but the prognostic impact is still debated, and the role as target of therapy is under investigation. We intended to study the frequency and prognostic importance of KRAS mutations in a large number of early stage lung cancers of all major histological subtypes.

Material and methods

Tumor tissue was obtained from 321 consecutively operated lung cancer patients admitted to Oslo University Hospital-Rikshospitalet in the period 2006-2012. Tissue was taken from the excised tumours, snap frozen in liquid nitrogen in the operation room, and stored at -80oC until DNA isolation. The tumour cell content in the specimens was found to be more than 70% in most samples. DNA was isolated according to standard procedures, and mutation analysis was done with a TaqMan-based wobble-enhanced amplification refractory mutation system, for detecting the seven most commonly reported mutations of clinical importance in the KRAS gene; g.34G&gt;C (p.G12R), g.34G&gt;A (p.G12S), g.34G&gt;T (p.G12C), g.35G&gt;A (p.G12D), g.35G&gt;C (p.G12A), g.35G&gt;T (p.G12V), and g.38G&gt;A (p.G13D).

After thorough follow-up (median 34.6 months, range 6.3-80.6), relapse-free survival was calculated with the Kaplan-Meier method using Chi-Square for significance assessment.

Results

Tissues from 154 females and 167 males were analyzed; 212 (66%) adenocarcinomas, 89 (28%) squamous cell carcinomas and 20 (6%) large cell carcinomas. 182 (57%) were in stage I, 88 (27%) II and 51 (16%) stage III. 24 (7,5%) were never-smokers. Overall, 89 patients (27.7%) harbored a KRAS mutation, 78 (36.8%) of adenocarcinomas, 5 (5.6%) of squamous cell carcinomas and 6 (30%) of large cell carcinomas. The most frequent mutation subtype was G12C (51.7%). In the total group there was a significant relapse-free survival difference (p=0.021) in favor of the wild-type. In the adenocarcinoma subgroup, however, there was no survival difference (p=0.316), whereas there was a major difference in the non-adenocarcinoma group (p&lt;0.0001), with a two-year relapse-free survival rate of 79.8% vs 25.4%. The difference was of similar magnitude in both squamous cell carcinomas (p=0.013) and large cell carcinomas (p=0.0073).

Conclusions

KRAS mutations confer a survival disadvantage in non-small cell lung cancers. This effect is only seen in non-adenocarcinoma subtypes, which might have implications in therapy strategies.

Citation Format: Odd Terje Brustugun, Marius Lund-Iversen, Maria M. Bjaanæs, Ann Rita Halvorsen, Martina L. Skrede, Lars H. Jørgensen, Elin H. Kure, Åslaug Helland. KRAS mutation status is a strong prognostic factor in some but not all subtypes of non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2398. doi:10.1158/1538-7445.AM2013-2398