Balkan Journal of Medical Genetics

THE FREQUENCY OF EGFR AND KRAS MUTATIONS IN THE TURKISH POPULATION WITH NON-SMALL CELL LUNG CANCER AND THEIR RESPONSE TO ERLOTINIB THERAPY
Demiray A, Yaren A, Karagenç N, Bir F, Demiray AG, Karagür ER, Tokgün O, Elmas L, Akça H, https://orcid.org/0000-0002-3343-0184.
*Corresponding Author: Professor Dr. Hakan Akça, Cancer Research Center, Pamukkale University, 11 University Street, Denizli Turkey. E-mail: hakca@pau.edu.tr (primary), hakanakca@yahoo.com
page: 21

DISCUSSION

Non-small cell lung cancer has different subtypes, mainly adenocarcinoma, squamous and other subtypes. Of these, adenocarcinoma is seen more often in patients with NSCLC [10-13]. Previous studies that showed correlation can be found in literature regarding to the subtypes of NSCLC in the Turkish population [9,14]. In this study, we found 76.0% adenocarcinoma, 20.7% squamous, 3.3% other subtypes in 300 patients. The distribution of gender has been reported in the literature as: in East Asian communities 54.0-65.0% males, 35.0-46.0% females [10], in England 55.0% males, 45.0% females [1], in America 58.0% males 42.0% females [1]. Two previous studies performed in the Turkish population, found 85.0% males and 15.0% females by Unal et al. [14], 75.0% males and 25.0% females by Akca et al. [9]. Our results showed a similar gender distribution (Table 2). It has been reported that EGFR mutation rates range between 12.2 and 50.0% in East Asia communities [10,15]. Recently, population studies have shown that European and American population have the lowest EGFR mutation rates, 6.0-16.0% and 15.0-20.0%, respectively, in the world [11,12]. We detected EGFR mutations in 33.0% of all 300 patients and 84.0% of EGFR mutation-carrying patients had adenocarcinoma. Previous studies also showed similar results, 66.0 and 81.0% EGFR mutation rates, respectively [9,14]. In our study, we found EGFR mutations in 48.0% female patients and in 28.0% male patients. This result is similar to previous reports that female patients who had NSCLC have higher EGFR mutations [10-13]. Regarding smoking habits, patients who do not smoke have more EGFR mutations [9-15]. In our study, we detected EGFR mutations in 49.0% of non smoking patients and in 28.0% of the smoking patients (Table 2). In the literature, EGFR mutations are seen more often in non smokers and female Asian patients [10]. Mutation rate also increases with advanced stages of NSCLC cancer (IIIB-IV) [10-13]. In our study, similar results were obtained in 18.6% early stage and 81.4% advanced stage in NSCLC patients with EGFR mutations. The KRAS mutation rates in NSCLC patients were reported as 2.3-9.4% in East Asian populations, 11.0- 29.0% in North America, 12.0-31.0% in Europe, 25.0% in Mexico, 12.0% in Columbia and 12.0% in Peru [10- 12]. In our research, we found 20.8% patients had KRAS mutations (Table 2). We detected 65.0% KRAS mutations in codons 12 and 13 and 35.0% in codon 64 [Table 3(B)]. We also found that 6.6% of the patients carry both EGFR and KRAS mutations (Table 2). In the literature, this rate varied between 1.0 and 15.0% [10-12]. This is the first study in the Turkish population showing KRAS mutations and erlotinib therapy in NSCLC patients. Fifty-nine of 97 patients with EGFR mutations were treated with EGFR-TKI agent (erlotinib). The average overall survival rates are 146 ± 22 weeks in EGFR-TKI treated patients and 84 ± 12 weeks in untreated patients. Similar results were published in the literature that erlotinib therapy increases overall survival [16] [Figure 1(B)]. The effect of EGFR-TKI treatment on a patient’s survival without progression was found to be statistically significant. Erlotinib-treated patients’ survival rate was 288 ± 11 weeks and 119 ± 11 weeks in untreated patients. This result is in accordance with the literature [16]. EGFR-TKI treatment provided longer survival rates in patients carrying only EGFR mutations compared to the patients with both mutations [Figure 2(B)]. We report that the overall survival rates are 34 ± 16 weeks in patients with KRASEGFR mutations and 98 ± 16 weeks in EGFR mutations without KRAS mutations in erlotinib-treated patients. Thus, the longest overall survival rates were observed in patients with EGFR but without KRAS mutations, and the lowest overall survival rates were found in patient with EGFR and KRAS mutations in EGFR-TKI-treated patients. Therefore, this indicated that KRAS is a prognostic factor for NSCLC. The mutations on the KRAS gene constantly activate K-ras protein, which in turn triggers cancer cell proliferation via the rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular signal regulated kinase (RAF/MEK/ERK) pathway, resulting in ERK transcriptional factor. Mutated K-ras also activates the phospo- inositide 3-kinase/phosphoinositide-dependent kinase/ protein kinase B (PI3K/PDK/AKT) and tuberous sclerosis complex 1/Ras homologue enriched in brain/mammalian target of rapamycin complex 1 (TSC-1/RHEB/mTORC1) pathways, which have a role in invasion and metastasis in cancer cells [17]. Our research showed that additional KRAS mutations are a strong parameter for prognosis. The KRAS mutations negatively affect survival rate with and without erlotinib therapy [18]. This result suggests that KRAS mutation analyses should be routinely performed together with EGFR mutation analyses in NSCLC patients. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This study was partly supported by the Pamukkale University Scientific Foundation [#2012SBE 002].

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