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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 4  |  Page : 699-701

k-RAS mutation and resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer


1 Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, Province 325200, PR China
2 Department of Pharmacy, Ruian People's Hospital, Ruian, Zhejiang, Province 325200, PR China

Date of Web Publication13-Sep-2017

Correspondence Address:
Jie Li
Department of Pharmacy, Ruian People's Hospital, Ruian, No. 108 Wansong Road, Ruian, Zhejiang, Province 325200
PR China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_468_17

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 > Abstract 

Objective: The aim of this study was to evaluate the relationship between k-RAS gene mutation and the resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with nonsmall-cell lung cancer (NSCLC).
Methods: Forty-five pathologies confirmed NSCLC patients who received EGFR-TKI (Gefitinib) treatment were retrospectively included in this study. The mutation of codon 12 and 13, located in exon1 and exon 2 of k-RAS gene were examined by polymerase chain reaction (PCR) and DAN sequencing in tumor samples of the included 45 NSCLC patients. The correlation between Gefitinib treatment response and k-RAS mutation status was analyzed in tumor samples of the 45 NSCLC patients.
Results: Eight tumor samples of the 45 NSCLC patients were found to be mutated in coden 12 or 13, with an mutation rate of 17.8% (8/45); the objective response rate (ORR) was 29.7%(11/37) with 1 cases of complete response (CR) and 10 cases of partial response in k-RAS mutation negative patients. Furthermore, the ORR was 0.0% in k-RAS mutation positive patients with none CR. The ORR between k-RAS mutation and nonmutation patients were significant different (P < 0.05).
Conclusion: k-RAS gene mutation status was associated with the response of Gefitinib treatment in patients with NSCLC.

Keywords: Epidermal growth factor receptor-tyrosine kinase inhibitor, k-RAS gene, lung carcinoma, nonsmall cell, response


How to cite this article:
Zhou B, Tang C, Li J. k-RAS mutation and resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer. J Can Res Ther 2017;13:699-701

How to cite this URL:
Zhou B, Tang C, Li J. k-RAS mutation and resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer. J Can Res Ther [serial online] 2017 [cited 2018 Aug 16];13:699-701. Available from: http://www.cancerjournal.net/text.asp?2017/13/4/699/214476


 > Introduction Top


Lung cancer is solid malignant tumor with the highest morbidity in men and second highest in women.[1],[2] However, this malignant carcinoma has the highest mortality rate in both males and females. Chemotherapy for advanced progressive nonsmall cell lung cancer (NSCLC) has poor effects with an overall objective response rate of less than 30%.[3],[4] In recent years, the advantages of targeted drug treatment for lung cancer have become more apparent with the progress in targeted drug research. The efficacy of the targeted drug treatment of the advantaged NSLC with epidermal growth factor receptor (EGFR) mutation was significantly higher than that of conventional chemotherapy.[5],[6] Gefitinib is an EGFR antagonist that binds specifically to the EGFR on the surface of the tumor cell membrane. This molecule disrupts the EGFR signal pathway, thereby inhibiting tumor cell DNA synthesis and cell division and proliferation, as well as promoting cell apoptosis. Several studies have shown the correlation between k-RAS gene mutation status and the clinical efficacy of the drug treatment of NSCLC.[7],[8],[9] In the present study, we retrospectively analyzed the association between EGFR-TKI treatment response and k-RAS gene mutation status in 45 NSCLC patients who received EGFR-TKI treatment.


 > Methods Top


Patients selection

We retrospectively analyzed 45 patients with advanced NSCLC who received EGFR-TKI (Gefitinib) treatment in our hospital from January 2014 to August 2016. The patients inclusion criteria were: (1) all the patients were clinically diagnosed of NSCLC with pathology or cytology confirmation; (2) NSCLC patients who received Gefitinib for at least 2 months; (3) patients had evaluable lesion; and (4) tumor samples can be obtain for k-RAS mutation detection. The participants consisted of 27 males and 18 females with average age of 62.8 ± 18.8 years and PS score of 0-1 in 25 cases, 2-3 in 20 cases. A total of 21 cases were diagnosed of adenocarcinoma, 21 cases of cell carcinoma, and 3 cases of pathological types. All patients were pathology or cytology confirmed of NSCLC.

Drugs and equipment

Gefitinib[AstraZeneca (Wuxi) Trading Co., Ltd] was administered at 250 mg/tablet. polymerase chain reaction (PCR) instrument used was ABI/2700 (ABI Company, USA). DNA extraction kit was purchased from Takara Company in Japan.

Detection of k-RAS gene mutation

Genomic DNA was extracted from the paraffin-embedded tumor group, and primers were synthesized by Shenzhen Huada Gene Biotechnology Co. Ltd. according to the primers sequence reported in the literature. Two pairs of primers k-RAS gene Ex1 and Ex2 exons were amplified by PCR [Table 1], containing 12 and 13 codons, respectively. PCR reaction was conducted according to the test process instructions. PCR amplification products were detected by 1.5% agarose gel electrophoresis to determine the presence of specific bands.
Table 1: k-RAS gene exon 1, 2 exon primer sequence

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Growth factor receptor-tyrosine kinase inhibitor treatment

Of the 45 patients with NSCLC, 20 had been treated with platinum-based chemotherapy and 15 patients who did not receive any treatment. All patients received oral gefitinib 250 mg, one time a day.

Treatment response evaluation

The treatment response of the 45 patients were evaluated after 2 months treatment according to Response Evaluation Criteria in Solid Tumors 1.1.[10] Complete response: disappearance of all target lesions. Any pathologically lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the base line sum diameters. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression disease (PD), taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression).

Statistical analysis

All the data were analyzed by SAS13.0 software (http://www-01.ibm.com/software/analytics/spss/). The enumeration data were expressed by relative number and compared with Chi-square or fisher's exact test. P < 0.05 was considered statistically significant.


 > Results Top


k-RAS gene mutation rate

Eight tumor samples of the 45 NSCLC patients were found to be mutated in coden 12 or 13, with an mutation rate of 17.8% (8/45).

Relationship between k-RAS gene mutation and clinical pathology characteristics

For the 8 k-RAS mutation patients, there was 6 (75.0%) male and 2 (25.0%) female cases. The clinical stage distribution was: IIIB one cases (12.5%), IV seven cases (87.5%). For pathology type, there were five (62.5%) case of adenocarcinoma, two (25.0%) cases of squamous cell carcinoma, and one (12.5%) cases of other pathology type. Four (50.0%) patients had smoking history and other four (50.0%) did not. There was no correlation between k-RAS gene mutation and sex (P > 0.05), clinical stage (P > 0.05), smoking status (P > 0.05), and previously treatment history (P > 0.05), [Table 2].
Table 2: Association between patients clinical characteristics and k-RAS status, n (%)

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k-RAS gene mutation and epidermal growth factor receptor-tyrosine kinase inhibitor treatment response

There were one cases of complete response, ten cases of partial response with the objective rate of 29.7% (11/45). The objective response rate in k-RAS mutation group was significant lower than those of wild-type patients (0.0% vs. 29.7%, P < 0.05), [Table 3].
Table 3: Association between k-RAS gene mutation and epidermal growth factor receptor tyrosine kinase inhibitors treatment response

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 > Discussion Top


Mortality caused by lung cancer reach 1.2 million deaths annually.[11] Thus, lung cancer has become a major threat to public health.[12] Patients with advanced lung cancer who received chemotherapy exhibits poor prognosis with a 5-year survival rate of only 30%. In recent years, targeted drugs, such as EGFR-TKI (gefitinib/erlotinib), for lung cancer have become a hotspot for cancer research. Gefitinib can bind to extracellular ligands to prevent intracellular tyrosine phosphorylation, further blocking downstream signal protein transduction. This process inhibits tumor cell growth, invasion, angiogenesis, and metastasis. However, recent studies have shown that gefitinib is not effective in all NSCLC patients, and some patients have tumor cell k-RAS gene mutation and are naturally resistant to gefitinib.[13],[14]

In this study, 45 patients with NSCLC treated with gefitinib were retrospectively analyzed. A total of eight cases were detected with 12/13 codon gene mutation with a mutation rate of 17.8% (8/45). The objective response rate of the mutant group was significantly lower than that of the wild-type patients. The results showed that NSCLC patients with 12/13 codon mutation of the k-RAS gene cannot benefit from EGFR-TKI (Gefitinib) therapy. Therefore, examining the mutation status of the k-RAS gene in the tumor tissues of patients with NSCLC before administration of gefitinib can result in a more accurate prediction of the effect of treatment. This process would screen the disadvantaged group of gefitinib treatment, thereby enhancing the relevance of EGRF-TKI treatment to simultaneously improve the treatment efficacy and reduce the cost of medical care. Therefore, the k-RAS gene status is an important biological marker of individualized treatment of gefitinib in patients with NSCLC. However, in our present study, we only included in 45 cases, the sample size is small and the statistical power is limited. Hence, multicenter prospective randomized clinical controlled studies are need to further explicate the relationship between k-RAS gene mutation and the resistance to EGFR-TKI treatment in patients with NSCLC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Varella-Garcia M, Mitsudomi T, Yatabe Y, Kosaka T, Nakajima E, Xavier AC, et al. EGFR and HER2 genomic gain in recurrent non-small cell lung cancer after surgery: Impact on outcome to treatment with gefitinib and association with EGFR and KRAS mutations in a Japanese cohort. J Thorac Oncol 2009;4:318-25.  Back to cited text no. 14
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