EGFR and K-RAS mutations and ERCC1, TUBB3, TYMS, RRM1 and EGFR mRNA expression in non-small cell lung cancer: Correlation with clinical response to gefitinib or chemotherapy

Abstract

Abstract. Personalizing medicines has refined the traditional treatments for non-small-cell lung cancer (NSCLC). In the present study, efforts towards personalizing delivery of care based on the status of EGFR and K-RAS mutations, and mRNA expression levels of ERCC1, TUBB3, TYMS, RRM1 and EGFR by choosing appropriate treatments for 52 patients with NSCLC were discussed. Among these 52 NSCLC patients, there were 14 patients treated with gefitinib. Ten patients with EGFR exon 21 point mutations or exon 19 deletions had better treatment outcomes following gefitinib treatment (71.4%). There were 38 patients treated with platinum-based chemotherapy. Docetaxel-platinum based chemotherapy was chosen as the first-line treatment when the patients had low or median ERCC1/TUBB3 expression and gemcitabine-platinum based chemotherapy was chosen when the patients had low or median ERCC1/RRM1 expression. In total, 26 cases had mRNA expression levels of ERCC1/TUBB3 or ERCC1/RRM1 that could be used to predict the treatment outcomes of chemotherapy (68.4%). The present results indicated that the mutation status of EGFR, as well as the mRNA expression levels of ERCC1, TUBB3 and RRM1, could be used as predictors of the response to gefitinib or chemotherapy. IntroductionLung cancer, of which nearly 80-85% is diagnosed as non-small-cell lung cancer (NSCLC), is one of the leading causes of fatality worldwide (1). The adjuvant chemotherapy, including the combinations of platinum and cytotoxic agents (such as docetaxel and gemcitabine) and epidermal growth factor receptor (EGFR)-targeted therapy, such as gefitinib (AstraZeneca, London, UK), has become common treatments for NSCLC (2). However, drug resistance causes unsatisfactory clinical responses to these medicines. Therefore, it is essential to understand the molecular markers associated with resistance to these medicines, to aid oncologists in choosing the more effective anti-tumor drugs for patients to achieve the most advantageous potential outcomes.The major molecular markers associated with clinical response to gefitinib or chemotherapy in NSCLC include the status of EGFR, K-RAS mutations and mRNA expression levels of excision repair cross-complementing 1 (ERCC1), class III β-tubulin (TUBB3), thymidylate synthase (TYMS), ribonucleotide reductase subunit M1 (RRM1) and EGFR (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). EGFR is a member of the ErbB family of receptors. Mutations within the tyrosine kinase domain of EGFR account for increased sensitivity to the tyrosine kinase inhibitor (TKIs), such as gefitinib (3,4). However, an insertion mutation and the point mutation T790M in exon 20 of EGFR are associated with resistance to TKIs (5). Previous studies have demonstrated that overexpression of EGFR was associated with increased sensitivity to gefitinib (6,7). K-RAS encodes a small guanosine triphosphate (GTP)-binding protein involved in numerous cellular processes, including proliferation and apoptosis (8). The wild-type K-RAS protein has intrinsic GTPase activity that catalyzes the...

Diagnostic and prognostic value of thymidylate synthase expression in breast cancer

“…Our further investigation of the prognostic value of TYMS in breast cancer using pooled database information indicated that higher TYMS expression in breast cancer correlated with worse OS, DFS, and RFS. Previous studies have reported that high expression of TYMS was an indicator of poor prognosis in prostate cancer, 8,16,17 non‐small cell lung cancer, 18‐20 and esophageal squamous cell carcinoma 21 . In contrast, high TYMS mRNA expression was associated with a significantly lower risk for relapse and death in patients with colorectal cancer 22…”

Personalized Prescription of Chemotherapy Based on Assessment of mRNA Expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBβ3, TYMS, and GSTP1 Genes in Tumors Compared to Standard Chemotherapy in the Treatment of Non-Small-Cell Lung Cancer

“…In a study evaluating EGFR and KRAS gene mutations along with the mRNA expression levels of ERCC1 , TUBβ3 , TYMS , RRM1 , and EGFR , it was shown that when using a personalized approach for prescribing neoadjuvant chemotherapy according to the docetaxel/platinum regimen, the response rate was 13.3% (4/30 cases) for complete regression, 63.3% (19/30 cases) for stabilization, and 23.4% (7/30 cases) for tumor progression. In the group that received a chemotherapy regimen of gemcitabine/platinum, the response rate was one patient (12.5%) with complete tumor regression, five patients with stabilization (62.5%), and two patients with tumor progression (25%) [ 34 ]. Notably, the personalized prescription of a conventional chemotherapy regimen for patients with NSCLC has made it possible to achieve much greater efficiency in terms of increasing patient survival compared to the use of many new targeted drugs.…”