Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland.
Oncol Rep. 2013 Nov;30(5):2385-98. doi: 10.3892/or.2013.2696. Epub 2013 Aug 26.
Platinum-based chemotherapy with third generation drugs (such as gemcitabine) is an efficacious regimen of first-line treatment of patients with advanced, unresectable non-small cell lung cancer (NSCLC), without activating EGFR mutations. Mechanism of action of cytostatics are distortions in the DNA. ERCC1 and RRM1 are key proteins involved in the repair of DNA, thus, they may be responsible for the ineffectiveness of therapy. We investigated whether ERCC1 (19007C>T) and RRM1 (-37C>A) polymorphisms impact response to chemotherapy and survival in 62 patients with NSCLC treated with platinum and gemcitabine. Single nucleotide polymorphisms (SNPs) were assessed using a PCR-RFLP method in DNA isolated from PBLs. There were no statistically significant relationships between ERCC1 genotypes and response to therapy (p=0.581, χ2=1.09) as well as patient overall survival (OS). Carriers of the RRM1 AC genotype showed disease progression significantly more frequently (p=0.019, χ2=5.473) compared to carriers of the AA or CC genotypes. Carriers of the ERCC1/RRM1TT/CC genotype combination showed disease control significantly more frequently (p=0.047, χ2=3.95) compared to carriers of other genotype combinations. Patients with AA or CC genotypes of RRM1 showed significantly higher progression-free survival probability (p=0.0001, HR=0.39, 95% CI, 0.22-0.70) and OS probability (p=0.0104, HR=0.39, 95% CI, 0.18-0.82) compared to those with the AC genotype. In Cox regression model, poor performance status (p=0.0016, HR=4.78, 95% CI, 1.82-12.56), AC genotype of RRM1 gene (p=0.0414, HR=2.47, 95% CI, 1.04-5.87), lack of prior surgical treatment (p=0.0425, HR=4.71, 95% CI, 1.06-20.92) and lack of subsequent lines of treatment (p=0.0127, HR=3.23, 95% CI, 1.29-8.11) were significantly associated with shortening of patient survival. The analysis of RRM1 (-37C>A) more than ERCC1 (19007C>T) polymorphism may be a promising tool in the qualification of NSCLC patients for chemotherapy containing platinum compounds and gemcitabine.
铂类化疗联合第三代药物（如吉西他滨）是治疗晚期不可切除非小细胞肺癌（NSCLC）患者的有效一线治疗方案，此类患者无 EGFR 突变。细胞抑制剂的作用机制是 DNA 扭曲。ERCC1 和 RRM1 是参与 DNA 修复的关键蛋白，因此它们可能是导致治疗无效的原因。我们研究了 ERCC1（19007C>T）和 RRM1（-37C>A）多态性是否影响 62 例接受铂类和吉西他滨化疗的 NSCLC 患者的化疗反应和生存。采用 PCR-RFLP 方法在从 PBL 中分离的 DNA 中评估单核苷酸多态性（SNP）。ERCC1 基因型与治疗反应（p=0.581，χ2=1.09）和患者总生存（OS）之间无统计学显著关系。与 AA 或 CC 基因型携带者相比，RRM1 AC 基因型携带者疾病进展更为频繁（p=0.019，χ2=5.473）。与其他基因型组合相比，携带 ERCC1/RRM1TT/CC 基因型组合的患者疾病控制更为频繁（p=0.047，χ2=3.95）。RRM1 中 AA 或 CC 基因型携带者的无进展生存概率（p=0.0001，HR=0.39，95%CI，0.22-0.70）和 OS 概率（p=0.0104，HR=0.39，95%CI，0.18-0.82）显著高于 AC 基因型携带者。在 Cox 回归模型中，较差的表现状态（p=0.0016，HR=4.78，95%CI，1.82-12.56）、RRM1 基因的 AC 基因型（p=0.0414，HR=2.47，95%CI，1.04-5.87）、缺乏先前的手术治疗（p=0.0425，HR=4.71，95%CI，1.06-20.92）和缺乏后续治疗线（p=0.0127，HR=3.23，95%CI，1.29-8.11）与患者生存时间缩短显著相关。分析 RRM1（-37C>A）而非 ERCC1（19007C>T）多态性可能是一种有前途的工具，可用于鉴定接受含铂化合物和吉西他滨化疗的 NSCLC 患者。
