Chua W, Goldstein D, Lee C K, Dhillon H, Michael M, Mitchell P, Clarke S J, Iacopetta B
Department of Medical Oncology, Sydney Cancer Centre, Concord Repatriation General Hospital, Sydney, NSW, Australia.
Br J Cancer. 2009 Sep 15;101(6):998-1004. doi: 10.1038/sj.bjc.6605239. Epub 2009 Aug 11.
To investigate three genetic alterations (TP53 mutation, Kras mutation and microsatellite instability (MSI)) and three polymorphisms (methylene tetrahydrofolate reductase (MTHFR) C677T, excision repair cross complementing group 1 (ERCC1)-118 and X-ray repair cross complementing group 1 (XRCC1)-399) for their ability to predict response, survival and toxicity to FOLFOX first line chemotherapy in the treatment of metastatic colorectal cancer (mCRC).
Tumour tissues from 118 mCRC patients who underwent FOLFOX treatment from three successive phase II trials were evaluated for mutations in TP53 (exons 5-8) and Kras (codons 12 and 13) and for MSI using PCR-based analysis. Genotyping for common single nucleotide polymorphisms in the MTHFR (codon 677), ERCC1 (codon 118) and XRCC1 (codon 399) genes was also carried out using PCR techniques. These genetic markers were correlated with clinical response, survival and toxicity to treatment.
Patients with the T allele of ERCC1-118 showed significantly worse progression-free survival in univariate analysis (HR=2.62; 95% CI=1.14-6.02; P=0.02). None of the genetic alterations or polymorphisms showed significant association with clinical response to FOLFOX. The MTHFR, ERCC1 and XRCC1 polymorphisms showed no associations with overall haematological, gastrointestinal or neurological toxicity to FOLFOX, although MTHFR 677 TT genotype patients showed a significantly higher incidence of grade 3 or 4 diarrhoea (26%) compared with CC or CT genotype patients (6%, P=0.02).
The ERCC1-118 and MTHFR C677T polymorphisms were associated with progression and severe diarrhoea, respectively, after FOLFOX treatment in mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.
研究三种基因改变（TP53突变、Kras突变和微卫星不稳定性（MSI））以及三种多态性（亚甲基四氢叶酸还原酶（MTHFR）C677T、切除修复交叉互补基因1（ERCC1）-118和X射线修复交叉互补基因1（XRCC1）-399）预测转移性结直肠癌（mCRC）一线FOLFOX化疗疗效、生存情况及毒性的能力。
对来自三项连续II期试验中接受FOLFOX治疗的118例mCRC患者的肿瘤组织进行TP53（外显子5-8）和Kras（密码子12和13）突变以及MSI的评估，采用基于PCR的分析方法。还使用PCR技术对MTHFR（密码子677）、ERCC1（密码子118）和XRCC1（密码子399）基因常见单核苷酸多态性进行基因分型。将这些基因标志物与临床疗效、生存情况及治疗毒性进行关联分析。
在单因素分析中，携带ERCC1-118 T等位基因的患者无进展生存期显著更差（HR=2.62；95%CI=1.14-6.02；P=0.02）。没有基因改变或多态性与FOLFOX的临床疗效显著相关。MTHFR、ERCC1和XRCC1多态性与FOLFOX的总体血液学、胃肠道或神经毒性无关联，尽管MTHFR 677 TT基因型患者3或4级腹泻的发生率（26%）显著高于CC或CT基因型患者（6%，P=0.02）。
在mCRC中，ERCC1-118和MTHFR C677T多态性分别与FOLFOX治疗后的疾病进展和严重腹泻相关。尽管我们的研究结果需要在大型前瞻性研究中得到证实，但它们强化了个体基因变异可实现化疗个体化选择以优化临床结局的概念。
