KRAS、FCGR、CYP3A5与CYP1A1检测对转移性结直肠癌化学靶向药物临床疗效预测作用的研究

Study of genetic detection of KRAS, FCGR, CYP3A5 and CYPIA1 in predicting clinical outcomes of chemotherapy/target therapy in metastatic colorectal cancer （mCRC）

目的研究鼠类肉瘤病毒癌基因同源基因（KRAS）、FCG受体（FCGR）、细胞色素P450—3A5（CYP3A5）、CYP1A1基因与转移性结直肠癌（mCRC）患者化疗疗效的动态关系，探讨其对临床疗效的预测作用。方法收集采用西妥昔单抗（C225）联合卡培他滨联合奥沙利铂（CapeOx）化疗，且治疗前实施KRAS基因检测所证实的KRAS野生型结直肠癌患者12例，对每例病例实施FCGR、CYP3A5、CYP1A1基因的突变检测，运用免疫组织化学染色法（sP）检测第10号染色体缺失的磷酸酶张力蛋白同源物基因（PTEN）在结直肠癌组织与对应的癌旁组织中的表达情况，分析FCGR、CYF3A5、CYP1A1突变和PTEN表达与生存期的关系。结果12例KRAS野生型患者中，检测到FCGR的突变率为16．7％，CYPA5的突变率为25％，CYPIAI的突变率为16．7％。PTEN主要在细胞核内表达，呈黄褐色；在癌旁组织内完全表达，表达率为100％；在病灶组织内的表达率为41．7％；PTEN在病灶组织中表达降低或缺失。KRAS、FCGR、CYP3A5、CYP1A1均为野生型的患者对C225联合CapeOx化疗的有效（CR＋PR）反应率为80％，但存在FCGR、CYP3A5、CYP1A1突变患者的有效（CR＋PR）反应率分别为0、33．6％以及50．0％（P〈0．05）。PTEN表达阳性的患者有效（CR＋PR）反应率为50％，明显高于PTEN表达阴性的患者（有效反应率37．5％，P〈0．05）。KRA^FCGR／CYP3AS／CYP1A1野生型患者无进展生存期、总生存期分别为15．56、25．03个月，明显大于FCGR、CYP3A5、CYP1A1突变患者无进展生存期、总生存期的8．12、19．21个月（均P〈0．05）。PTEN阳性表达患者无进展生存期、总生存期分别为9．13、24．25个月，明显大于PTEN阴性表达患者无进展生存期、总生存期的7．87、18．74个月（均P〈0．05）。结论FCGR、CYP3A5、CYP1A1突变和PTEN表达的缺失明显影响C225联合CapeOx化疗的临床治疗效果及生存期，可用于mCRC临床疗效及预后的预测。

Objective To investigate the predictive and prognostic value of genetic detection of Kirsten rat sarcoma viral oncogene homolog（ KRAS）, Fc gamma receptors （FCGR）, cytochrome P450 3A5 （CYP＇3AS） and CYP1A1 in patients with metastatic colorectal cancer （mCRC） receiving C225 combined with CapeOx chemotherapy. Methods Twelve KRAS wild-type （WT） mCRC patients were selected recelying C225 （cetuximab） combined with CapeOx （capecitabine/oxaliplatin） chemotherapy. KRAS, FCGR, CYP3AS, CYP1A1 gene mutation were detected before treatment. The expressions of phosphatase and ten- sin homolog deleted on chromosome ten （PTEN） were detected in colorectal cancer tissues and the corre- sponding adjacent tissues expression with immunohistochemical staining （SP method）. The relationship be- tween FCGR, CYP3A5, CYP1A1 mutation, and PTEN expression and survival time were analyzed. Results The mutation rates of FCGR, CYP3A5, and CYP1A1 were 16. 7% （2/12）, 25% （3/12） and 16. 7% （2/12） in 12 patients with KRAS WT, respectively. PTEN was expressed mainly in the nucleus in yellow- ish brown. The rates of expression in the tissue adjacent to the cancer and in the tumor tissue were 100% （12/12） and 41.7% （5/12） , respectively. PTEN expression in tumor tissue was reduced or absent. The study indicated that the objective response rate [ complete response ＋ partial response （ CR ＋ PR） ] was 80% in patients whose KRAS, FCGR, CYP3AS, and CYP1A1 were all in wild type, the CR ＋ PR rates in FCGR, CYP3AS, and CYP1A1 gene mutation group were 0, 33.6% and 50%. The objective response rates of patients with PTEN expression or null were 50% and 37.5% , respectively （ P 〈 0. 05 ）. The progression free survival （PFS） with KRAS/FCGR/CYP3AS/CYP1A1 wild type or mutation were 15.56 or 8.12 months （P 〈0. 05）. The overall survival （OS） with wild type or mutation of KRAS/FCGR/CYP3AS/ CYP1 A1 were 25.03 or 19. 21 months （P 〈 0. 05 ）. The PFSs of positive or negative expression of PTEN in patients were 9. 13 or 7.87 months （P 〈 0. 05 ）, and the OSs of positive or negative expression of PTEN in patients were 24. 25 or 18.74 months （P 〈0. 05）. Conclusions FCGR, CYP3A5 and CYP1A1 mutations and PTEN expression null both have been associated with resistance to cetuximab in mCRC patients. FCGR, CYP3AS, CYP1 A1 and PTEN can be served as the predictive biomarkers for the response to cetuximab.