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晚期结直肠癌(metastatic colorectal cancer,mCRC)给予一线化疗联合贝伐珠单抗可使病人的生存获益,目前尚无确切的生物标志物用于疗效预测[1]。贝伐珠单抗属人源性血管内皮生长因子(VEGF)抑制剂,具有抗转移器官血管生成的作用[2]。存在KRAS基因突变提示mCRC病人复发转移的风险较高,将其作为生物标志物用于预测贝伐珠单抗抗VEGF的作用尚存争议[3]。本研究对mCRC病人给予一线化疗联合贝伐珠单抗治疗,探讨KRAS基因状态对疗效的预测价值。现作报道。
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入组的216例mCRC病人,分别采用ARMS法对163例、Sanger测序法对53例病人的KARS基因进行检测。检测出KRAS基因突变型79例(36.6%),其中ARMS法61例,Sanger法18例;主要突变位点是第12位密码子(64.6%,51/79)和第13位密码子(32.9%,26/79);KRAS基因野生型137例(ARMS法102例,Sanger法35例;63.4%);2组年龄、性别、原发部位、ECOG评分、治疗情况及转移部位数差异均无统计学意义(P>0.05)。KRAS基因突变组低分化型多于中/高分化型,差异有统计学意义(P < 0.05)。KRAS基因突变型组转移至肺与肝多于KRAS基因野生型组(P < 0.05和P < 0.01)。KRAS基因突变型与野生型比较,低分化型多于中/高分化型,差异有统计学意义(P < 0.01)(见表 1)。
分组 n 年龄(x±s)/岁 男 女 ECOG评分 原发部位 肿瘤病理分型 治疗情况 转移部位 转移部位数 0~1级 2级 左半结肠 右半结肠 直肠 中/高分化腺癌 低分化腺癌 其他(未分化、鳞癌) 术后辅助化疗 初次暴露 肺 肝 淋巴结 腹膜 骨 膀胱 其他部位 ≥2 < 2 KRAS突变组 79 65.6±11.6 46(58.2) 33(41.8) 65(82.3) 14(17.7) 33(41.8) 21(26.6) 25(31.6) 21(26.6) 51(64.6) 7(8.8) 31(39.2) 48(60.8) 61(77.2) 59(74.7) 68(86.1) 25(31.6) 33(41.8) 23(29.1) 15(19.0) 39(54.7) 40(45.3) KRAS野生组 137 66.3±12.5 75(54.7) 62(45.3) 98(71.5) 39(28.5) 57(41.6) 45(32.8) 35(25.5) 53(38.7) 43(31.4) 41(29.9) 63(46.0) 74(54.0) 85(62.0) 76(56.5) 106(77.4) 41(29.9) 46(33.6) 41(29.0) 39(28.5) 63(46.0) 74(54.0) χ2 — 0.41* 0.25 3.13 1.05 24.82 1.12 5.27 7.89 2.42 0.07 1.451 0.00 2.40 0.23 P — >0.05 >0.05 >0.05 >0.05 < 0.01 >0.05 < 0.05 < 0.01 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 *示t值 表 1 2组一般临床资料比较[n;百分率(%)]
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给予一线化疗联合贝伐珠单抗的化疗方案,KRAS基因突变组总体RR为34.2%,KRAS基因野生型组总体RR为45.2%,2组总体RR差异无统计学意义(χ2=2.494,P>0.05)。KRAS基因突变组和基因野生型组的PFS分别为(9.7±3.6)月和(10.3±3.4)月,2组PFS差异无统计学意义(t=1.223,P>0.05)。KRAS基因突变组比基因野生型组OS减少,分别为(16.5±3.5)月和(17.3±3.4)月,但差异无统计学意义(t=1.648,P>0.05)。Cox生存分析模型显示,KRAS基因突变不能作为PFS(风险比0.967,95%CI=0.731~1.358,t=0.193,P>0.05)和OS(风险比0.533,95%CI=0.238~1.352,t=0.161,P>0.05)的预后因素。
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给予一线化疗联合贝伐珠单抗治疗,KRAS基因突变型组与KRAS基因野生型组比较,病人出现发热、消化道反应、疲乏感、蛋白尿、骨髓抑制等不良反应情况类似,差异均无统计学意义(P>0.05)(见表 2)。
分组 n 发热 消化道反应 疲乏感 蛋白尿 高血压 鼻出血 脱发 骨髓抑制 KRAS突变组 79 65(82.3) 70(88.6) 29(36.7) 10(12.7) 13(16.5) 7(8.9) 53(67.1) 65(82.3) KRAS野生组 137 109(79.6) 120(87.6) 45(32.8) 20(14.6) 21(15.3) 11(8.0) 89(65.0) 110(80.3) χ2 — 0.236 0.049 0.332 0.158 0.048 0.045 0.101 0.129 P — >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 表 2 2组不良反应比较[n;百分率(%)]
KRAS基因状态对晚期结直肠癌一线化疗联合贝伐珠单抗疗效的预测价值
Predictive value of KRAS gene status on the effects of the first-line chemotherapy combined with bevacizumab treating metastatic colorectal cancer
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摘要:
目的研究KRAS基因状态对晚期结直肠癌(mCRC)给予一线化疗联合贝伐珠单抗疗效的预测价值。 方法选取mCRC病人216例,进行KRAS基因检测,给予一线化疗联合贝伐珠单抗的治疗方案。拟定4~8周期化疗。每4周期化疗后,通过结肠镜、腹部B超、增强CT等检查,根据实体瘤疗效评价标准(RECIST 1.0),观察KRAS基因突变状态与治疗的应答率(RR)、无进展生存时间(PFS)和总生存时间(OS)的相互关系。 结果mCRC病人中34.2%存在KRAS基因突变。KRAS基因突变组转移至肺与肝多于KRAS基因野生组(P < 0.05和P < 0.01)。KRAS基因突变型与野生型比较,低分化型多于中/高分化型(P < 0.01)。2组总体RR、PFS差异均无统计学意义(P>0.05)。KRAS基因突变组比基因野生型组OS减少,但差异无统计学意义(P>0.05)。2组出现中性粒细胞减少、消化道反应、疲乏感、蛋白尿等不良反应情况类似(P>0.05)。Cox生存分析模型显示,KRAS基因突变不能作为PFS和OS的预后因素(P>0.05)。 结论mCRC给予一线化疗联合贝伐珠单抗治疗,KRAS基因突变状态对疗效尚无预测作用。 Abstract:ObjectiveTo investigate the predictive value of KRAS gene status on the effects of the first-line chemotherapy combined with bevacizumab treating metastatic colorectal cancer(mCRC). MethodsKRAS gene in 216 patients with mCRC was detected, and the patients were treated with the first-line chemotherapy combined with bevacizumab for 4~8 cycles.After every 4 cycles of chemotherapy, the patients were detected using colonoscopy, abdominal B-ultrasound and enhanced CT.The relationships between the mutation status of the KRAS gene, and response rate(RR), pogression free survival(PFS), total survival(OS) in all patients were analyzed according to the evaluation criteria of solid tumor efficacy. ResultsKRAS gene mutations were found in 34.2% of patients with mCRC.The number of patients with tumor transferring to the lung and liver in KRAS gene mutation group was more than that in KRAS gene wild-type group(P < 0.05 and P < 0.01).Compared to the KRAS gene wild-type group, the case of low differentiation type tumor in KRAS gene mutation group was more than that of the medium/high differentiation type tumor(P < 0.01).The differences of the RR and PFS between two groups were not statistically significant(P>0.05).The OS in KRAS gene mutation group decreased compared to the wild-type group, but the difference of which between two groups was not statistically significant(P>0.05).The neutropenia, gastrointestinal reaction, fatigue, proteinuria and other adverse reactions in two groups were similar.The Cox survival analysis model showed that the KRAS gene mutation was not set as a prognostic factor of PFS and OS(P>0.05). ConclusionsThe mutation status of the KRAS gene does not play a prognostic role in mCRC patients treated with the first-line chemotherapy combined with bevacizumab. -
Key words:
- colorectal neoplasms /
- KRAS gene /
- bevacizumab
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表 1 2组一般临床资料比较[n;百分率(%)]
分组 n 年龄(x±s)/岁 男 女 ECOG评分 原发部位 肿瘤病理分型 治疗情况 转移部位 转移部位数 0~1级 2级 左半结肠 右半结肠 直肠 中/高分化腺癌 低分化腺癌 其他(未分化、鳞癌) 术后辅助化疗 初次暴露 肺 肝 淋巴结 腹膜 骨 膀胱 其他部位 ≥2 < 2 KRAS突变组 79 65.6±11.6 46(58.2) 33(41.8) 65(82.3) 14(17.7) 33(41.8) 21(26.6) 25(31.6) 21(26.6) 51(64.6) 7(8.8) 31(39.2) 48(60.8) 61(77.2) 59(74.7) 68(86.1) 25(31.6) 33(41.8) 23(29.1) 15(19.0) 39(54.7) 40(45.3) KRAS野生组 137 66.3±12.5 75(54.7) 62(45.3) 98(71.5) 39(28.5) 57(41.6) 45(32.8) 35(25.5) 53(38.7) 43(31.4) 41(29.9) 63(46.0) 74(54.0) 85(62.0) 76(56.5) 106(77.4) 41(29.9) 46(33.6) 41(29.0) 39(28.5) 63(46.0) 74(54.0) χ2 — 0.41* 0.25 3.13 1.05 24.82 1.12 5.27 7.89 2.42 0.07 1.451 0.00 2.40 0.23 P — >0.05 >0.05 >0.05 >0.05 < 0.01 >0.05 < 0.05 < 0.01 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 *示t值 表 2 2组不良反应比较[n;百分率(%)]
分组 n 发热 消化道反应 疲乏感 蛋白尿 高血压 鼻出血 脱发 骨髓抑制 KRAS突变组 79 65(82.3) 70(88.6) 29(36.7) 10(12.7) 13(16.5) 7(8.9) 53(67.1) 65(82.3) KRAS野生组 137 109(79.6) 120(87.6) 45(32.8) 20(14.6) 21(15.3) 11(8.0) 89(65.0) 110(80.3) χ2 — 0.236 0.049 0.332 0.158 0.048 0.045 0.101 0.129 P — >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 -
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