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Volume 44 Issue 5
May  2019
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Article Navigation >  Journal of Bengbu Medical College  > 2019,  44 > 5: (593-596)  

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Predictive value of KRAS gene status on the effects of the first-line chemotherapy combined with bevacizumab treating metastatic colorectal cancer

  • 1.

    Department of Oncology, Yanjiao People's Hospital, Sanhe Hebei 065201

  • 2.

    Department of Oncology, The Fourth Medical Center of PLA General Hospital, Beijing 100010

  • 3.

    Department of Internal Medicine, South Fort Development District Hospital, Tangshan Hebei 063300, China

  • Corresponding author: BAI Li, 838219106@qq.com ; 
  • Received Date: 2018-01-18
    Accepted Date: 2019-04-01
  • 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.
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  • [1] BOKEMEYER C, BONDARENKO I, HARTMAN JT, et al.Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer:the OPUS study[J].Ann Oncol, 2011, 22(7):1535. doi: 10.1093/annonc/mdq632
    [2] GARDE NOGUERA J, JANTUS-LEWINTRE E, GIL-RAGA M, et al.Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab:a retrospective analysis[J].Mol Clin Oncol, 2017, 6(3):403. doi: 10.3892/mco.2017.1149
    [3] GARCÍA-ALFONSO P, GRANDE E, POLO E, The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to KRAS status[J].Angiogenesis, 2014, 17(4):805. doi: 10.1007/s10456-014-9433-6
    [4] 朱晓丽, 蔡旭, 张玲, 等.中国结直肠癌患者中KRAS与BRAF基因突变特征及其临床病理相关性[J].中国病理学杂志, 2012, 41(9):584.
    [5] KIM ST, PARK KH, SHIN SW, et al. Dose KRAS mutation status affect on the effect of VEGF therapy in metastatic colon cancer patients?[J]. Cancer Res Treat, 2014, 46(1):48. doi: 10.4143/crt.2014.46.1.48
    [6] MAUGHAN TS, ADAMS RA, SMITH CG, et al.Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer:results of the randomised phase 3 MRC COIN trial[J].Lancet, 2011, 377(9783):2103. doi: 10.1016/S0140-6736(11)60613-2
    [7] VALE CL, TIERNEY JF, FISHER D, et al.Does anti-EGFR therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis[J].Cancer Treat Rev, 2012, 38(6):618. doi: 10.1016/j.ctrv.2011.11.002
    [8] PRICE TG, HARDINGHAM JE, LEE CK, et al.Impact of KRAS and BRAF Gene Mutation Status on Outcomes From the Phase Ⅲ AGITG MAX Trial of Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer[J].Clin Oncol, 2011, 29(19):2675. doi: 10.1200/JCO.2010.34.5520
    [9] HURWITZ HI, YI J, INCE W, et al.The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status:analysis of a phase Ⅲ study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer[J].Oncologist, 2009, 14(1):22. doi: 10.1634/theoncologist.2008-0213
    [10] NORGUET E, DAHAN L, GAUDART J, et al.Cetuximab after bevacizumab in metastatic colorectal cancer:is it the best sequence?[J].Dig Liver Dis, 2011, 43(11):917. doi: 10.1016/j.dld.2011.06.002
    [11] BASSO M, STRIPPOLI A, ORLANDI A, et al.KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastaticcolorectal cancer patients[J].Br J Cancer, 2013, 108(1):115. doi: 10.1038/bjc.2012.526
    [12] PRICE TJ, HARDINGHAM JE, LEE CK, et al.Impact of KRAS and BRAF gene mutation status on outcomes from the Phase Ⅲ AGITG MAX Trial of capecitabine alone or in Combination with bevacizumab and mitomycin in advanced colorectal cancer[J].J Clin Oncol, 2011, 29(19):2675. doi: 10.1200/JCO.2010.34.5520
    [13] BRUDVIK KW, KOPETZ SE, LI L, et al.Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases[J].Br J Surg, 2015, 102(10):1175. doi: 10.1002/bjs.2015.102.issue-10
    [14] KARAPETIS CS, KHAMBATA-FORD S, JONKER DJ, et al.KRAS mutations and benefit from cetuximab in advanced colorectal cancer[J].N Engl J Med, 2008, 359:1757. doi: 10.1056/NEJMoa0804385
    [15] REINACHER-SCHICK A, SCHULMANN K, MODEST DP, et al.Effect of KRAS codon13 mutations in patients with advanced colorectal cancer (advanced CRC) under oxaliplatin containing chemotherapy:results from a translational study of the AIO colorectal study group[J].BMC Cancer, 2012, 12(6):349.
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    沈阳化工大学材料科学与工程学院 沈阳 110142

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Predictive value of KRAS gene status on the effects of the first-line chemotherapy combined with bevacizumab treating metastatic colorectal cancer

    Corresponding author: BAI Li, 838219106@qq.com; 
  • 1. Department of Oncology, Yanjiao People's Hospital, Sanhe Hebei 065201
  • 2. Department of Oncology, The Fourth Medical Center of PLA General Hospital, Beijing 100010
  • 3. Department of Internal Medicine, South Fort Development District Hospital, Tangshan Hebei 063300, China
  • Received Date: 2018-01-18
  • Accepted Date: 2019-04-01
  • Available Online: 2019-05-15

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.

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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。

1.   资料与方法

    1.1.   一般资料

  • 选择2013年6月至2018年6月就诊的mCRC病人。mCRC诊断标准参照中华医学会肿瘤学分会“中国结直肠癌诊疗规范(2015版)”。所有病人均有病理或细胞学检查支持并签署知情同意。采用等位基因特异PCR扩增法(ARMS)及Sanger测序法对KARS基因突变进行检测。有216例行KRAS基因突变检测的mCRC病人入组。其中男129例，女87例；年龄35~76岁。

    • 1.2.   化疗方案

  • 根据mCRC病人的病史、影像学和病理检查结果等临床资料，无禁忌证者准予化疗。选择一线化疗(5-氟尿嘧啶、奥沙利铂、卡培他滨和伊立替康)联合贝伐珠单抗的治疗方案(FOLFOX/ FOLFIRI/CapeOx+贝伐珠单抗)。药物剂量及疗程根据具体给药方案制定。拟定为6周期化疗。每4周期化疗结束后，通过结肠镜、腹部B超、增强CT等检查项目，根据实体瘤疗效评价标准(RECIST 1.0)观察病情变化及不良反应。

    • 1.3.   临床观察指标及终点目标

  • 根据KRAS基因有无突变分为KRAS基因突变型组和KRAS基因野生型组。观察2组的原发肿瘤部位、ECOG评分、肿瘤病理分型、术后治疗情况、转移部位及转移部位数等项目有无差异。观察一线化疗联合贝伐珠单抗的反应率(response rate，RR)、无进展生存时间(progress free survival，PFS)和总生存时间(overall survival，OS)。比较2组治疗期间的不良反应。

    • 1.4.   统计学方法

  • 采用t检验、χ2检验、秩和检验及Cox比例风险模型。

2.   结果

    2.1.   一般临床资料的比较

  • 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

    • 2.2.   KRAS基因野生型组与突变组疗效终点比较

  • 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。

    • 2.3.   KRAS基因野生型组与突变型组治疗的主要不良反应比较

  • 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
3.   讨论

  • mCRC病人给予5-氟尿嘧啶、奥沙利铂、伊立替康、卡培他滨联合靶向制剂为基础的新辅助化疗方案，可使病人的生存时间从12个月增加到2年左右[4]。研究[5]发现，上皮生长因子受体(EGFR)和VEGF与肿瘤细胞的生长、存活、增殖和转移有关。VEGF和EGFR通路相互作用，Ras信号通路则增加VEGF的表达。KRAS蛋白是EGFR信号通路下游的小分子G蛋白，为EGFR信号通路的重要组成部分之一，30%~50%的mCRC在早期进展阶段可以检测到KRAS基因突变。KRAS基因突变后可以导致VEGF信号通路异常激活[6]。提示KRAS基因突变可能影响抗肿瘤血管生成的反应。近年来，已经确立KRAS基因及其下游信号通路在肿瘤发展中的重要性，对KRAS基因突变的生物学和临床作用的监测标志着mCRC治疗出现转折。在我们的研究中，216例mCRC病人进行KRAS基因突变检测，检测出KRAS基因突变型79例(36.6%)，KRAS基因野生型137例，KRAS基因野生型与基因突变型比较，年龄、性别、原发部位、ECOG评分及治疗情况相似，具有可比性。在一线化疗的基础上联合贝伐珠单抗治疗，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%。表明联合贝伐珠单抗的化疗方案可明显提高mCRC病人的反应率。2组治疗期间主要不良反应发生情况类似，对药物治疗的耐受性相似。KRAS基因突变组比野生型组更易转移至肺与肝。表明KRAS基因突变的mCRC病人易于出现转移，加重病情。KRAS基因突变型与野生型比较，低分化型多于中/高分化型。表明KRAS基因突变型恶性程度更高。研究[6]表明，mCRC病人给予抗EGFR药物(如西妥昔单抗和帕尼单抗)治疗，KRAS基因突变具有重要预测价值。贝伐珠单抗是人源性抗VEGF单克隆抗体，具有抑制血管生成的作用。目前，由于尚未发现适合的生物标志物推荐用于贝伐珠单抗治疗，将KRAS基因突变作为生物标志物预测贝伐珠单抗抗VEGF的作用仍存在争议。作为对治疗反应有预测作用的生物标志物，一般取决于宿主与肿瘤间的微环境、肿瘤独特的生物学特征、肿瘤自身特点等多个方面[7]。贝伐珠单抗的临床益处是否独立于KRAS基因状态尚不明确。

    mCRC发病与特定基因突变导致相关信号通路失调有关。RAS-RAF-MAPK、PI3K-AKT-mTOR两条信号通路，参与细胞的生长、分化、增殖过程。细胞信号通路中分子标志物的异常表达可导致通路的持续活化，在mCRC的发病中起重要作用。KRAS基因突变导致VEGF信号通路异常激活后，可不受VEGF上游蛋白的调控[8]。我们研究发现，KRAS基因突变组和基因野生型组的PFS分别为9.7个月和10.3个月，2组差异无统计学意义。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。在HURWITS等[9]研究中，受检标本的KRAS基因突变率分别为34%和29.5%。给予5-氟尿嘧啶、伊立替康福联合贝伐珠单抗的化疗方案(IFL)，KRAS基因突变状态与PFS的改善无关，但2组的RR有明显差异；此外，该研究的亚组分析表明，KRAS基因突变病人总PFS和OS较低。

    目前，KRAS基因突变状态对mCRC病人抗VEGF治疗的预测价值仍有争议。研究评估KRAS基因状态和生存率之间的关系，分析给予最佳支持治疗对预后的影响[10]。KRAS野生型或其他基因突变类型病人的OS差异无统计学意义。我们采用Cox生存分析模型研究结果显示，KRAS基因突变不能作为PFS和OS的预后因素。国外学者[11]也报道没有证据表明KRAS基因状态对含靶向药物治疗的mCRC病人具有预后价值，我们的研究结果与之类似。同样，PRICE等[12]研究报道表明，对于mCRC病人，KRAS基因突变状态不能用于预测OS及联合贝伐珠单抗治疗的预后观察。然而，BRUDVIK等[13]研究则得出相反结论。该研究共有3 439名病人进入了多变量分析，评价mCRC各阶段KRAS基因突变及对预后的影响。在KRAS基因的第12和13密码子可能的12个突变中，发现有8.6%病人第12密码子出现由甘氨酸到缬氨酸的基因突变，基因突变组的PFS和OS比野生型组有明显的统计学差异，且对Dukes′C肿瘤比Dukes′B肿瘤的影响更大。研究[14-15]表明，在排除了混杂因素后，KRAS基因突变状态与mCRC复发和死亡的风险增加有关，并对Duke′s C G12V突变病人的不良预后有重要的预测价值。

    综上所述，我们的研究表明，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。由于本研究仅对原发部位肿瘤进行KRAS基因状态检测，且不同基因检测方法存在一定的特异性及阳性率，可能影响结果的判断。因此，后续研究应扩大KRAS基因检测数量，统一基因检测的标准，对KRAS基因状态与贝伐珠单抗抗VEGF治疗的相互关系进行深入探索。

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