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Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance
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摘要: 增殖失控是恶性肿瘤的重要特征之一。细胞周期依赖性激酶4/6(cyclin-dependent kinase 4/6, CDK4/6)抑制剂能作用于各种原因导致的过度活化的CDK4/6，恢复正常细胞周期，并可通过增强免疫、改变肿瘤微环境等发挥抗肿瘤作用。目前，CDK4/6抑制剂在激素受体阳性乳腺癌治疗中取得了良好疗效，已被批准联合内分泌治疗作为此类肿瘤的一线治疗方案，在其他肿瘤中的应用亦逐渐开展，疗效有待验证。对CDK4/6抑制剂天然或获得性耐药是影响其疗效的重要因素，目前激素受体阳性(主要为雌激素受体阳性)能较为准确预测内分泌联合CDK4/6抑制剂治疗的反应性，其他标志物需进一步探索和验证。本文对CDK4/6抑制剂治疗恶性肿瘤的作用机制、应用现状及耐药机制进行梳理和总结，并对当前CDK4/6抑制剂治疗乳腺癌尚存争议的临床决策问题作简要讨论。
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关键词:
- 细胞周期依赖性激酶4/6抑制剂 /
- 细胞周期调控 /
- 乳腺癌 /
- 治疗 /
- 耐药机制
Abstract: Uncontrolled cell proliferation is one of the important hallmarks of malignancies. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors act on CDK4/6 that is over activated by various causes. CDK4/6 inhibitors play anti-tumor roles by restoring normal cell cycle, enhancing anti-tumor immunity, and reforming tumor microenvironment. Currently, CDK4/6 inhibitors have been confirmed to be effective in hormone-receptor-positive breast cancer and were approved as the first-line treatment for this breast cancer in combination with endocrine therapy. Furthermore, CDK4/6 inhibitors have been gradually applied to the treatment of other tumors, but the efficacy remains to be evaluated. Natural or acquired resistance to CDK4/6 inhibitors is a major factor affecting their efficacy. However, at present, only hormone receptor-positive (mainly estrogen receptor-positive) can relatively accurately predict the responsiveness of CDK4/6 inhibitors in combination with endo- crine treatment, and other markers need to be further explored and verified in clinical studies. The mechanism of action, the status of application, and mechanisms of drug-resistance of CDK4/6 inhibitors in the treatment of malignancies were reviewed and summarized in this paper, and the controversy over clinical decision-making on the treatment of breast cancer with CDK4/6 inhibitors was briefly discussed. -
结肠癌是常见的消化道肿瘤，全球发病率以每年约2%的速度增长，而我国发病率的上升速度更为明显[1-2]。对于未出现远处转移的结肠癌患者，根治性手术是主要的治疗手段，其中已有淋巴结转移的Ⅲ期结肠癌患者更是一组与治疗密切相关的人群。近年来，腹腔镜结肠癌根治术发展迅速，不仅具有创伤小、恢复快等短期疗效优势，而且腹腔镜手术治疗结肠癌的长期生存率亦不劣于传统开腹手术[3-6]。但是，腹腔镜技术对于局部进展期结肠癌的肿瘤学疗效仅在既往研究中作为亚组分析，未见大宗病例报道。本研究旨在评价腹腔镜结肠癌根治性切除术治疗Ⅲ期结肠癌患者的临床疗效和长期预后。
资料和方法
临床资料
收集北京协和医院基本外科结直肠专业组2007年1月至2012年12月收治的Ⅲ期结肠癌手术患者资料，按手术方式分为腹腔镜组和开腹组。排除标准：(1)结肠癌因结肠穿孔或梗阻需要急诊手术；(2)多原发性癌。
所有患者术前通过结肠CT重建或者结肠镜明确肿瘤定位，根据胸部X线片、腹部超声或CT进行分期。术后病理均证实为TNM Ⅲ期结肠腺癌，均给予术后6个月的辅助化疗，方案为奥沙利铂+亚叶酸/5-氟尿嘧啶(FOLFOX-4)或奥沙利铂+卡培他滨(XELOX)。局部复发定义为影像学或组织学检查确定肿瘤位于吻合口及其附近肠管、Trocar孔、切口和盆壁。转移定义为肿瘤位于腹膜和肝脏、肺、脑等其他远隔组织器官。
手术方法
对于肿瘤部位相同的患者，腹腔镜组和开腹组肠管切除长度及淋巴结清扫范围一致。肿瘤位于盲肠及升结肠时行右半结肠切除术，根部结扎回结肠血管和右结肠血管或结肠中血管右支，清扫此区域内淋巴结。肿瘤位于横结肠中部时行横结肠切除术，根部结扎中结肠血管并清扫淋巴结。肿瘤位于降结肠时行左半结肠切除术，根部结扎肠系膜下血管，清扫相应区域淋巴结。肿瘤位于乙状结肠时行乙状结肠切除术，根部结扎乙状结肠血管并清扫相应区域淋巴结。腹腔镜手术行体外或体内(乙状结肠癌时)端-端肠吻合术。
随访情况
术后2年内每3个月随访一次，复查胸部X线、腹部B超、血癌胚抗原和CA19-9，每年复查1次结肠镜，并行胸腹盆增强CT代替X线和B超检查；术后2~5年每6个月随访一次，5年后每年随访一次。复查项目如有异常则进一步行全身骨扫描、MRI/CT、PET-CT等检查以明确复发或转移。本组患者末次随访时间为2014年6月。
统计学处理
采用SPSS 17.0软件进行数据分析。计数资料用卡方检验或者Fisher精确检验。计量资料采用均值±标准差表示，组间比较采用两独立样本t检验或秩和检验。用Kaplan-Meier法计算患者5年总体生存率、无病生存率，用Log-rank法进行组间比较。由手术结束累积至肿瘤死亡的时间为总生存时间；由手术结束累积至复发、转移或非肿瘤死亡的时间为无病生存时间。以双侧检验P＜0.05为差异有统计学意义。
结果
患者临床病理特征
共纳入169例Ⅲ期结肠癌患者，其中腹腔镜组75例，开腹组94例。两组患者在性别、年龄、手术方式、肿瘤分化程度、肿瘤分期上差异均无统计学意义(P＞0.05)。腹腔镜组手术时间显著长于开腹组[(171.3±43.2)min比(132.7±60.4)min，P＜0.001]，但术中出血量显著少于开腹组[(86.3±61.7)ml比(109.8±74.6)ml, P=0.030]。腹腔镜组检出淋巴结数目显著多于开腹组(23.3±12.2比19.3±9.6, P=0.022)(表 1)。
表 1 Ⅲ期结肠癌患者临床病理特征组别 性别(例) 年龄
(x±s，岁)术式(例) 手术时间
(x±s，min)出血量
(x±s，ml)组织分化程度(例) 淋巴结获取数目
(x±s)T分期(例) N分期(例) TNM分期(例) 男 女 右半结肠
切除术横结肠
切除术左半结肠
切除术乙状结肠
切除术高 中 低 T2 T3 T4 N1 N2 Ⅲa Ⅲb Ⅲc 腹腔镜组(n=75) 39 36 63.6±13.3 45 3 5 22 171.3±43.2 86.3±61.7 16 47 12 23.3±12.2 4 60 11 51 24 3 56 16 开腹组(n=94) 53 41 63.8±12.6 43 5 13 32 132.7±60.4 109.8±74.6 10 68 16 19.3±9.6 3 82 9 60 34 2 67 25 P值 0.680 0.929 0.341 ＜0.001 0.030 0.157 0.022 0.441 0.686 0.596 患者局部复发、转移情况及5年生存率
共纳入169例Ⅲ期结肠癌患者，其中腹腔镜组75例，开腹组94例。两组患者在性别、年龄、手术方式、肿瘤分化程度、肿瘤分期上差异均无统计学意义(P＞0.05)。腹腔镜组手术时间显著长于开腹组[(171.3±43.2)min比(132.7±60.4)min，P＜0.001]，但术中出血量显著少于开腹组[(86.3±61.7)ml比(109.8±74.6)ml, P=0.030]。腹腔镜组检出淋巴结数目显著多于开腹组(23.3±12.2比19.3±9.6, P=0.022)(表 1)。
腹腔镜组和开腹组患者的中位随访时间分别为38个月(6~88个月)和32.1个月(8~88.7个月)，差异无统计学意义(P=0.748)。腹腔镜组5例(6.7%)术后局部复发，开腹组8例(8.5%)术后局部复发，两组差异无统计学意义(P=0.876)。腹腔镜组和开腹组分别有21例(28%)和29例(30.9%)患者发生术后远处转移(P=0.815)(表 2)。
表 2 Ⅲ期结肠癌患者术后复发、转移情况(例)组别 局部复发 远处转移 吻合口 腹腔内 总计 肝 骨 肺 脑 卵巢 腹膜后 总计 腹腔镜组(n=75) 0 5 5 15 1 3 1 0 1 21 开腹组(n=94) 1 7 8 21 2 5 0 1 2 29 本组患者5年总生存率和5年无病生存率分别为63.9%和58.7%。其中腹腔镜组和开腹组患者5年累积总生存率分别为73.6%和58.8%(P=0.317)(图 1)；5年累积无病生存率分别为61.6%和56.3% (P=0.544)，差异均无统计学意义(图 2)。
讨论
早在九十年代初腹腔镜技术就开始应用于结肠癌手术中。初期由于腹腔镜结肠癌切除术后切口肿瘤复发以及Trocar孔种植发生率较高[7]，使得人们对于腹腔镜结肠癌手术的肿瘤学安全性产生了疑虑。但是，随着腹腔镜技术的进步和器械的更新，腹腔镜技术在结肠癌治疗中的应用也越来越广泛，其长期的肿瘤学疗效也逐渐被接受[4-6]。
根治性结肠癌切除术至少应该做到：(1)完整系膜切除(complete mesocolic excision, CME)原则以及系膜根部淋巴结的清扫；(2)操作过程中不能造成肿瘤细胞的转移或播散。对于Ⅲ期结肠癌，手术的根治性对于提高预后尤为重要，大量研究也显示，Ⅲ期结肠癌患者的生存率随着检出淋巴结数目的增多而提高[8-10]。本研究中，腹腔镜组获取淋巴结总数为(23.3±12.2)个，而开腹组获取的淋巴结数目为(19.3±9.6)个，两组之间的差异具有统计学意义，检出淋巴结数目与以往文献报道相似[5, 11]。由此可见腹腔镜手术在区域淋巴结清扫上更优于开腹手术，这可能是导致5年总生存率优于开腹手术(73.6%比58.8%)的原因之一，虽然这种差异还没有达到统计学意义。
两组患者的局部复发/远处转移率相当(34.7%比39.4%), 其中开腹组有1例吻合口复发，其余均为腹腔内复发。本研究中两组均无手术切口或Trocar孔复发发生。曾有学者认为腹腔镜操作中气体流动、器械进出和更换等可能会造成脱离的肿瘤细胞种植于穿刺孔而降低腹腔镜结肠癌切除术的肿瘤学安全性[7]。可见随着腹腔镜技术的进步，避免结肠损伤以及常规使用切口保护装置可以有效减少腹腔镜手术中切口或者Trocar孔的复发[12]。
既往研究针对Ⅲ期结肠癌亚组的长期生存分析显示，腹腔镜手术组的5年总生存率(P=0.048)、无病生存率(P=0.048)和肿瘤相关生存率(P=0.02)均显著高于开腹手术组[13]。而在其他研究中，Ⅲ期结肠癌腹腔镜手术组的5年总生存率和无病生存率为72%~77.5%和67%~74.2%, 略高于开腹手术组，但差异无统计学意义[5, 11, 14]。在本研究中，腹腔镜组的5年总生存率和5年无病生存率均高于开腹手术组(73.6%比58.8%和61.6%比56.3%)，但是二者差异均无统计学意义，与文献报道结果相当。这一结果可能得益于腹腔镜手术能够获取更多的淋巴结。
综上，本研究显示，在Ⅲ期结肠癌根治性手术中，腹腔镜手术可以获得不劣于开腹手术的长期预后结果，腹腔镜技术是安全有效的。
作者贡献:唐辉负责文献检索、数据分析、示意图绘制、论文撰写；应红艳参与文献检索、数据分析、论文修改；白春梅提供修改建议并帮助修改论文。利益冲突 无 -
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