Prospective evaluation of fluorouracil chemotherapy based on the genetic makeup of colorectal cancer.
Prospective evaluation of fluorouracil chemotherapy based on the genetic makeup of colorectal cancer.
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基于结直肠癌基因组成的氟尿嘧啶化疗的前瞻性评价。
DOI：
10.1136/gut.2005.085274
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发表时间：
2006
期刊：
影响因子：
24.5
通讯作者：
Carethers,JM
中科院分区：
文献类型：
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作者：
Carethers,JM
目前治疗晚期结肠癌患者的金标准是以5-氟尿嘧啶（5-FU）为基础的化疗方案。1该标准基于使用5-FU和左旋咪唑的令人信服的临床试验，并证明了TNM III期（Dukes-Aston Collier C期）结肠癌患者的生存益处。2-4虽然没有治疗II期患者的既定标准，但一些II期患者确实接受了5-FU化疗，尽管该阶段结肠癌的自然史在超过70%的五年生存率方面是合理有利的。1直肠癌患者可接受II期或III期疾病的新辅助或辅助化疗，因为这两个肿瘤阶段的治疗均有利于患者生存。1 I期结直肠癌患者不接受5-FU治疗，因为切除肿瘤后预后良好，IV期患者可接受5-FU缓解。总体而言，使用基于5-FU的化疗的决定完全基于患者就诊时的结直肠癌分期。在过去的十年里，我们对结直肠癌的遗传和生物学行为有了卓有成效的了解，我们在这方面的知识仍在增长。结直肠癌是一种遗传性疾病，肿瘤细胞基因组的变化有利于肿瘤的生长和远程扩散。从遗传性非息肉病性结直肠癌（HNPCC或Lynch综合征）中了解到的知识，其中在编码DNA错配修复（MMR）蛋白的基因中发生种系突变，发现约15%的散发性结直肠癌缺乏完整的MMR，这是由于MMR蛋白hMLH 1的表观遗传失活而没有遗传突变。5因此，散发性结直肠癌可以分为两组：MMR熟练（即表达MMR系统所有组分的癌症）和MMR缺陷（即缺乏MMR系统组分的癌症，如hMLH 1，并表现出微卫星不稳定性，MMR功能丧失的标志物）。完整的DNA MMR将修复DNA聚合酶的错误，以保持复制DNA的保真度。此外，MMR系统可以识别嵌入或掺入DNA的某些化疗剂，并且可能是执行细胞死亡的重要触发因素。6-9由于MMR缺陷，缺乏聚合酶错误的修复，受影响的细胞积累了可能驱动肿瘤发生的突变。重要的是，MMR缺陷可能会阻止DNA损伤化疗的识别，从而启动该试剂的细胞杀伤。8 11 12 MMR缺陷型肿瘤的生物学行为与MMR活性型肿瘤相比存在差异。MMR缺陷型肿瘤更可能位于近端（右侧）结肠，并且在组织学上更可能显示粘蛋白的存在，具有周围淋巴反应，并且组织学分级较差。尽管组织学分级较差，但有证据表明MMR缺陷型肿瘤患者的生存预后更好。这在50岁以下的MMR缺陷肿瘤患者中尤其明显，13但在一些研究中也延伸到老年人。14 15汇集多项研究证实了MMR缺乏与患者生存之间的关系，与MMR缺乏相关的总生存的综合风险比为0.65（95%置信区间为0.59-0.71）。16事实上，MMR缺陷型肿瘤患者的预后可能优于MMR熟练型肿瘤患者，这一事实混淆了一些原始的...
The current gold standard for treat-ing patients with advanced colon cancer is chemotherapy with 5-fluorouracil (5-FU) based regimens. 1 This standard is based on compelling clinical trials utilising 5-FU and levamisole, and demonstrating a survival benefit for patients with TNM stage III (Dukes-Aston Collier stage C) colon cancer. 2–4 Although there is no set standard for treating stage II patients, some stage II patients do receive 5-FU chemotherapy, albeit the natural history of this stage of colon cancer is reasonably favourable at more than 70% five year survival. 1 Patients with rectal cancer may receive neoadjuvant or adjuvant chemotherapy for stage II or III disease, as treatment in both of these stages of tumour benefit patient survival. 1 Stage I patients with colorectal cancer do not receive 5-FU as their prognosis is excellent with removal of the tumour, and stage IV patients may receive 5-FU for palliation. Overall, determination for use of 5-FU based chemotherapy is completely based on the stage of the colorectal cancer in the patient at presentation. The past decade has brought a fruitful understanding of the genetic and biological behaviour of colorectal cancer, and our knowledge is still growing in this aspect. Colorectal cancer is a genetic disease, with changes in the genome of the tumour cell that are favourable for the tumour’s growth and remote spread. Taking knowledge learned from hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) in which a germline mutation occurs in genes that encode proteins for DNA mismatch repair (MMR), it was discovered that approximately 15% of sporadic colorectal cancers lack intact MMR due to the epigenetic inactivation of the MMR protein hMLH1 without genetic mutation. 5 Sporadic colorectal cancers can thus be categorised into two groups: those that are MMR proficient (that is, cancers that express all components of the MMR system) and those that are MMR deficient (that is, cancers that lack a component of the MMR system, such as hMLH1, and exhibit microsatellite instability, a marker for loss of MMR function). Intact DNA MMR will repair DNA polymerase mistakes to maintain the fidelity of replicating DNA. Additionally, the MMR system can recognise certain chemotherapeutic agents that intercalate or get incorporated into DNA, and may be an important trigger to execute cell death. 6–9 With MMR deficiency, repair of polymerase mistakes are lacking and affected cells accumulate mutations that may drive tumorigenesis. 5 10 Importantly, MMR deficiency may prevent the recognition of DNA damaging chemotherapy to initiate cell killing by that agent. 8 11 12 There are differences in the biological behaviour of MMR deficient tumours compared with MMR proficient tumours. MMR deficient tumours are more likely to be located in the proximal (right) colon, and on histology are more likely to demonstrate the presence of mucin, have a surrounding lymphoid reaction, and be of poor histological grade. 5 Despite this poor histological grade, there is some evidence that patients with MMR deficient tumours have a more favourable prognosis for survival. This has been particularly shown in patients with MMR deficient tumours who were under the age of 50 years, 13 but extends to older ages as well in some studies. 14 15 Pooling multiple studies confirmed the relationship between MMR deficiency and patient survival, with a combined hazard ratio for overall survival associated with MMR deficiency of 0.65 (95% confidence interval 0.59–0.71). 16 The fact that patients with MMR deficient tumours may have a better prognosis over patients with MMR proficient tumours confounded some original …