Tougeron David, Sha Dan, Manthravadi Sashidhar, Sinicrope Frank A
Authors' Affiliations: Departments of Medicine and Oncology, and Cancer Center, Mayo Clinic, Rochester, Minnesota.
Clin Cancer Res. 2014 Mar 1;20(5):1087-94. doi: 10.1158/1078-0432.CCR-13-2563. Epub 2013 Dec 10.
Abundant epidemiologic evidence indicates that regular and long-term use of aspirin is associated with a significant reduction in the incidence of colorectal cancer. The long duration of aspirin needed to prevent colorectal cancer is believed to be due to inhibition of precursor lesions known as adenomas, the recurrence of which is inhibited by aspirin in randomized trials. Aspirin intake has also been associated with a statistically significant improvement in patient survival after curative resection of colorectal cancer in large observational studies. In these cohorts, the survival benefit of aspirin was shown to depend upon the level of COX-2 expression in the primary colorectal cancer. More recent analysis of patient tumors from these observational cohorts suggests that the benefit of aspirin may be limited to specific molecular subtypes. Aspirin intake following colorectal cancer resection was associated with a significant improvement of survival in patients whose tumors carried mutant, but not wild-type, copies of the phosphoinositide 3-kinase (PI3KCA) gene, especially tumors that overexpressed COX-2. A mechanistic explanation is suggested by the finding that inhibition of COX-mediated prostaglandin E2 synthesis by aspirin attenuates PI3K signaling activity that is known to regulate cancer cell proliferation and survival. Aspirin has also been shown to reduce the incidence of colorectal cancers bearing wild-type, but not mutant alleles of the BRAF(V600E) oncogene. Although provocative, the potential utility of these molecular markers for predicting aspirin efficacy awaits prospective evaluation in clinical trials. If validated, these findings may support a personalized approach to using aspirin for the therapy of colorectal cancer.
大量流行病学证据表明，长期规律服用阿司匹林与结直肠癌发病率显著降低相关。预防结直肠癌所需的阿司匹林服用时长较长，这被认为是由于其对称为腺瘤的前驱病变具有抑制作用，在随机试验中，阿司匹林可抑制腺瘤复发。在大型观察性研究中，服用阿司匹林还与结直肠癌根治性切除术后患者生存率的统计学显著改善相关。在这些队列研究中，阿司匹林的生存获益显示取决于原发性结直肠癌中COX-2的表达水平。对这些观察性队列研究中患者肿瘤的最新分析表明，阿司匹林的获益可能仅限于特定分子亚型。结直肠癌切除术后服用阿司匹林与肿瘤携带磷酸肌醇3-激酶（PI3KCA）基因突变而非野生型拷贝的患者生存率显著改善相关，尤其是那些COX-2过表达的肿瘤。阿司匹林抑制COX介导的前列腺素E2合成可减弱已知调节癌细胞增殖和生存的PI3K信号活性，这一发现提示了一种机制性解释。阿司匹林还被证明可降低携带BRAF（V600E）癌基因野生型而非突变等位基因的结直肠癌发病率。尽管颇具启发性，但这些分子标志物预测阿司匹林疗效的潜在效用仍有待在临床试验中进行前瞻性评估。如果得到验证，这些发现可能支持采用个性化方法使用阿司匹林治疗结直肠癌。
