阿司匹林可降低BRAF野生型结直肠癌风险

JAMA 6月26日发表的一份研究报告表明，定期服用阿司匹林与BRAF野生型结直肠癌风险下降相关，但与BRAF突变结直肠癌风险无关。

美国哈佛大学Dana-Farber癌症研究所的Reiko Nishihara博士及其同事称，大约10%~15%的结直肠癌患者存在BRAF癌基因激活突变，既往研究提示BRAF激活突变在某些前列腺素的上调和合成中起到了一定的作用。鉴于阿司匹林是一种抗前列腺素，因此“我们推测BRAF突变克隆细胞可能对阿司匹林的抗肿瘤效应不太敏感，而BRAF野生型肿瘤细胞可能更容易受到阿司匹林抗肿瘤效应的影响”。


最新研究表明，无论男女，只要定期服用阿司匹林可显著降低患结直肠癌的风险

Nishihara博士及其同事采用来自两项大规模全国性前瞻性队列研究(追踪受试者自20世纪80年代以来的阿司匹林使用情况)的数据，分析了使用阿司匹林与结直肠癌BRAF突变状态之间的相关性。分析对象包括来自护士健康研究(NHS)的82,095名女性以及来自医务人员随访研究(HPFS)的45,770名男性，每隔2年对饮食和其他暴露进行一次详细监测。研究者称：“不断更新的详细暴露数据使我们得以控制潜在混杂因素的影响，比如结直肠癌形成过程中涉及的其他饮食和生活方式因素。”

受试者服用阿司匹林主要是为了预防心血管疾病，以及治疗关节炎、其他肌肉骨骼疼痛和头痛。

在长达28年(超过300万人-年)的随访期内，共有1,226名受试者罹患结直肠癌。不出所料，与没有使用阿司匹林的受试者相比，定期使用阿司匹林的男性或女性出现结直肠癌的风险显著降低。

研究者从保存的肿瘤组织样本中提取DNA组织以确定BRAF状态。结果显示，使用阿司匹林与BRAF野生型结直肠癌风险显著降低相关。就这类肿瘤而言，非阿司匹林使用者经年龄校正的发病率约为40.2/10万人-年，而阿司匹林使用者仅为30.5/10万人-年。

然而，使用阿司匹林与BRAF突变结直肠癌风险无关。非阿司匹林使用者经年龄校正的发病率约为5.0/10万人-年，阿司匹林使用者约为5.7/10万人-年(JAMA 2013;309:2563-71)。

研究者还针对降胆固醇药物、抗高血压药物和NSAIDs等合并用药情况开展了敏感性分析，结果并无改变。

进一步研究表明，阿司匹林每周用量越大，患BRAF野生型结直肠癌的风险就越低。此外，阿司匹林使用时间越长，该风险也越低。相比之下，阿司匹林的剂量和使用时间对BRAF突变结直肠癌风险均无影响。

Nishihara博士及其同事总结道：“上述研究结果支持了由于前列腺素通路上调BRAF突变细胞可能对阿司匹林的抗癌效应不敏感的假设。”

研究者还指出，鉴于发病风险上的绝对差异不是太大，因此还需开展进一步的研究以明确上述结果的临床意义。但这些结果的确提示BRAF状态有一天可能成为反映阿司匹林治疗敏感性的标志物之一。此外，这些研究结果还有助于更好地针对肿瘤特征制定个体化治疗策略。“这些结果加深了我们对结直肠肿瘤分子学发病机理的认识，使我们进一步了解到阿司匹林可能通过何种机制来发挥其抗肿瘤效应。”

该研究由美国国立卫生研究院、Bennett Family靶向治疗研究基金以及美国国立结直肠癌研究联盟共同资助。Nishihara博士声明无相关经济利益冲突。一名作者声明与拜耳、Millenium Pharmaceuticals、辉瑞和Pozen公司之间存在利益关系。

随刊述评：尚需在黑人患者中验证研究结果

Boris Pasche博士称，这项研究发现了一种可以预测肿瘤对阿司匹林应答水平的生物标志物，无论是预防性还是治疗性使用阿司匹林，这最终可能有助于个性化制定结直肠癌的预防和治疗策略。

这项研究的局限性之一是，受试人群中白人占到了95%~98%，而在美国，黑人的结直肠癌发病率是最高的，因此黑人才是完善结直肠癌防治策略的最大受益人群。所以，有必要确定这些研究结果是否同时适用于白人和黑人患者。

Pasche博士来自美国阿拉巴马大学伯明翰分校血液学/肿瘤学系，是JAMA的特约编辑之一。他声明与诺华、Amgen Vectibix、HudsonAlpha Institute、 Hirslanden和LACORE公司之间存在利益关系。上述评论摘自他针对Nishihara博士的研究的随刊述评(JAMA 2013;309:2598-9)。

爱思唯尔版权所有  未经授权请勿转载

By: MARY ANN MOON, Internal Medicine News Digital Network

Regular aspirin use has been linked to a lower risk of BRAF wild-type, but not BRAF mutated, colorectal cancer, according to a report in the June 26 issue of JAMA.

The absolute difference in risk was considered modest, so further investigation is required to clarify the clinical implications of these study findings. But the results do indicate that BRAF status may someday serve as a marker of sensitivity to aspirin therapy, said Reiko Nishihara, Ph.D., of the Dana-Farber Cancer Institute and Harvard University, Boston, and her associates.

Activating mutations in the BRAF oncogene occur in 10%-15% of colorectal cancers, and are thought to play a role in the upregulation and synthesis of certain prostaglandins. Since aspirin is an antiprostaglandin, "we hypothesized that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin, whereas BRAF wild-type neoplastic cells might be more susceptible to its antitumor effects," they said.

A new study suggests both men and women who use aspirin regularly have a significantly lower risk of developing colorectal cancer than aspirin nonusers.

The study findings also could lead to new treatment strategies that are better tailored to tumor characteristics. And they "enhance understanding of the molecular pathogenesis of colorectal neoplasia and the mechanisms through which aspirin may exert its antineoplastic effects," the investigators noted.

Dr. Nishihara and her colleagues examined the association between aspirin use and colorectal cancer’s BRAF mutation status using data from two large national prospective cohort studies that tracked participants’ aspirin use beginning in the 1980s. They analyzed data on 82,095 women in the Nurses' Health Study (NHS) and 45,770 men in the Health Professionals Follow-Up Study (HPFS), in which numerous dietary and other exposures were monitored in detail at 2-year intervals.

"Our detailed, updated exposure data allowed us to control for the effects of potential confounding by other dietary and lifestyle factors implicated in colorectal carcinogenesis," they said.

The study participants used aspirin primarily to prevent cardiovascular disease and to treat arthritis, other musculoskeletal pain, and headache.

During 28 years (more than 3 million person-years) of follow-up, 1,226 of these subjects developed colorectal cancer. As expected, both men and women who used aspirin regularly showed a significantly lower risk of developing the disease than did aspirin nonusers.

DNA tissue was extracted from stored samples of tumor tissue so that BRAF status could be determined.

Aspirin use was associated with a significantly lower risk of BRAF-wild-type cancer. For this tumor, the age-adjusted incidence was 40.2 per 100,000 person-years among aspirin nonusers, compared with 30.5 per 100,000 person-years for aspirin users.

In contrast, aspirin use showed no relation to the risk of BRAF-mutated cancer. The age-adjusted incidence was 5.0 per 100,000 person-years among nonusers and 5.7 per 100,000 among aspirin users (JAMA 2013;309:2563-71).

In a sensitivity analysis that accounted for the concomitant use of cholesterol-lowering agents, antihypertensive medications, and NSAIDs, the results were unchanged.

Further investigation showed that the risk of BRAF-wild-type colorectal cancer decreased as the weekly dose of aspirin increased. In addition, this risk decreased as the duration of aspirin therapy increased.

In contrast, neither dose nor duration of aspirin therapy affected the risk for BRAF-mutated cancer.

"These findings support the hypothesis that BRAF-mutated cells may show resistance to the anticancer effects of aspirin due to upregulation of the [prostaglandin] pathway," Dr. Nishihara and her associates said.

This study was supported by the National Institutes of Health, the Bennett Family Fund for Targeted Therapies Research, and the National Colorectal Cancer Research Alliance. Dr. Nishihara reported no financial conflicts. An associate reported ties to Bayer Healthcare, Millenium Pharmaceuticals, Pfizer, and Pozen.

View on the News
Confirm findings in black patients

This study identifies a biomarker of the tumor response to aspirin that is administered either preventively or therapeutically, and so may eventually help tailor both preventive and treatment approaches to colorectal cancer, said Dr. Boris Pasche.

One limitation was that the study population was 95%-98% white, whereas blacks have the highest incidence of colorectal cancer in the United States and stand to benefit the most from improvements in prevention and treatment. Thus, it will be important to determine whether these findings apply to black patients as well as white, he said.

Dr. Pasche is in the division of hematology/oncology at the University of Alabama at Birmingham and is a contributing editor at JAMA. He reported ties to Novartis, Amgen Vectibix, HudsonAlpha Institute, Hirslanden, and LACORE. These remarks were taken from his editorial accompanying Dr. Nishihara’s report (JAMA 2013;309:2598-9).