一项针对日本转移性结直肠癌患者KRAS、NRAS、BRAF和PIK3CA突变的临床病理特征的回顾性观察研究。
A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer.
作者信息
Kawazoe Akihito, Shitara Kohei, Fukuoka Shota, Kuboki Yasutoshi, Bando Hideaki, Okamoto Wataru, Kojima Takashi, Fuse Nozomu, Yamanaka Takeharu, Doi Toshihiko, Ohtsu Atsushi, Yoshino Takayuki
机构信息
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan.
出版信息
BMC Cancer. 2015 Apr 11;15:258. doi: 10.1186/s12885-015-1276-z.
BACKGROUND
The mutation in KRAS exon 2 is a validated biomarker of resistance to anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). Several reports have confirmed associations of other RAS mutations with resistance to anti-EGFR therapy. However, the impact of BRAF and PIK3CA mutations on the efficacy of anti-EGFR therapy remains controversial. Little is known about the frequencies and clinicopathological features of these mutations, as well as the therapeutic effects of anti-EGFR therapy in mCRC patients with these mutations, especially in the Asian population.
METHODS
In this retrospective observational study, frequencies and clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations were evaluated in patients with mCRC. Among patients treated with anti-EGFR therapy, objective response, progression-free survival (PFS), and overall survival (OS) were evaluated according to gene status.
RESULTS
Among 264 patients, mutations in KRAS exon 2, KRAS exons 3 or 4, NRAS, BRAF and PIK3CA were detected in 34.1%, 3.8%, 4.2%, 5.4% and 6.4%, respectively. Thus, a total of 12.1% of patients without KRAS exon 2 mutations had other RAS mutations. Primary rectal tumors tended to be more frequently observed in RAS mutant tumors. BRAF mutations were more frequently observed with right-sided colon, poorly differentiated or mucinous adenocarcinoma, and peritoneal metastasis. Among the 66 patients with KRAS exon 2 wild-type tumors treated with anti-EGFR agents, PFS (5.8 vs. 2.2 months) and OS (17.7 vs. 5.2 months) were significantly better in patients with all wild-type tumors (n = 56) than in those with any of the mutations (n = 10). The response rate also tended to be better with all wild-type tumors (26.8 vs. 0%).
CONCLUSION
Other RAS and BRAF mutations were observed in KRAS exon 2 wild-type tumors, which were associated with some clinicopathological features and resistance to anti-EGFR therapy in our patient cohort.
背景
KRAS外显子2突变是转移性结直肠癌（mCRC）中抗表皮生长因子受体（EGFR）治疗耐药的有效生物标志物。多项报告证实了其他RAS突变与抗EGFR治疗耐药之间的关联。然而，BRAF和PIK3CA突变对抗EGFR治疗疗效的影响仍存在争议。对于这些突变的频率、临床病理特征以及抗EGFR治疗在携带这些突变的mCRC患者中的治疗效果，尤其是在亚洲人群中，了解甚少。
方法
在这项回顾性观察研究中，对mCRC患者中KRAS、NRAS、BRAF和PIK3CA突变的频率及临床病理特征进行了评估。在接受抗EGFR治疗的患者中，根据基因状态评估客观缓解率、无进展生存期（PFS）和总生存期（OS）。
结果
在264例患者中，KRAS外显子2、KRAS外显子3或4、NRAS、BRAF和PIK3CA突变的检出率分别为34.1%、3.8%、4.2%、5.4%和6.4%。因此，在无KRAS外显子2突变的患者中，共有12.1%存在其他RAS突变。RAS突变肿瘤中原发性直肠肿瘤的发生率往往更高。BRAF突变在右半结肠癌、低分化或黏液腺癌以及腹膜转移中更常见。在66例接受抗EGFR药物治疗的KRAS外显子2野生型肿瘤患者中，所有基因均为野生型的患者（n = 56）的PFS（5.8个月对2.2个月）和OS（17.7个月对5.2个月）显著优于存在任何一种突变的患者（n = 10）。所有基因均为野生型的患者的缓解率也往往更高（26.8%对0%）。
结论
在KRAS外显子2野生型肿瘤中观察到其他RAS和BRAF突变，这些突变与我们患者队列中的一些临床病理特征及抗EGFR治疗耐药相关。
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