FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer.
FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer.
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DOI：
10.1016/j.ejca.2015.04.007
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Tejpar S
中科院分区：
文献类型：
--
作者：
Bokemeyer C;Köhne CH;Ciardiello F;Lenz HJ;Heinemann V;Klinkhardt U;Beier F;Duecker K;van Krieken JH;Tejpar S
OPUS研究表明，在KRAS外显子2野生型转移性结直肠癌（mCRC）患者的一线治疗中，西妥昔单抗联合5-氟尿嘧啶、亚叶酸和奥沙利铂（FOLFOX 4）治疗可显著改善客观缓解和无进展生存期（PFS）。在KRAS外显子2突变患者中，西妥昔单抗加用FOLFOX 4后观察到有害影响。本研究报告了扩展RAS检验定义的亚组结局。使用BEAMing重新分析OPUS研究KRAS外显子2野生型肿瘤样本中4个额外KRAS密码子（外显子3-4）和6个NRAS密码子（外显子2-4）的其他RAS突变。选择突变/野生型序列的0.5%的截止值来定义RAS状态;我们还报告了使用基于突变鉴定技术下限（0.1%）的截止值进行的分析。在31/118例（26%）可评价患者中检测到其他RAS突变。在RAS野生型肿瘤的扩展分析中（n = 87），西妥昔单抗加用FOLFOX 4可显著改善客观缓解（58% vs 29%;比值比3.33 [95%置信区间1.36-8.17]; P = 0.0084）;尽管受到人口规模的限制，在RAS野生型患者中，在PFS和总生存期方面，西妥昔单抗组似乎也有优势趋势，与RAS可评价组相比，没有证据表明患有其他RAS突变的患者从西妥昔单抗中受益，但由于数量较少，无法准确估计治疗效果。在有任何RAS突变（KRAS外显子2或其他RAS）的合并患者人群中，西妥昔单抗与FOLFOX 4联合治疗明显相关。RAS突变型mCRC（定义为KRAS和NRAS外显子2-4突变）患者在FOLFOX 4中添加西妥昔单抗后不会获益，反而可能受到损害。限制RAS野生型肿瘤患者使用西妥昔单抗将进一步调整治疗以最大化获益。
The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing. Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3–4) and six NRAS codons (exons 2–4) using BEAMing. A cutoff of ⩾ 5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%). Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n = 87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36–8.17]; P = 0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4. Patients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2–4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.
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影响因子：
50.5
作者：
Bokemeyer, C.;Bondarenko, I.;Koralewski, P.
通讯作者：
Koralewski, P.
DOI：
10.1073/pnas.0507904102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Diehl, F;Li, M;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
50.5
作者：
Tougeron, D.;Lecomte, T.;Karayan-Tapon, L.
通讯作者：
Karayan-Tapon, L.
影响因子：
3.7
作者：
KAPLAN, EL;MEIER, P
通讯作者：
MEIER, P