文章(zhang)來源(yuan)：
2015年ASCO年會于5月29日(ri)—6月2日(ri)在美國(guo)芝加哥召開。5月30日(ri)下午消(xiao)化(hua)系統(tong)（結直(zhi)腸）腫瘤口(kou)頭報(bao)告專場上，一(yi)項來(lai)自PETACC8和N0147試驗3934例患(huan)者的匯總分析顯(xian)示了(le)，BRAF V600E與KRAS外顯(xian)子2突變對經輔助(zhu)FOLFOX+/-西(xi)妥昔(xi)單抗治療(liao)，微衛星穩定(ding)（MMS），III期結腸癌患(huan)者的預測價值。醫脈通整理如下：
既往發表的(de)研(yan)究(jiu)因混雜了II期與(yu)III期，微衛星不(bu)穩定性(xing)（MSI）和MSS，結(jie)腸(chang)癌(ai)(ai)與(yu)直腸(chang)癌(ai)(ai)，治(zhi)療方案不(bu)固定等情況(kuang)，BRAF和KRAS基(ji)因突變對術后(hou)結(jie)腸(chang)癌(ai)(ai)患(huan)者的(de)預后(hou)影(ying)響尚(shang)存(cun)爭(zheng)議(yi)。因此，本(ben)項研(yan)究(jiu)前瞻性(xing)從(cong)接受FOLFOX+/-西妥昔單(dan)抗輔助治(zhi)療的(de)III結(jie)腸(chang)癌(ai)(ai)患(huan)者中收(shou)集生物標志。
研究方法：
研究人員對(dui)腫瘤(liu)BRAF V600E和(he)KRAS外顯子2基因(yin)突(tu)(tu)變(bian)進行分(fen)(fen)(fen)析(xi)，僅將(jiang)(jiang)MSS患者(zhe)納入組(zu)。將(jiang)(jiang)這些入組(zu)患者(zhe)分(fen)(fen)(fen)為(wei)BRAF突(tu)(tu)變(bian)，KRAS突(tu)(tu)變(bian)，和(he)雙重(zhong)野生型(xing)(xing)（WT）三組(zu)。采用(yong)一(yi)致(zhi)性(xing)結果(guo)評估指標(biao)，在全組(zu)和(he)各亞(ya)組(zu)中評估預后影響，然后將(jiang)(jiang)所有(you)數據匯(hui)總(zong)。采用(yong)分(fen)(fen)(fen)層(ceng)Cox比例風險(xian)模(mo)型(xing)(xing)對(dui)基因(yin)突(tu)(tu)變(bian)與復(fu)發間期（TTR），復(fu)發后生存(cun)(cun)期（SAR），和(he)總(zong)生存(cun)(cun)期（OS）相關性(xing)進行分(fen)(fen)(fen)析(xi)。多變(bian)量模(mo)型(xing)(xing)對(dui)治療和(he)協變(bian)量（年齡，性(xing)別(bie)，腫瘤(liu)分(fen)(fen)(fen)級(ji)，T/N分(fen)(fen)(fen)期，腫瘤(liu)部位(wei)，ECOG PS）進行了校正。
研究結果：
一共(gong)入組(zu)(zu)(zu)5577例(li)，僅對3934例(li)MSS患者評估BRAF和(he)(he)KRAS基因(yin)；其(qi)中279例(li)BRAF突(tu)(tu)變(bian)，1450例(li)KRAS突(tu)(tu)變(bian)，以及2205例(li)雙(shuang)重WT。與WT組(zu)(zu)(zu)不同，突(tu)(tu)變(bian)兩(liang)組(zu)(zu)(zu)的(de)TTR和(he)(he)OS較短，且(qie)多因(yin)素(su)分析也證實該(gai)結果（表(biao)）。WT組(zu)(zu)(zu)，KRAS突(tu)(tu)變(bian)組(zu)(zu)(zu)，BRAF突(tu)(tu)變(bian)組(zu)(zu)(zu)的(de)中位SAR分別為2.57，2.09和(he)(he)1.0年(nian)，其(qi)中KRAS（HR：1.20-95%CI：1.01-1.44，P＜0.0001），BRAF突(tu)(tu)變(bian)組(zu)(zu)(zu)（HR：3.01-95%CI：2.32-3.93，P＜0.0001）。本項研究中治療（聯合(he)(he)或不聯合(he)(he)西(xi)妥昔單抗）和(he)(he)KRAS/BRAF雙(shuang)突(tu)(tu)變(bian)的(de)TTR（P值=0.38）和(he)(he)OS（P值=0.16）無明(ming)顯差異。
結論：
本項研究通過一(yi)項大型III期術后(hou)結腸癌接(jie)受(shou)FOLFOX輔(fu)助(zhu)治療試驗(yan)(yan)的匯(hui)總分(fen)(fen)析，發(fa)現BRAF V600E或KRAS 外(wai)顯子(zi)2，包括密碼(ma)子(zi)12或13突(tu)變，是TTR，SAR和OS的獨(du)立預測因子(zi)。在以后(hou)的臨床試驗(yan)(yan)輔(fu)助(zhu)試驗(yan)(yan)中應將這些突(tu)變納入為重(zhong)要分(fen)(fen)層因素。
會議專題(ti)》》》2015年(nian)ASCO年(nian)會專題(ti)報道
Prognostic value of BRAF V600E and KRAS exon 2 mutations in microsatellite stable (MSS), stage III colon cancers (CC) from patients (pts) treated with adjuvant FOLFOX+/- cetuximab: A pooled analysis of 3934 pts from the PETACC8 and N0147 trials.（Abstract 3507）
Authors：Julien Taieb, Karine Le Malicot，et al.
Session Type：Oral Abstract Session
Background: The prognostic value of BRAF and KRAS mutations in resected CC pts remains controversial due to published studies that include stage II & III, microsatellite instability (MSI) and MSS, colon and rectal tumors, and variable treatment regimens. We examined this question in prospectively collected biospecimens from MSS stage III CC pts receiving adjuvant FOLFOX +/- cetuximab.
Methods：Tumors were analyzed for BRAF V600E and KRAS exon 2 mutations, only MSS tumors were included. Three groups were defined: BRAF Mutant, KRAS Mutant and double wild-type (WT). The analytic strategy estimated study- and arm-specific prognostic effects to assess homogeneity of results, and then analysis of pooled data. Associations of mutations with time-to-recurrence (TTR), survival after relapse (SAR) and overall survival (OS) were analysed using a stratified Cox proportional hazards model. Multivariate models were adjusted for treatment and covariates (age, sex, tumor grade, T/N stage, tumor location, ECOG PS).
Results：Of the 5,577 pts enrolled, 3,934 tumors were MSS and evaluable for BRAF and KRAS; 279 pts were BRAF Mutant, 1,450 KRAS Mutant, and 2,205 WT. Both mutations were linked to shorter TTR and OS vs WT, and results were confirmed in multivariate analyses (table). Median SAR was 2.57, 2.09 and 1.0 year in WT, KRAS Mutant (HR: 1.20- 95%CI: 1.01-1.44, p < 0.0001) and BRAF mutant (HR: 3.01-95%CI: 2.32-3.93, p < 0.0001), respectively. No interaction was found between treatment (with or without cetuximab) and KRAS/BRAFmutations for TTR (p = 0.38) or OS (p = 0.16).
Conclusions：In a large pooled analysis of pts with resected stage III MSS colon cancers receiving adjuvant FOLFOX, BRAFV600E or KRAS exon 2 mutations, including codons 12 or 13, are independent predictors of significantly shorter TTR, SAR and OS. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.