2015年ASCO年會(huì)于5月29日—6月2日在美國(guó)芝加哥召開。5月30日下午消化系統(tǒng)（結(jié)直腸）腫瘤口頭報(bào)告專場(chǎng)上，一項(xiàng)來(lái)自PETACC8和N0147試驗(yàn)3934例患者的匯總分析顯示了，BRAF V600E與KRAS外顯子2突變對(duì)經(jīng)輔助FOL**+/-西妥昔單抗治療，微衛(wèi)星穩(wěn)定（MMS），III期結(jié)腸癌患者的預(yù)測(cè)價(jià)值。

    既往發(fā)表的研究因混雜了II期與III期，微衛(wèi)星不穩(wěn)定性（MSI）和MSS,結(jié)腸癌與直腸癌，治療方案不固定等情況，BRAF和KRAS基因突變對(duì)術(shù)后結(jié)腸癌患者的預(yù)后影響尚存爭(zhēng)議。因此，本項(xiàng)研究前瞻性從接受FOL**+/-西妥昔單抗輔助治療的III結(jié)腸癌患者中收集生物標(biāo)志。

    研究方法：

    研究人員對(duì)腫瘤BRAF V600E和KRAS外顯子2基因突變進(jìn)行分析，僅將MSS患者納入組。將這些入組患者分為BRAF突變，KRAS突變，和雙重野生型（WT）三組。采用一致性結(jié)果評(píng)估指標(biāo)，在全組和各亞組中評(píng)估預(yù)后影響，然后將所有數(shù)據(jù)匯總。采用分層Cox比例風(fēng)險(xiǎn)模型對(duì)基因突變與復(fù)發(fā)間期（TTR），復(fù)發(fā)后生存期（SAR），和總生存期（OS）相關(guān)性進(jìn)行分析。多變量模型對(duì)治療和協(xié)變量（年齡，性別，腫瘤分級(jí)，T/N分期，腫瘤部位，ECOG PS）進(jìn)行了校正。

    研究結(jié)果：

    一共入組5577例，僅對(duì)3934例MSS患者評(píng)估BRAF和KRAS基因；其中279例BRAF突變，1450例KRAS突變，以及2205例雙重WT.與WT組不同，突變兩組的TTR和OS較短，且多因素分析也證實(shí)該結(jié)果（表）。WT組，KRAS突變組，BRAF突變組的中位SAR分別為2.57,2.09和1.0年，其中KRAS（HR:1.20-95%CI:1.01-1.44,P<0.0001），BRAF突變組（HR:3.01-95%CI:2.32-3.93,P<0.0001）。本項(xiàng)研究中治療（聯(lián)合或不聯(lián)合西妥昔單抗）和KRAS/BRAF雙突變的TTR（P值=0.38）和OS（P值=0.16）無(wú)明顯差異。

    結(jié)論：

    本項(xiàng)研究通過(guò)一項(xiàng)大型III期術(shù)后結(jié)腸癌接受FOL**輔助治療試驗(yàn)的匯總分析，發(fā)現(xiàn)BRAF V600E或KRAS 外顯子2,包括密碼子12或13突變，是TTR,SAR和OS的***預(yù)測(cè)因子。在以后的臨床試驗(yàn)輔助試驗(yàn)中應(yīng)將這些突變納入為重要分層因素。

    會(huì)議專題》》》2015年ASCO年會(huì)專題報(bào)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 FOL**+/- cetuximab: A pooled **ysis 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 FOL** +/- cetuximab.

    Methods:Tumors were **yzed 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 **ytic strategy estimated study- and arm-specific prognostic effects to assess homogeneity of results, and then **ysis of pooled data. Associations of mutations with time-to-recurrence （TTR）， survival after relapse （SAR） and overall survival （OS） were **ysed 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 **yses （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 **ysis of pts with resected stage III MSS colon cancers receiving adjuvant FOL**, 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.