分子標(biāo)記物指導(dǎo)下的結(jié)直腸癌治療課件

1、北京大學(xué)腫瘤醫(yī)院 消化腫瘤內(nèi)科王晰程分子標(biāo)記物指導(dǎo)下的結(jié)直腸治療當(dāng)前結(jié)直腸癌治療的藥物和方案氟尿嘧啶類（5FU Cape）奧沙利鉑、伊立替康含奧沙利鉑的方案FOLFOXBev/cetXELOXBevFOLFOXIRIBev含伊立替康的方案CPT-11XELIRIFOLFIRICet/Bev西妥昔、帕尼單抗貝伐珠單抗其它：瑞格菲尼細(xì)胞毒藥物 分子靶向藥物Catalano V,Loupakis F,Graziano F, et al. Br JCancer.2009 Mar 24;100(6):881-7.粘液腺癌對(duì)比非粘液腺癌一線治療療效差FIRE3研究：不同原發(fā)腫瘤部位患者的PFS及OSFOL

2、FIRI+西妥昔單抗 (A組)FOLFIRI+貝伐珠單抗 (B組)PFS時(shí)間 (月)左側(cè) (n=127)中位PFS=10.5個(gè)月右側(cè) (n=39)中位PFS=8.8個(gè)月P=0.065HR=0.69 (0.47-1.03)OS時(shí)間 (月)左側(cè) (n=127)中位OS=28.0個(gè)月右側(cè) (n=39)中位OS=22.7個(gè)月P=0.034HR=0.63 (0.41-0.97)1.000.750.500.250.001224364860721.000.750.500.250.00122436486072PFS時(shí)間 (月)左側(cè) (n=137)中位PFS=10.8個(gè)月右側(cè) (n=30)中位PFS=6.9個(gè)月

3、P0.0001HR=0.35 (0.23-0.53)OS時(shí)間 (月)左側(cè) (n=137)中位OS=38.7個(gè)月右側(cè) (n=30)中位OS=16.1個(gè)月P0.0001HR=0.26 (0.16-0.42)1.000.750.500.250.001224364860721.000.750.500.250.00122436486072Heinemann V, et al. 2014 ASCO Abstract 3600.西妥昔單抗、貝伐單抗一線治療，KRAS野生型的左半結(jié)腸患者OS明顯優(yōu)于右半結(jié)腸患者生物標(biāo)記物為個(gè)體化治療提供了依據(jù)傳統(tǒng)治療個(gè)體化治療Kalia M. Metabolism.2013;

4、62 Suppl 1:S11-S14.結(jié)直腸癌患者治療有效無效副作用大組織、血液、DNA、核酸分析治療有效抗EGFR單抗的生物標(biāo)記物研究進(jìn)展標(biāo)記物蛋白功能CRC中的缺陷發(fā)生率作用EGFR跨膜酪氨酸激酶受體蛋白表達(dá)突變拷貝數(shù)增加25-90%極少見0-50%與抗EGFR單抗療效不相關(guān)尚未知是否與抗EGFR單抗療效相關(guān)不確定是否與抗EGFR單抗療效相關(guān)KRASGDP-/GTP-結(jié)合蛋白，促進(jìn)配體依賴的信號(hào)轉(zhuǎn)導(dǎo)激活突變（密碼子12, 13, 61, 146）；導(dǎo)致MAPK信號(hào)通路的激活30-40%若是突變的話，會(huì)對(duì)抗EGFR單抗治療無反應(yīng)NRASEGFR信號(hào)傳導(dǎo)通路中的蛋白突變（密碼子12、13、59

5、、61、117、146）3-5%若是突變的話，會(huì)對(duì)抗EGFR單抗治療無反應(yīng)BrafKras下游絲氨酸-蘇氨酸蛋白激酶激活突變（V600E）5-12%突變者預(yù)后差，Crystal/OPUS薈萃分析發(fā)現(xiàn)應(yīng)用愛必妥治療可能獲益PTEN蛋白酪氨酸磷酸酶；滅活PI3K通路蛋白表達(dá)丟失；突變；雜合性缺失13-19%預(yù)后差，可能會(huì)對(duì)抗EGFR單抗治療無反應(yīng)上皮調(diào)節(jié)蛋白，雙調(diào)蛋白（高表達(dá)）EGFR配體，與EGFR結(jié)合激活下游通路50-60%高表達(dá)者，應(yīng)用愛必妥治療可能獲益更多1. Krasinskas AM. Patholog Res Int.2011 Feb 14;2011:932932. 2. Luo H

6、Y,Xu RH. World J Gastroenterol.2014;20(14):3858-3874.標(biāo)記物蛋白功能CRC中的缺陷發(fā)生率作用EGFR跨膜酪氨酸激酶受體蛋白表達(dá)突變拷貝數(shù)增加25-90%極少見0-50%與抗EGFR單抗療效不相關(guān)尚未知是否與抗EGFR單抗療效相關(guān)不確定是否與抗EGFR單抗療效相關(guān)KRASGDP-/GTP-結(jié)合蛋白，促進(jìn)配體依賴的信號(hào)轉(zhuǎn)導(dǎo)激活突變（密碼子12, 13, 61, 146）；導(dǎo)致MAPK信號(hào)通路的激活30-40%若是突變的話，會(huì)對(duì)抗EGFR單抗治療無反應(yīng)NRASEGFR信號(hào)傳導(dǎo)通路中的蛋白突變（密碼子12、13、59、61、117、146）3-5%若

7、是突變的話，會(huì)對(duì)抗EGFR單抗治療無反應(yīng)BRAFKras下游絲氨酸-蘇氨酸蛋白激酶激活突變（V600E）5-12%突變者預(yù)后差，Crystal/OPUS薈萃分析發(fā)現(xiàn)應(yīng)用愛必妥治療可能獲益PTEN蛋白酪氨酸磷酸酶；滅活PI3K通路蛋白表達(dá)丟失；突變；雜合性缺失13-19%預(yù)后差，可能會(huì)對(duì)抗EGFR單抗治療無反應(yīng)上皮調(diào)節(jié)蛋白，雙調(diào)蛋白（高表達(dá)）EGFR配體，與EGFR結(jié)合激活下游通路50-60%高表達(dá)者，應(yīng)用愛必妥治療可能獲益更多KRAS是第一個(gè)被證實(shí)預(yù)測(cè)抗EGFR單抗療效的生物標(biāo)記物* KRAS-WT exon 2 subset檢測(cè)位點(diǎn)不統(tǒng)一：全RAS檢測(cè)需包括6個(gè)外顯子1。ASCO GI 20

8、14 2。N Engl J Med 2013; 369:1023-1034 3。Bokemeyer, et al. ASCO 2014. Abstract 3505 4。Ciardiello, et al. ASCO 2014. Abstract 3506 5。ESMO 2013 0%2.0%3.8%NRAS12 1312 136114659 61117 146EXON 2EXON 3EXON 4EXON 2EXON 3EXON 4FIRE346%0%PRIME35%2.8%0.9%CRYSTAL3.5%5.1%0.8%OPUS6.8%5.8%0%PEAK5.4%4.3%4%3.3%5.9%4

9、%4.9%67%5.6%9.3%7.6%FIRE3PRIMECRYSTALOPUSPEAKKRASKRAS WTKRAS MUT: codons 12, 13TreatmentFOLFOX(N=331)Panitumumab + FOLFOX(N=325)FOLFOX(N=219)Panitumumab + FOLFOX(N=221)PFS, mosHR (95% CI)P value8.6100.80 (0.67-0.95)0.019.27.41.27 (1.04-1.55)0.02OS, mosHR (95% CI)P value19.723.90.88 (0.73-1.06)0.1719

10、.215.51.17 (0.95-1.45)0.15ORR,* %(95% CI)48(42-53)57(51-63)41(34-48)40(33-47) Odds ratio (95% CI)1.47 (1.07-2.04)P=0.020.98 (0.65-1.47)P=0.92Douillard JY, et al. Presented at ASCO 2011 (abstr 3510). Siena S, et al. Presented at ASCO GI. 2011 (abstr3510).PRIME研究：療效(By KRAS Status)RAS WT aRAS MUT bTre

11、atmentFOLFOX(N=253)Panitumumab + FOLFOX(N=259)FOLFOX(N=276)Panitumumab + FOLFOX(N=272)PFS, mosHR (95% CI)P value7.910.10.72 (0.58 0.90)0.018.77.31.31 (1.07 1.60)0.01OS, mosHR (95% CI)P value20.226.00.78 (0.62 0.99)0.0419.215.61.25 (1.02 1.55)0.04a WT in KRAS and NRAS exons 2,3, and 4. b. MUT in any

12、KRAS or NRAS exon 2, 3, or 4PRIME研究：療效(By KRAS Status)17% of patients with non-mutated KRAS exon 2 had other RAS mutations52% of all patients had some RAS mutationN Engl J Med 2013;369:1023-34KRASBRAF 狀態(tài) 與總生存的相關(guān)性Roth AD, et al (2010) J Clinical OncologyII期和III期結(jié)直腸癌術(shù)后BRBRAFKRAS結(jié)直腸癌中的BRAF突變結(jié)直腸癌中，BRAF

13、突變率約為5%-10%。導(dǎo)致信號(hào)通路活化和腫瘤細(xì)胞增殖與KRAS突變相互排斥提示預(yù)后不良BRAF抑制劑單獨(dú)使用無效RasRaf*MEKERKProliferationSurvivalBRAF抑制劑單獨(dú)使用對(duì)結(jié)直腸癌療效欠佳Therapeutic inhibitors for BRAF mutant cancers in trials:PLX-4032 in BRAF mutated melanoma Flaherty et al ASCO 200970% objective responsePLX-4032 in BRAF mutated colorectal cancer Kopetz et

14、 al ASCO 2010, Abstr 353421 patients1 partial response (5%) and 4 minor responsesReactivation of EGFR signaling upon BRAF inhibition Signaling in BRAF CRCPartial inhibition of MAPK pathway signaling with inhibition of BRAF and EGFRUpdated modelRobust inhibition of MAPK pathway signaling with inhibit

15、ion of BRAF, MEK, EGFRBRAF抑制劑(dabrafenib)聯(lián)合MEK抑制劑(trametinib) 治療36例BRAF突變的CRC患者M(jìn)aximum Percent ReductionFrom Baseline MeasurementUnconfirmed responses (CR+PR):4 (11%) 2 confirmed responses (1 CR and 1 PR)Unconfirmed minor responses: 8 (22%)Corcoran et al ASCO 2013Best Unconfirmed ResponseComplete re

16、sponseProgressive diseasePartial responseNot evaluableStable diseaseMaximum Tumor ResponseBars are grouped by best unconfirmed response. *Indicates maximum reduction from baseline is 0%. a Denotes that subject received prior anti-EGFR therapy. b denotes progressive disease secondary to presence of n

17、ew lesion. c Patient had a 30% reduction in target lesions but was deemed to have PD due to presence of one new lesion. Johanna C. Bendell MD,2014 ASCOAbstract 351580%16%4%Died despite maximal treatmentCured by the addition of chemotherapyCured by surgery aloneIs treating 100 patients with essential

18、ly good prognosis (as a whole population) with potentially toxic chemotherapy for 6 months justified to cure an extra 4 patients?Survival Benefit Stage II CRCdMMR leads to accumulation of mutations and therefore tumorigenesis and to the characteristic finding of MSI錯(cuò)配修復(fù)基因缺陷(dMMR)PCR on tumor DNA for

19、 MSI (microsatellite instability)IHC for MMR protein statusMLH1+MSH2+MLH1-MSH2-dMMR 是預(yù)后良好的標(biāo)志SourceStage / TreatmentEndpointdMMR vs pMMRHR (95% CI); p-valueRibic et al1II/IIISurgery aloneOverall survival0.31 (0.14-0.72) p=0.004Sargent et al2II/IIISurgery aloneDisease-free survivalOverall survival0.46

20、 (0.22-0.95); p=0.030.51 (0.24-1.10); p=0.06Gray et al3(QUASAR) IISurgery aloneRecurrence-free interval0.31 (0.15-0.63) p0.001Roth et al4(PETACC-3)II5FU irinotecanRelapse-free survival0.30 p=0.004Ribic CM, et al. N Engl J Med. 2003;349:247-257.Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226. The

21、15% of stage II colon cancer patients with dMMR tumors have been found consistently to have a lower risk of recurrence and/or deathGray R, et al. J Clin Oncol. In press.Roth AD, et al. J Clin Oncol. 2009;27: abstract 288.Colon Cancer Technical FeasibilityDevelopment StudiesSurgery AloneNSABP C-01/C-

22、02 (n=270) Cleveland Clinic (n = 765)Selection of Final Gene List & AlgorithmDevelopment Studies Surgery + 5FU/LVNSABP C-04 (n=308) NSABP C-06 (n=508)Clinical Validation Study Stage II Colon CancerQUASAR (n=1,436)Test Prognosis and Treatment Benefit2-stage Establishment of Recurrence Score : Develop

23、ment and ValidationStandardization and Validation of Analytical MethodsKerr et al., ASCO 2009, #4000The suggested 12-Gene Oncotype DX Colon Cancer Recurrence Score from Development StudiesCELL CYCLEKi-67C-MYCMYBL2ATP5EGPX1PGK1UBBVDAC2GADD45BRecurrence ScoreSTROMALFAPINHBABGNReference GenesRS = 0.15

24、x Stromal Group - 0.30 x Cell Cycle Group + 0.15 x GADD45B Recurrence Riskin Pre-specified Recurrence Risk GroupsComparison of High vs. LowRecurrence Risk Groups using Cox Model: HR = 1.47 (p=0.046)Recurrence Risk GroupRange of RSProportion of patientsLow3043.7%Intermediate30-4030.7%High4125.6%n=711

25、Integrating the Quantitative Recurrence Score into Recurrence Risk Assessment and Treatment Planning for Stage II Colon CancerResected stage II colon cancerT stage, MMR statusT3 and dMMRlow riskT3 and pMMRstandard riskT4 and pMMRhigh riskConsider observationOncotype DXColon Cancer AssayConsider chem

26、otherapydMMR, mismatch repair deficient; pMMR, mismatch repair proficientPIK3CA基因突變:阿司匹林治療的潛在靶點(diǎn)15-20% 結(jié)直腸癌存在PIK3CA 基因突變。突變多見于外顯子9 和外顯子20。PIK3CA 突變的患者可能從阿司匹林的治療中獲益。阿司匹林可以延長(zhǎng)PIK3CA突變的生存期Liao X et al (2009) NEJM二氫嘧啶脫氫酶(DPD)基因多態(tài)性與5-FU毒性相關(guān)氟尿嘧啶類藥物通過DPD酶代謝從體內(nèi)降解。DPD酶的部分或全部缺乏可加重5-Fu相關(guān)不良反應(yīng)，嚴(yán)重時(shí)可導(dǎo)致死亡。DPD酶是否缺乏可通過

27、檢測(cè)DPD酶的活性或DPD基因的測(cè)序來預(yù)測(cè)。DPD基因突變的位點(diǎn)和頻率在不同人種間存在較大差別。Saif MW .(2013) Cancer Genom & ProteomiUGT1A1多態(tài)性與伊立替康不良反應(yīng)相關(guān)性UGT1A1是伊立替康代謝的關(guān)鍵酶。UGT1A1多態(tài)性可能與伊立替康的毒性相關(guān)。UGT1A1 *28 和UGT1A1 *6 在人種間具有差異性。Derwinger K,Gustafson. Anticancer Res.2011 Jun;31(6):2347-50.*28 40% vs 15% hetero 10% vs 5% homo*6 ? vs 28% hetero ? vs

28、 7% homoPalomaki GE et al(2009) Genetics Med Severe DiarrheaUG1A1*28 與伊立替康毒性的相關(guān)性Severe NeutropeniaHeterozygous mutationHomozygous mutationCheng L. et al(2014) Cancer Chemother Pharmacol Severe Diarrhea亞洲人群中,UGT1A1*6 與嚴(yán)重腹瀉和粒缺相關(guān)Severe NeutropeniaHeterozygous mutationHomozygous mutationKE Caudle et al(

29、2013) Clini Pharm TheraClinical Pharmacogenetics Implementation Consortium Guidelines結(jié)直腸癌個(gè)體化治療RAS基因的檢測(cè)縮小了治療人群，但目標(biāo)人群的生存受益更為顯著。BRAF、PIK3CA突變?nèi)绾芜x擇更適宜的治療仍在探索當(dāng)中。II期結(jié)直腸癌的MIS狀態(tài)結(jié)合分子水平的基因表達(dá)譜可更好地篩選高危復(fù)發(fā)人群。UGT1A1和DPD基因的多態(tài)性與藥物不良反應(yīng)存在一定相關(guān)性，應(yīng)進(jìn)一步研究如何提高其預(yù)測(cè)的準(zhǔn)確性。大數(shù)據(jù)時(shí)代的結(jié)直腸癌再分型？CRC個(gè)體化治療需要多方面考慮CMS：Concensus Molecular Subty

30、pe Dienstmann, et al. ASCO 2014. Abstract 3511CMS114%超突變, BRAF mut, MSI, 免疫通路活化/ 表達(dá), 右側(cè)腫瘤, 診斷時(shí)年齡更大, 女性CMS241%EGFR 擴(kuò)增/過表達(dá), CIN高表達(dá), MSS, 強(qiáng)WNT/MYC通路, 左側(cè)腫瘤, TP53 mut, CMS38%KRAS mut, CIN低表達(dá), 適度WNT/MYC 通路活化, PIK3CA mut, IGFBP2過表達(dá)CMS420%CIN/MSI 異質(zhì)性, 間質(zhì)/TGF-beta活化, 診斷時(shí)年齡更輕,NOTCH3/VEGFR2過表達(dá)生存時(shí)間一般生存時(shí)間更好生存時(shí)間一

31、般生存時(shí)間最差謝謝！Greystoke A et al. (2012) Gastroenterol Res PrctKRASBRAF 突變率與腫瘤部位的相關(guān)性KRAS野生型患者中,約15-26%為RAS突變不同研究的RAS突變率：BEAMING焦磷酸測(cè)序雙脫氧測(cè)序/WAVE雙脫氧測(cè)序/WAVEBEAMING1。ASCO GI 2014 2。N Engl J Med 2013; 369:1023-1034 3。Bokemeyer, et al. ASCO 2014. Abstract 3505 4。Ciardiello, et al. ASCO 2014. Abstract 3506 5。ESM

32、O 2013 mCRC生物制劑十年發(fā)展 201420082011西妥昔單抗+伊立替康2L貝伐珠單抗+化療1L貝伐珠單抗+化療2L西妥昔單抗僅用于既往伊立替康治療失敗的KRAS WT（2L）帕妥木單抗+FOLFOX1L帕妥木單抗+FOLFIRIKRAS WT2L瑞戈非尼2L+貝伐珠單抗跨線阿柏西普+ FOLFIRI 2L帕妥木單抗以及西妥昔單抗不能用于RAS MT或RAS未知帕妥木單抗+FOLFOXKRAS-WT (US)自2004年以來，多個(gè)mCRC靶向藥物獲得FDA批準(zhǔn)2013基礎(chǔ)生物學(xué)的多樣性和異質(zhì)性Budinska E et al Asco 2012 5 clusters with su

33、fficient sample size were retained as CRC subtypes A, B, C, D and E.Novel subtypes are characterized by distinct biological components that predict patient survival腫瘤部位與療效的關(guān)系原發(fā)腫瘤部位定義右側(cè)CRC(“中腸”)：盲囊肝曲左側(cè)CRC(“中腸”)：直腸結(jié)腸脾曲排除橫結(jié)腸腫瘤 (n=9) 統(tǒng)計(jì)學(xué)分別采用雙側(cè)Fishers精確和log-rank檢驗(yàn)方法評(píng)估兩組間緩解率(ORR)和生存期(PFS/OS)的差異根據(jù)后向消除設(shè)計(jì)，采用

34、COX回歸方法對(duì)基線特征、BRAF和PIK3CA突變進(jìn)行分析FIRE-3研究中右側(cè)與左側(cè)原發(fā)腫瘤分布3%*44%20%77%*進(jìn)一步分析排除了橫結(jié)腸腫瘤 33%Heinemann V, et al. 2014 ASCO Abstract 3600.1. Van Cutsem E, et al. JCO 2011; 29:2011-2019.2. Forbes SA, et al. Nucleic Acids Res 2011; 39:D945-950.Derwinger K,Gustafson. Anticancer Res.2011 Jun;31(6):2347-50.腫瘤部位與生存狀況的關(guān)系Weiss JM,Pfau PR,OConnor ES, et al. J Clin Oncol.2011 Nov 20;29(33):4401-9.allStage IStage IIIStage IIP=0.001P0.001相同分期下，生存狀況也有差異藥物治療發(fā)展提高了mCRC患者的OS2014200420082000200720112013Venook12Saltz1Goldberg3Saltz6Bokemeyer7Saltz1Douillard2H