抗EGFR治療結(jié)直腸癌療效的潛在預(yù)測(cè)標(biāo)記.ppt

抗EGFR治療結(jié)直腸癌療效的 潛在預(yù)測(cè)標(biāo)記,浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院 腫瘤中心 化療科 徐 農(nóng),腫瘤治療,療效,毒性,選擇,EGFR狀態(tài)作為結(jié)直腸癌的預(yù)后因素,82%的結(jié)直腸癌EGFR有不同程度的表達(dá),Nicholson et al. Eur J Cancer 2019;37(Suppl. 4):S915,Frequency(%) of studies showing an association between increased EGFR level and decreased survival,預(yù)測(cè)抗EGFR療效指標(biāo),皮疹 檢測(cè) EGFR 狀態(tài) EGFR蛋白表達(dá)IHC 基因表達(dá)FISH 基因突變 基因水平 基因考貝數(shù) 檢測(cè) EGFR 激活 EGFR 配體 EGFR 磷酸化 KRAS,其他信號(hào)通路 PTEN失活 VEGF基因表達(dá) P21 丟失 STAT3激活 胚系基因多態(tài)性 EGFR基因多態(tài)性（CA雙核苷酸重復(fù)序列） FcR多態(tài)性（FcRIIa131位點(diǎn)和FcRIIIa 158位點(diǎn)） cyclin D1 A870G和EGF A61G的多態(tài)性 Cox-2的G765C多態(tài)性,臨床預(yù)測(cè)標(biāo)記,痤瘡樣皮疹,痤瘡樣皮疹是抗EGFR靶向藥物常見的不良反應(yīng)，并呈劑量依賴性。 抑制EGFR介導(dǎo)的信號(hào)通路 - 抑制生長(zhǎng)、促進(jìn)凋亡、 - 抑制細(xì)胞遷移 - 增加細(xì)胞黏附和分化 - 刺激炎癥進(jìn)而影響角質(zhì)化細(xì)胞 導(dǎo)致特有的皮膚表現(xiàn),抗EGFR治療 所致皮膚反應(yīng),1 2 3 4 5 6 7 8 9,抗EGFR治療 所致皮膚反應(yīng),Description of severe cases,后炎癥效應(yīng),痤瘡樣皮疹,甲溝炎,皮膚干燥,Topical antiacne creams (drying effect) tetracyclines antihistamines,Pruritus,Pulse dye laser,Emollients,Hydrocolloid dressing or propylene glycol acetylsalicyl,Antiseptic soaks, silver nitrate (pyogenic granuloma),皸裂,Segaert S, et al. Ann Oncol. 2019;16:1425-1433.,Therapy Suggestions,西妥昔單抗治療 皮疹與生存期關(guān)系,1. Saltz L, et al. Proc ASCO. 2019. 2. Saltz L, et al. J Clin Oncol. 2019;22:1201-1208. 3. Cunningham D, et al. N Engl J Med. 2019;351:337-345. 4. Van Cutsem E, et al. EORTC/NCI Geneva. 2019. 5. Xiong H, et al. J Clin Oncol. 2019;22:2610-2616. 6. Kies MS, et al. Proc ASCO. 2019.,0,No reaction,Grade 2,Grade 1,Grade 3,Survival (Months),16,12,8,4,CRC 9923 Saltz (2019)1,CRC 0141 Saltz (2019)2,CRC BOND Cunningham3,CRC Van Cutsem (2019)4,Pancreatic Xiong (2019)5,SCCHN Kies (2019)6,*There were no grade 4 skin reactions.,Van Cutsem E, et al. ASCO 2019. Abstract 4000.,Skin reaction grade 0 or 1 (n = 244),0.0,2.5,5.0,7.5,10.0,12.5,15.0,17.5,20.0,PFS Time (Months),1.00,0.75,0.50,0.25,0.00,PFS Estimate,Skin reaction grade 2 (n = 243),Skin reaction grade 3* (n = 112),11.3 months,5.4 months,9.4 months,CRYSTAL: PFS by On-Study Skin Reactions: Cetuximab + FOLFIRI,皮膚毒性與腫瘤療效的機(jī)理,一些研究者提出假設(shè)，皮疹是西妥昔單抗與受體結(jié)合飽和程度的替代標(biāo)志 獲得所需皮膚毒性的靶向劑量就能進(jìn)一步提高該藥物的療效 證實(shí)假說，進(jìn)行了一項(xiàng)隨機(jī)多中心I、II期研究（EVEREST試驗(yàn)） 另一種假說的解釋是皮膚毒性的預(yù)測(cè)價(jià)值可能與個(gè)體間胚系遺傳多態(tài)性有關(guān),Tejpar S, et al. ASCO 2019. Abstract 4037.,Patients with EGFR-positive mCRC failing irinotecan-based therapy (N = 166),Arm A: Irinotecan + standard-dose Cetuximab 250 mg/m2/week,Arm B: Irinotecan + dose-escalated* Cetuximab dose increases of 50 mg/m2 q2w up to maximum 500 mg/m2/wk,Arm C: Irinotecan + standard-dose Cetuximab 250 mg/m2/week,Day 1,Day 22, Grade 1 rash (n = 89), Grade 2 rash (n = 77),*Dose escalated by 50 mg/m2/week until grade 2 toxicity, tumor response, or dose reaches 500 mg/m2.,EVEREST: Study Design,Cetuximab 400 mg/m2 initial dose then 250 mg/m2/wk + Irinotecan (180 mg/m2 q2w),Not eligible for randomization,randomization,Tejpar S, et al. ASCO 2019. Abstract 4037.,Arm C (Standard Dose),Arm C (Standard Dose),Response Rate,PFS,Months,Response (%),Arm A (Fixed Dose),Arm B (Dose Escalation),Arm A (Fixed Dose),Arm B (Dose Escalation),0,5,10,15,20,25,30,35,0,1,2,3,4,5,6,EVEREST Phase I/II Cetuximab in mCRC Study: Preliminary Results,EGFR表達(dá)狀態(tài),EGFR表達(dá)(IHC),EGFR 突變,與NSCLC相反,體細(xì)胞EGFR基因突變?cè)诮Y(jié)直腸癌患者中罕見 不論EGFR基因狀態(tài)是野生型還是突變型,抗EGFR治療都有效,Khambata-Ford S, et al. J Clin Oncol. 2019;25:3230-3237. Tsuchihashi Z, et al. N Engl J Med. 2019;353:208-209.,EGFR 基因拷貝數(shù),Metastatic colorectal cancer patients treated with cetuximab or panitumumab (N = 31) screened for EGFR copy number and mutation profile Objective response (n = 10) Stable or progressive disease (n = 21),Moroni M, et al. Lancet Oncol. 2019;6:279-286.,89.9,4.8,0,20,40,60,80,100,Objective responders,Nonresponders,Increased EGFR Copy Number by FISH (%),P 0.0001,EGFR FISH表達(dá),Retrospective analyses suggest a correlation between anti-EGFR therapy and EGFR gene copy numbers by FISH 2,3 Methodology issues for translation into clinical practice4,Cetuximab Treatment of mCRC (n = 85)1,1. Cappuzzo F, et al. Ann Oncol. 2019;Epub. 2. Moroni M, et al. Lancet 2019;6:279-286. 3. Sartore-Bianchi A, et al. J Clin Oncol. 2019;25:3238-3245. 4. Personeni N, et al. J Clin Oncol. 2019;25:18S. Abstract 10569.,6.6,11.3,3.5,8.5,0,4,8,12,16,TTP,OS,Months,EGFR FISH+,EGFR FISH-,P = .02,P = .8,100,70,30,0,20,40,60,80,100, 2.47, 2.47,CR + PR,PD + SD,100,32,0,20,40,60,80,100, 43%, 43%,68,P = .0009,P = .0007,Patients (%),Patients (%),EGFR gene copy number,Chromosome 7 polysomy or amplification,EGFR 基因拷貝數(shù),Sartore-Bianchi A, et al. J Clin Oncol. 2019;25:3238-3245.,Survival, response outcomes on panitumumab associated with EGFR gene copy number,EGFR 磷酸化（激活）,Measuring EGFR phosphorylation by immunohistochemistry may predict higher response rates Major methodological issues for translation into clinical practice,pEGFR 7 (n = 7),pEGFR 7 (n = 13),0,20,40,60,80,100,Disease Control Rate (%),100,54,P = 0.05,Level of EGFR Phosphorylation,Personeni N, et al. Semin Oncol. 2019;32:S59-S62.,EGFR 配體表達(dá): A Predictor for Increased PFS?,EGFR Ligand Expression,High,Low,0,20,40,60,80,100,120,140,Median PFS (Days),103.5 days,115.5 days,57 days,57 days,EREG (P = .0002),AREG (P = .0002),n = 110, cetuximab monotherapy.,Khambata-Ford S, et al. J Clin Oncol 2019;25:3230-3237.,EREG:epireulin 表皮調(diào)節(jié)素,AREG:amphiregulin 雙調(diào)蛋白,Association of PFS and OS with the baseline expression level of epiregulin (EREG),Van Cutsem E, et al. WCGIC 2019. Abstract 0034.,EVEREST 研究: 表皮調(diào)節(jié)素,PFS,Survival,High Low,1.0 0.8 0.6 0.4 0.2 0.0,0 100 200 300 400 500,0 200 400 600 800,High Low,P = .013,P = .00033,Time (Days),Time (Days),Proof of PFS,Proof of OS,1.0 0.8 0.6 0.4 0.2 0.0,KRAS突變,預(yù)測(cè)西妥昔單抗療效的生物學(xué)指標(biāo),RAS是細(xì)胞內(nèi)信號(hào)傳導(dǎo)途徑中的“下游區(qū)”的一種信號(hào)傳導(dǎo) 蛋白，對(duì)細(xì)胞的生長(zhǎng)，存活和分化等功能具有重要影響,K-RAS基因,KRAS 基因突變時(shí)，不管EGFR是否活化，KRAS 蛋白（p 21 ras）激活,KRAS 基因突變是早期事件，結(jié)直腸患者發(fā)生率4045%,KRAS 突變總體與預(yù)后差有關(guān),KRAS突變患者 西妥昔單抗治療 生存期明顯縮短,30 mCRC patients treated with cetuximab 43% with KRAS mutation KRAS mutation observed in 0% of 11 responders 68% of 19 nonresponders P = .0003,Lievre A, et al. Cancer Res. 2019;66:3992-3995.,6.3,16.9,0,5,10,15,20,Median Survival (months),Mutated KRAS,Wild type KRAS,P = .016,Predictive Role of KRAS in CRC,P = .003,Khambata-Ford S, et al. J Clin Oncol. 2019;25:3230-3237.,11,51,89,46,0,20,40,60,80,100,Disease Control Group,Patients (%),Mutant at KRAS codon 12 or 13,Wild-type KRAS,Nonresponders,Single-Arm Studies: KRAS as a Biomarker for EGFR Inhibitors,KRAS Status and Response to Panitumumab: Phase III Trial Analysis,Amado RG, et al. GI Cancers Symposium 2019. Abstract 278.J Clin Oncol 2019,26,1626,Panitumumab 6 mg/kg every 2 weeks + Best Supportive Care (n = 231),Best Supportive Care* (n = 232),Colorectal cancer patients stratified by ECOG 0-1 vs 2 and region (N = 463),*Optional crossover to panitumumab upon disease progression.,PFS by KRAS Status and Treatment,Amado RG, et al. GI Cancers Symposium 2019. Abstract 278. J Clin Oncol 2019,26,1626,The relative effect of panitumumab vs best supportive care was significantly greater in patients with WT vs mutant KRAS The quantitative-interaction test comparing the magnitude of the relative treatment effect on PFS between WT and mutant KRAS was statistically significant (P .0001) PFS was significantly greater for panitumumab treatment compared with best supportive care in the WT KRAS group (stratified log-rank test: P .0001).,Mutant KRAS,WT KRAS,Pmab + BSC,BSC alone,7.4,7.3,HR: 0.99 (95% CI: 0.73-1.36),Proportion Event Free,Weeks,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,4,8,12,16,20,24,28,32,36,40,44,48,52,HR: 0.45 (95% CI: 0.34-0.59) Stratified log-rank test: P .0001,Proportion Event Free,Weeks,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,4,8,12,16,20,24,28,32,36,40,44,48,52,Pmab + BSC,BSC alone,12.3,7.3,Median PFS,Median PFS,OS by KRAS Status and Treatment,Amado RG, et al. GI Cancers Symposium 2019. Abstract 278. . J Clin Oncol 2019,26,1626,Median OS (Months),8.1,7.6,4.9,4.4,0,2,4,6,8,10,WT KRAS,WT KRAS,Mutant KRAS,Mutant KRAS,Pmab,BSC,Pmab,BSC,FOLFIRI 5-FU bolus 400 mg/m2, 46-hr infusion 2400 mg/m2 + Irinotecan 180 mg/m2 + Leucovorin 400 mg/m2 every 2 wks,Patients with previously untreated EGFR-expressing metastatic colorectal cancer (N = 1217),FOLFIRI + Cetuximab 5-FU bolus 400 mg/m2, 46-hr infusion 2400 mg/m2 + Irinotecan 180 mg/m2 + Leucovorin 400 mg/m2 every 2 wks + Cetuximab 400 mg/m2 initial dose, then 250 mg/m2 wkly,Van Cutsem E, et al. ASCO 2019. Abstract 2.,CRYSTAL Trial FOLFIRI Cetuximab: Study Schema,Patients stratified by region and ECOG performance score Safety population: n = 1202 ITT population: n = 2019,ITT人群與KRAS不同狀態(tài)患者療效數(shù)據(jù)對(duì)比,KRAS 突變率 35.6%（192/540）,FOLFOX4,Patients with previously untreated EGFR-detectable mCRC (N = 237),FOLFOX4 + Cetuximab,Van Cutsem E, et al. ASCO 2019. Abstract 2.,OPUS Trial FOLFOX Cetuximab: Study Schema,Patients stratified by region and ECOG performance score Safety population: n = 1202 ITT population: n = 2019,Cetuximab 400 mg/m2 initial dose, then 250 mg/m2 wkly,ITT人群與KRAS不同狀態(tài)患者療效數(shù)據(jù)對(duì)比,KRAS 突變率 42.5%（99/233）,Tejpar S, et al. ASCO 2019. Abstract 4037.,Patients with EGFR-positive mCRC failing irinotecan-based therapy (N = 166),Arm A: Irinotecan + standard-dose Cetuximab 250 mg/m2/week,Arm B: Irinotecan + dose-escalated* Cetuximab dose increases of 50 mg/m2 q2w up to maximum 500 mg/m2/wk,Arm C: Irinotecan + standard-dose Cetuximab 250 mg/m2/week,Day 1,Day 22, Grade 1 rash (n = 89), Grade 2 rash (n = 77),*Dose escalated by 50 mg/m2/week until grade 2 toxicity, tumor response, or dose reaches 500 mg/m2.,EVEREST: Study Design,Cetuximab 400 mg/m2 initial dose then 250 mg/m2/wk + Irinotecan (180 mg/m2 q2w),Not eligible for randomization,randomization,EVEREST: PFS (ITT Population),0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,Days,PFS Estimate,800,P .0001,KRAS mutant,WT KRAS,KRAS mutation present,83 days (95% CI: 75.9-90.2),173 days (95% CI: 141.3-204.7),Tejpar S, et al. ASCO 2019. Abstract 4001. Reproduced with permission.,EVEREST: PFS by Treatment Group and KRAS Status,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,Days,Days,Days,KRAS mutant,WT KRAS,Control,KRAS mutation present,P = .014,KRAS mutant,WT KRAS,Dose Escalation,KRAS mutation present,KRAS mutant,WT KRAS,Nonrandomized,KRAS mutation present,P .001,P = .020,Tejpar S, et al. ASCO 2019. Abstract 4001. Reproduced with permission.,PFS Estimate,PFS Estimate,PFS Estimate,CAIRO2 Study of the Dutch Colorectal Group (DCCG): Schema,Stratified by previous adjuvant chemotherapy, serum LDH, number of affected organs, and institution,Patients with advanced colorectal cancer, with no previous systemic treatment for advanced disease, and WHO performance score 0-1 (N = 755),Arm A Cycles 1-6 Capecitabine 1000 mg/m2 BID on Days 1-14 + Oxaliplatin 130 mg/m2 on Day 1 + Bevacizumab 7.5 mg/kg on Day 1 Cycles 7 and beyond Capecitabine 1250 mg/m2 BID on Days 1-14 + Bevacizumab 7.5 mg/kg on Day 1 (n = 368),Arm B* Capecitabine, Oxaliplatin, Bevacizumab as above + Cetuximab 400 mg/m2 initial dose then 250 mg/m2 weekly (n = 368),Punt , et al. ASCO 2019. Abstract 4011.,Primary endpoint: PFS Secondary endpoints: OS, response rate, toxicity, quality of life,*3-wk cycles.,CAIRO2: Impact of KRAS on PFS/OS,KRAS 突變率 39.1%（196/501）,其他信號(hào)通路,PTEN 磷酸酯酶和腫瘤抑癌蛋白,調(diào)節(jié)PI-3K-Akt信號(hào)通路 40%的結(jié)直腸癌PTEN表達(dá)下降，與PTEN突變或缺失有關(guān),Romagnani et al. Gastrointestinal Cancers Symposium 2019 abstract 427,n=10,n=17,0,20,40,60,80,100,有效,PTEN表達(dá),P =0.001,Patients (%),無效,35,100,上調(diào)VEGF和其他血管發(fā)生介質(zhì),A431鱗狀細(xì)胞癌移植瘤模型EGFR過表達(dá)的體內(nèi)實(shí)驗(yàn)提示，通過增加EGFR產(chǎn)物能夠誘導(dǎo)西妥昔單抗的獲得性耐藥 Ciardiello等提示對(duì)西妥昔單抗或吉非替尼耐藥的結(jié)腸癌細(xì)胞株活化的磷酸MAPK、COX-2表達(dá)和VEGF增高510倍 Vallbohmer的研究也表明，在39例轉(zhuǎn)移性結(jié)直腸中，用定量PCR檢測(cè)發(fā)現(xiàn)，腫瘤內(nèi)VEGF基因低表達(dá)與西妥昔單抗治療療效有關(guān),Viloria-Petit et al. Cancer Res 2019;61:50905101 Ciardiello et al. Clin Cancer Res 2019;10:784793 Vallbohmer et al. J Clin Oncol 2019;23:35363544.,p21,Ogino的研究提示結(jié)直腸癌p21表達(dá)，尤其伴有p53突變，是預(yù)測(cè)化療加吉非替尼耐藥的指標(biāo),Ogino et al. Clin Cancer Res 2019;11:66506656,0,20,40,60,80,100,有效率 (%),25,67,0,20,40,60,80,100,Patients (%),9,68,P =0.05,p21丟失,p21表達(dá)陽(yáng)性,P =0.005,p21表達(dá)丟失伴野生型p53,p21表達(dá)伴p53突變,STAT3激活,在EVEREST研究中，用IHC檢測(cè)pSTAT3，初步結(jié)果顯示西妥昔單抗治療有效患者的STAT磷酸化程度輕度升高,Spano et al.Eur J Cancer 2019;42:26682670.,胚系基因多態(tài)性預(yù)測(cè)指標(biāo),EGFR基因多態(tài)性 EGFR G+497A EGF A+61G,0,0.4,0.8,1.2,2,PFS (月),1.3,1.8,0,0.4,0.8,1.2,1.6,2,1.2,1.4,P =0.0017,EGFR G+497A,EGFR +497 GG,P =0.042,EGF +61 GG,EGF +61 A-allele,PFS (月),1.6,Lurje et al. submitted for publication,13