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1、抗EGFR治疗结直肠癌疗效的 潜在预测标记,浙江大学医学院附属第一医院 肿瘤中心 化疗科 徐 农,肿瘤治疗,疗效,毒性,选择,EGFR状态作为结直肠癌的预后因素,82%的结直肠癌EGFR有不同程度的表达,Nicholson et al. Eur J Cancer 2001;37(Suppl. 4):S915,Frequency(%) of studies showing an association between increased EGFR level and decreased survival,预测抗EGFR疗效指标,皮疹 检测 EGFR 状态 EGFR蛋白表达IHC 基因表达FISH
2、 基因突变 基因水平 基因考贝数 检测 EGFR 激活 EGFR 配体 EGFR 磷酸化 KRAS,其他信号通路 PTEN失活 VEGF基因表达 P21 丢失 STAT3激活 胚系基因多态性 EGFR基因多态性（CA双核苷酸重复序列） FcR多态性（FcRIIa131位点和FcRIIIa 158位点） cyclin D1 A870G和EGF A61G的多态性 Cox-2的G765C多态性,临床预测标记,痤疮样皮疹,痤疮样皮疹是抗EGFR靶向药物常见的不良反应，并呈剂量依赖性。 抑制EGFR介导的信号通路- 抑制生长、促进凋亡、- 抑制细胞迁移- 增加细胞黏附和分化- 刺激炎症进而影响角质化细胞
3、 导致特有的皮肤表现,抗EGFR治疗 所致皮肤反应,1 2 3 4 5 6 7 8 9,抗EGFR治疗 所致皮肤反应,Description of severe cases,后炎症效应,痤疮样皮疹,甲沟炎,皮肤干燥,Topical antiacne creams (drying effect) tetracyclines antihistamines,Pruritus,Pulse dye laser,Emollients,Hydrocolloid dressing or propylene glycol acetylsalicyl,Antiseptic soaks, silver nitrat
4、e (pyogenic granuloma),皲裂,Segaert S, et al. Ann Oncol. 2005;16:1425-1433.,Therapy Suggestions,西妥昔单抗治疗 皮疹与生存期关系,1. Saltz L, et al. Proc ASCO. 2001. 2. Saltz L, et al. J Clin Oncol. 2004;22:1201-1208. 3. Cunningham D, et al. N Engl J Med. 2004;351:337-345. 4. Van Cutsem E, et al. EORTC/NCI Geneva. 200
5、4. 5. Xiong H, et al. J Clin Oncol. 2004;22:2610-2616. 6. Kies MS, et al. Proc ASCO. 2002.,0,No reaction,Grade 2,Grade 1,Grade 3,Survival (Months),16,12,8,4,CRC 9923 Saltz (2001)1,CRC 0141 Saltz (2004)2,CRC BOND Cunningham3,CRC Van Cutsem (2004)4,Pancreatic Xiong (2004)5,SCCHN Kies (2002)6,*There we
6、re no grade 4 skin reactions.,Van Cutsem E, et al. ASCO 2007. 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
7、.4 months,CRYSTAL: PFS by On-Study Skin Reactions: Cetuximab + FOLFIRI,皮肤毒性与肿瘤疗效的机理,一些研究者提出假设，皮疹是西妥昔单抗与受体结合饱和程度的替代标志 获得所需皮肤毒性的靶向剂量就能进一步提高该药物的疗效 证实假说，进行了一项随机多中心I、II期研究（EVEREST试验） 另一种假说的解释是皮肤毒性的预测价值可能与个体间胚系遗传多态性有关,Tejpar S, et al. ASCO 2007. Abstract 4037.,Patients with EGFR-positive mCRC failing irin
8、otecan-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 ra
9、sh (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 dosethen 250 mg/m2/wk + Irinotecan (180 mg/m2 q2w),Not eligible for randomization,randomization,Tejpar S, et al. ASCO 2007. Abstract 4037.
10、,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表达状态,EGFR表达(IHC),EGFR 突变,与N
11、SCLC相反,体细胞EGFR基因突变在结直肠癌患者中罕见 不论EGFR基因状态是野生型还是突变型,抗EGFR治疗都有效,Khambata-Ford S, et al. J Clin Oncol. 2007;25:3230-3237. Tsuchihashi Z, et al. N Engl J Med. 2005;353:208-209.,EGFR 基因拷贝数,Metastatic colorectal cancer patients treated with cetuximab or panitumumab (N = 31) screened for EGFR copy number and
12、 mutation profile Objective response (n = 10) Stable or progressive disease (n = 21),Moroni M, et al. Lancet Oncol. 2005;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表达,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,
