肺癌耐药分子标志与个体性化疗

肺癌耐药分子标志 与个体性化疗 徐 萌 暨南大学附属第一医院肿瘤科 肺癌耐药分子标志：药理遗传学和药理基因 组学的研究表明与肺癌多药耐药相关的基因 及其异常信号传导通路。 个体性化疗：根据肺癌患者药理遗传学和基 因组学特点，采用特异和最佳的化疗药物方 案，提高化疗疗效，尽量降低化疗副反应， 最大延长患者生存期。 1 肺癌化疗耐药的复杂性 2 肺癌耐药逆转药物的局限性 3 肺癌个体性化疗的实践性 4 典型病例 l 以铂类药物为基础的联合化疗比单一化疗效果好，是 中晚期肺癌一线治疗的金标准; l 紫杉醇、诺维本、多西紫杉醇、吉西他滨; l 在过去三十年中，非小细胞肺癌的中位生存时间只延 长了大约三个月; l 中晚期非小细胞肺癌经验性化疗疗效停滞于平台期， 致力于寻找各种敏感的化疗耐药分子标志和高效的耐 药逆转剂具有广泛的应用前景。 Corey Langer 2000; Breathnach et al 2001; Schiller et al 2002 一. 肺癌化疗耐药的复杂性 What is the Scope of the Problem? New Cancer Cases 121:823-835 K-ras conditioning mouse limiting dilution assay Stem Cells-Drug Resistance n High levels of ABC drug transporters n Quiescence n Capacity for DNA repair n Accumulation of mutations Nature Review Cancer 2005;5:275-284 Nature Review Drug Discovery 2006;5:219-234 Resistance-ABC Transporter Targeting ABC Transporter Nature Review Drug Discovery 2006;5:219-234 Cancer Stem Cell -high drug efflux capacity nCancer stem cell has ABC transporters with drug-efflux capacity. Proc. Natl. Acad. Sci. USA 101, 1422814233 (2004) human tumor cell lines SP: side population JF N Engl J Med, 2002 lPlatinum doublets have a marginally increased RR (17%) vs third generation non-platinum doublets but OS is not improved. DAddario, Pintilie et al.; J Clin Oncol, 2005 Clinically important mediators of DNA repair for platinum based damage l Essential NER DNA unwinding: ERCC2 (XPD) Incision of DNA: ERCC1 (XPF) l Transcription coupled NER BRCA1 l Base Excision Repair XRCC1 General mechanisms of platinum resistance l Detoxification l Inhibitors of apoptosis l DNA methylation l Changes in influx/efflux l Increased DNA repair capacity Rabik and Dolan; Cancer Treat Rev, 2006 Established mediators of platinum resistance in NSCLC l BRCA1 l ERCC1 Germline polymorphisms Tumor expression by mRNA Immunohistochemistry l Polymorphisms in ERCC2 Hum Mol Genet, 2004 BRCA1 mRNA expression levels and survival in NSCLC patients treated with neo-adjuvant gemcitabine Bottom: N=15, Middle=28, Top=12; p=0.01 Taron, Rosell et al.; Hum Mol Genet, 2004 Two strands of evidence for customizing therapy based on BRCA1 mRNA levels in SCAT lAmong several DNA repair genes, BRCA1 is the most reliable predictive marker of chemotherapy outcome in stage IV and stage III NSCLC lIn early-stage chemonaive NSCLC patients, BRCA1 is the best prognostic marker of survival lBRCA1 has been selected as the marker for assigning chemotherapy in the SCAT experimental arm Low BRCA1 gem/cis Intermediate BRCA1 doc/cis High BRCA1 doc Resected NSCLC pN1 / pN2 Q 2 ASCO 07 Increased BRCA1 mRNA: an independent prognostic variable in completely resected chemonaive NSCLC patients ERCC1 l Essential component of NER l Assessed by: Functional germ-line polymorphisms Expression levels by mRNA Expressional levels by IHC Polymorphisms of ERCC1 and survival in cisplatin treated NSCLC. lERCC1单核苷酸多态性预测铂类药物的疗效及患者预后 :ERCC1研究比较多的单核苷酸多态性位点主要是Asn118Asn （C/T），第118位密码子的同义突变。携带有C/C基因型的非 小细胞肺癌患者对铂类化疗疗效比携带T/T 或C/T 基因型患者好 ，总体生存的时间长。 lAsn118Asn（C/T）单核苷酸位点在不同人种中分布不同，这 可能是解释不同的研究小组在不同人种中所做研究结果不同。 在亚洲人种中，目前发表的研究结果支持C/C基因型是预测铂类 敏感的指标。 Isla, Sarries et al.; Ann Oncol, 2004 ERCC1 mRNA levels in advanced NSCLC treated with gemcitabine-cisplatin. l56 patients with advanced NSCLC. lLow vs high ERCC1 mRNA RR: 52% and 36% (p = NS), MS: 15 months and 5 months (P 55 lFor the study population as a whole, ERCC1 had no prognostic value. lOlaussen, Dunant et al.; N Engl J Med, 2006 Olaussen, Dunant et al.; N Engl J Med, 2006 ERCC1阴性的患者术后辅助铂类联合化疗 能明显提高患者的生存（OR 0.65; 95% CI: 0.50-0.86; p=0.002）， 然而ERCC1阳性的患者对术后含铂类方案 却不能获益（OR 1.14; 95% CI: 0.84-1.55; p=0.40）。 Low genotypic group docetaxel / cisplatin High genotypic group docetaxel / gemcitabine R A N D O M I Z E Genotypic arm ERCC1 levels 1:2 docetaxel / cisplatin Control arm low ERCC1 mRNA high ERCC1 mRNA Customizing cisplatin-based chemotherapy on quantitative ERCC1 mRNA expression: a phase III randomized trial in NSCLC Cobo et al. JCO 2007 Customizing cisplatin-based chemotherapy on quantitative ERCC1 mRNA expression: a phase III randomized trial in NSCLC Cobo et al. JCO 2007 IALT Bio (Olaussen et al, NEJM 06) ERCC1 is a prognostic factor in CT-nave patients Tumor tissue availableTumor tissue not available Never smokerSmoker EGFR mutations erlotinib mRNA levels (QPCR) BRCA1 ERCC1 MZF1 MAD2 BubR1 Q1 gem/cis Q2 25:2735-2740 2007 Fig 2. Kaplan-Meier analyses of overall survival according to treatment (A) in patients with p27Kip1-negative tumors and (B) in patients with p27Kip1-positive tumors NSCLC patients with p27-negative tumors benefit from adjuvant cisplatin-based chemotherapy Prognostic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non Small-Cell Lung Cancer lthe prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II nonsmall-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. lResults: Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy compared with patients with p53-negative tumors. Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. lConclusion: p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients. lJournal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5240-5247 RRM1和ERCC是靶向化疗的敏感性分子指标。可根据基因表 达高低选择个体化疗方案，RRM1高表达者建议避免使用吉西 他滨，ERCC1阴性者可考虑使用铂类药物治疗，可根据下列 四种表达情况知道临床化疗： ERCC1(+)/RRM1() 多选择紫杉醇/吉西他滨化疗方案； ERCC1(+)/RRM1(+)可选择长春瑞滨/紫杉醇方案； ERCC1(-)/RRM1()可选择铂类/吉西他滨方案； ERCC1(-)/RRM1(+)可选择铂类/紫杉醇方案。 Molecular signatures in resected patients Potential clinical implications lPrognosis assessment lObjective; selection of patients for adjuvant CT:Adjuvant chemotherapy in patients with high-risk gene signature lMolecular signatures should be validated in adjuvant therapy trials lHow to integrate molecular signatures with single gene prognostic and predictive markers should be explored 肺癌抗血管生成化疗 Adapted from Poon RT, et al. J Clin Oncol 2001;19:120725 新生血管生成在肿瘤发展过程的不同阶段所扮演的角色 恶变前期恶性肿瘤肿瘤生长血管侵袭微转移处于 休眠状态 明显的转移 (肿瘤无血管)(血管新生开始)(肿瘤形成血管)(肿瘤细胞进入血管内)(远道种植)(再次形成新生血管) l 传统的化疗用药方法在理论上可对抗内皮细胞的增殖， 但不能起到持续阻断血管生成的作用。 l 密集式低剂量给药可能会增加化疗药对再生内皮细胞的 抗血管生成效应以及对肿瘤细胞的促凋亡效应。这种剂 量低、间歇期短、能持续应用的给药方式称抗血管生成 化疗 ,是迄今肿瘤化疗新的治疗模式之一。 l 小剂量(最大耐受量的1/ 101/ 3)