杨建伟结直肠癌的个体化治疗

结直肠癌的个体化治疗,杨建伟 福建省肿瘤医院,大肠癌的治疗进展,1980,1985,1990,1995,2000,2005 2006,5-FU,Irinotecan,Capecitabine,Oxaliplatin,Cetuximab,Bevacizumab panitumumab,Best supportive care (BSC),median overall survival,NCCN V.2. 2010 recommendations for first-line treatment of mCRC,NCCN clinical practice guidelines in oncology: colon cancer. V.2.2010,Previously untreated mCRC,Patients appropriatefor intensive therapy,FOLFOX bevacizumab,FOLFIRI + bevacizumab,FOLFOX cetuximab* or panitumumab*,FOLFIRI cetuximab* or panitumumab*,5-FU/LV + bevacizumab,FOLFOXIRI,XELOX bevacizumab,*KRAS wild-type onlyCategory 2B recommendation,Patients not appropriatefor intensive therapy,Capecitabine bevacizumab,Infusional 5-FU/LV bevacizumab,Cetuximab*,Panitumumab*,Colorectal Cancer Tumorigenesis,5,Genomic mechanisms in cancer care,2010,2000,1990,1980,BCR-ABL,HER2,Cytogenetics,EGFR,KRAS,C-KIT,MET,EML4-ALK,PIK3CA,BRAF,PDGFR,PTEN,Trastuzamab (Herceptin),Cetuximab(Erbitux),Imatinib(Gleevec),Erlotinib (Tarceva),Sunitinib (Sutent),Sorafenib (Nexavar),CYP2D6,UGT1A1,Dasatinib(Sprycel),Gefitinib (Iressa),Panitumumab (Vectibix),Bevacizumab (Avastin),Nilotinib (Tasigna),Lapatinib (Tykerb),Temsirolimus (Torisel),Personalized Oncology,Microsatellite lnstability Is a Favorable Prognostic lndicator in Patients With Colorectal Cancer Receiving Chemotherapy,Thymidilate Synthase Expression: An Independent Prognostic Factor for Local Recurrence, Distant Metastasis, Disease-free and Overall Survival in Rectal Cancer,Thymidilate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients,Thymidylate Synthase Protein Expression in Primary Colorectal Cancer Compared with the Corresponding Distant Metastases and Relationship with the Clinical Response to 5-Fluorouracil,Evidence for post-transcriptional downregulation of the apoptosis-related gene bcl-2 in human colorectal cancer,EVALUATION OF MULTIPLE BIO-PATHOLOGICAL FACTORS IN COLORECTAL ADENOCARCINOMAS: INDEPENDENT PROGNOSTIC ROLE OFp53 AND Bcl-2,VEGF,TP, DPD,TS UGT 1A1,ERCC1,?,RAS RAF,Molecular Assessment of Response in Disseminated Disease,TS,MSI,ERCC-1,EGFR,TP/DPD,UGT,KRAS,Intratumoral Expression:,Copies of gene Transcription of gene Synthesis of protein Expression,PIK3CA,5-FU的疗效预测指标,在肿瘤细胞内5-FU的3个活性代谢产物分别是：FdUMP抑制 TSFdUTP渗入 DNAFUTP渗入 RNA5-FU的代谢酶主要是TS、TP、DPD,Thymidylate Synthase (TS),TS:catalyzes conversion of dUMP to dTMPTarget of FU therapy.TS predicts response to FU therapy,TS,Thymidylate Synthase,Evidence:Prospective: PCR TS gene expression analysis correlates with response to PI 5-FU N=42, Leichman, JCO 1997Prospective: IHC TS expression correlates with response to bolus, IA 5-FUN=41, Cascinu, CCR 1999; N=36, Davies, CCR 1999,TS,Molecular Assessment of Response in Disseminated DiseaseTS:QUANTITATION IN DISSEMINATED COLORECTAL CANCER,5-FU的疗效预测指标,一、TS（胸苷酸合成酶）FdUMP可与TS、CF形成三元复合物TS可作为5-FU生物利用度的预测指标TS基因表达越高，5-FU疗效越差TS基因表达越低，5-FU疗效越好,Thymidine Phosphorylase,Catalyzes the reversible phosphorylation of thymidine to thymine,TP,5-FU 糖化 磷酸化 活性代谢产物FdUMP,TP,Thymidine Phosphorylase, levels in tumor cells = sensitivity to FUs,TP,5-FU的疗效预测指标,二、TP（胸苷酸磷酸化酶） TP5-FU 糖化 磷酸化 活性代谢产物TP可作为5-FU生物利用度的预测指标TP基因表达越高，5-FU的生物利用度越高,Dihydropyrimidine Dehydrogenase,Initial and rate-limiting step in FU catabolism levels in CRC non-responders vs responders,DPD,DPD5-FU DHFU NH3+CO2,5-FU的疗效预测指标,三、DPD（二氢嘧啶脱氢酶） DPD5-FU DHFU NH3+CO2NH3是引起呕吐的重要物质DPD基因表达高，呕吐发生率高，5-FU的生物利用度低DPD基因表达低， 5-FU的生物利用度高，但毒性增加,*p-value based on Fishers Exact test (2-tail),Molecular Assessment of Response in Disseminated DiseaseResponse to CI 5-FU in colon cancer: Effect of TS, TP, and DPD,TS TP DPD小结,TS、TP基因的表达情况对5-FU类的疗效预测作用目前还没有完全确定，需进一步临床试验证实。DPD基因的表达情况与5-FU生物利用度的相关性已确定，DPD基因表达越低，5-FU的生物利用度越高。MMR和MSI的基因状态目前尚不能作为以5-FU为基础的CRC化疗的预测指标。,OXA的疗效预测指标,ERCC-1, levels of DNA repair enzymes confer tumor resistance.ERCC-1 participates in repair of interstrand crosslinking caused by cisplatin intratumoral ERCC-1=platinum resistance,TS and ERCC-1 in GI TumorsMolecular Markers Resistance/Sensitivity,TS=5FU target. TS mRNA quantitation inversely associated with 5FU response in CRC and Gastric Cancer (J Clin Oncol, 1996 and 1998),ERCC-1=DNA repair gene. ERCC-1 mRNA quantitation inversely associated with 5FU/DDP response in primary gastric cancer (J Clin Oncol, 1997),ERCC-1 and repair in Colorectal Cancer,ERCC-1,Shirota et al, JCO 2001,Tx: 5FU and oxaliplatin N=50,OXA的疗效预测指标,ERCC1（切除修复交叉互补组1）ERCC1基因表达越高，肿瘤细胞损伤的DNA修复能力越强。ERCC1可作为铂类药物的疗效预测指标。ERCC1基因低表达，含OXA化疗的CRC患者有更好的OS。位于密码子118的SNP可影响ERCC1基因的表达和ERCC1的活性，但此位点的SNP结论有矛盾，临床应用需慎重。,3. Hahn K, et al. Am J Health-Syst Pharm. 2006;63(22):2211-2217,CPT-11的毒性预测指标,Toxicities,Hematological : Neutropenia Grade 4 12%EFebrile neutropenia 2-6%EThrombocytopeniaGrade 42%EHepatic :Increased bilirubinGrade 7%Elevated LFTsGrade 13%Gastrointestinal :Diarrhea Early 51%Late88%,UGT1A1,TATA promotor regionVariable repeats of thymine-adenine (TA)WILD TYPE promotor (UGT1A1*1) = 6 TA repeats3 variant alleles with 5, 7 and 8 TA repeats (TA)5, (TA)7, (TA)8 respectively. (TA)7 polymorphism UGT1A1*28 Homozygous genotype10% of North Americans2 alleles have 7 TA repeats 7/7(TA)5 & (TA)8 less common, African origin,UGT1A1*28 and Toxicity,Innocenti et al, (JCO 2004)5 :66 patients with advanced malignanciesIrinotecan 350mg/m2 q 3weeksPrimary objective : association btwn UGT1A1 genetic variations and toxicities.,Innocenti et al.,Frequency grade 4 neutropenia :9.5%6 patients : 7/7 (homozygous) 3 developed grade 4 neutropenia. 9.3 fold higher risk 2 / 24 patients with 6/7 genotype 0 / 28 patients with 6/6 genotypeGrade 3 diarrhea 5%No grade 4,“ Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele. ”,CPT-11的毒性预测指标,UGT1A1（尿嘧啶葡萄糖醛酸基转换酶） UGT1A1 小肠 CPT-11 SN38 SN38G SN38 重吸收 肝脏 UGT1A1基因的变化会显示不同水平的酶活性 UGT1A1*28的患者用CPT-11有较大毒性,So what do we do in practice ,Our patient : 7/7 homozygous for UGT1A1*28 polymorphism. Irinotecan100mg/m2 weeklyNo complications developed.,CPT-11的毒性预测指标,UGT1A1美国FDA批准了一种试剂盒检测UGT1A1*28及UGT1A1野生型等位基因。但并不是UGT1A1*28的患者用CPT-11都有较大毒性（MRC FOCUS试验显示UGT1A1的等位基因与毒性没有相关性）。因此临床上检测UGT1A1的基因状态不是必须的。,CPT-11的疗效预测指标,TOPO-I（拓扑异构酶-1）CPT-11是TOPO-I抑制剂根据TOPO-I蛋白表达水平可将CRC分为对CPT-11敏感或不敏感的两个亚组。这个结论由FOCUS3证实，但目前还没有临床常规应用。,西妥昔单抗的疗效预测指标,K-RASN-RASB-RAFPIK3CAPTEN双调蛋白表皮调节素,K-RAS mutation and Resistance,KRAS operates downstream of the cell-surface location of the epidermal growth factor in the signal transduction pathwayMutations at KRAS codons 12 and 13 cause constitutive KRAS activationMutations at these cites associated with anti-EGFR antibody resistanceMutations found in 30-50% of colon cancers,KRAS,西妥昔单抗的疗效预测指标,K-RAS基因状态可作为西妥昔单抗疗效的预测指标。应用抗EGFR药物之前要进行K-RAS基因的检测。40%的CRC患者K-RAS基因是突变型，对西妥昔单抗和帕尼单抗的治疗没有反应。K-RAS基因的突变位点：12、13、61、146密码子。,Impact of mutations in the PIK3CA signal transduction pathway,PIK3CA Mutation Is Associated With Poor Prognosis Among Patients With Curatively Resected Colon Cancer Ogino, et al, JCO 2009450 resected colon cancer PTS stages I-III18% had mutated PIK3CAWorse colon CA specific survival mutated vs wild-type PIK3CAWorse survival with mutated PIK3CA seen in KRAS wild-type vs mutated,PIK3CA,Impact of mutations in the PIK3CA signal transduction pathway,Ogino, et al, JCO 2009,PIK3CA,Impact of mutations in the BRAF signal transduction pathway,Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer Di Nicolantonio et al, JC