1、肺癌个体化精准治疗1.Jemal A,et al.CA Cancer J Clin 2011;61(2):69-90.2.Zheng R,et al.China Cancer 2012;21(1):1-12.2015:中国肺癌发病率和死亡率居世界最高2012年新发中国肿瘤患者占世界肿瘤患者比例020000040000060000080000010000001200000140000016000001800000食道癌胃癌结直肠癌肝癌肺癌乳腺癌中国以外世界中国52.1%58.8%27.0%35.6%51.2%46.5%其中肺癌治疗的疗效差别也较大 中美肿瘤5年OS分别为31%vs 68%(IJC
2、-2015)主要是中美两国在患者的临床期别和治疗手段的差别所有肿所有肿瘤瘤结直肠结直肠癌癌中枢肿中枢肿瘤瘤中国中国美国美国肺癌肺癌胃癌胃癌肝癌肝癌食管食管癌癌乳腺癌乳腺癌宫颈癌宫颈癌白血病白血病膀胱癌膀胱癌q 解除武装力量：消灭癌细胞的增殖、血管生成、免疫逃逸等q 歼灭特种部队：肿瘤细胞、肿瘤干细胞、微环境q 根据不同战场设计战术：原发灶和转移灶的异质性 为何50年抗癌之战收效不大的反思改变生活方式；早诊早治；优化治疗策略；转化医学研究孙子兵法之谋攻篇：不战而屈人之兵，要以小代价取大胜Rethink the war on Cancer.Lancet 2014美国近15年SCLC疗效无改善;非小
3、细胞肺癌5年OS仅提高4%抗癌之战 前路漫漫 个体化治疗解决肺癌异质性 空间异质性:Spatial患者个体异质性 时间异质性:Temporal Nature 2013异质性是肿瘤遗传不稳定性与环境因素导致分子多样性 Science 2012已发现众多肺癌相关分子但？基因水平突变基因水平突变肺癌的发生肺癌的发生个体化治疗个体化治疗肿瘤细胞生成 功能学改变解剖结构改变需要个体化精准与整合医学肺癌治疗是复杂的系统工程肺癌治疗是复杂的系统工程 治疗现状治疗现状:盲人摸象盲人摸象?肺癌治疗方案选择肺癌治疗方案选择 疗效评价疗效评价=Survival;LocalSurvival;Local Control
4、;QualityControl;Quality 有效有效 低低毒毒 经济经济 肺癌治疗的核心是使复杂的技术简单化 Cost Cost Effective toEffective to Cost ToxicityCost Toxicity 解决个体与优化 与循证医学依赖解决标准与平衡但循证不能教条肺癌治疗模式进展肺癌治疗模式进展TrTr Advances:Art of Oncology Advances:Art of Oncology循证医学循证医学精准医学个体医学解决整合与最大更依赖于大数据 治疗决策=临床证据+临床经验肺癌个体化治疗之策略年龄性别年龄性别身体状况身体状况治疗选择治疗选择传统因
5、素传统因素(病人因素病人因素)肿瘤位置肿瘤位置肿瘤分期肿瘤分期病理类型病理类型传统因素传统因素(肿瘤因素肿瘤因素)医生水平医生水平医生责任医生责任治疗依从治疗依从传统因素传统因素(治疗因素治疗因素)影像学组学影像学组学基因学组学基因学组学信息学组学信息学组学新型因素新型因素(难以确定难以确定)治疗与相关分子靶点关系治疗与相关分子靶点关系未知已知协同拮抗无关有无 治 疗 相 关 靶 点Potential Interactions between SBRT&Target drugsRECEL Results:RECEL Results:Cut-off 2015/05/31Cut-off 2015/
6、05/31%（n）Erlotinib+RT（n=13）EP+RT（n=12）CR30.8（4）16.7（2）PR15.4（2）16.7（2）SD46.2（6）33.3（4）PD0(0)8.33（1）NAa7.69（1）25（3）ORR46.2（6）33.3（4）DCR92.3（12）66.7（8）TKI EP PFS:21.3 m vs 6.2 mPFS:21.3 m vs 6.2 m CCRT Vs CTRT for IIIm(+)NSCLC个体医学分子靶向治疗新模式Clin Cancer Res 2015;21:151424.(同病异治)(异病同治)带有相同基因靶点的不同肿瘤给予相同治疗把
7、同一肿瘤所包含不同基因靶点行分类研究肺癌个体化治疗理念和实践肿瘤肿瘤3病人疗效差且很难预测 疗效高 损伤小 费用低肿瘤肿瘤 1肿瘤肿瘤2同样的治疗方案 同样组织类型及同样临床分期同样组织类型及同样临床分期方案 1肿瘤肿瘤1肿瘤肿瘤2肿瘤肿瘤3分子分型和分期不同同样组织类型及同样临床分期同样组织类型及同样临床分期方案2方案3 个体化全程管理与排兵布阵个体化全程管理与排兵布阵 首先要确定治疗目的或目标首先要确定治疗目的或目标科学随访病理诊断临床分期与分子分型精准治疗(几线几代?）个体化治疗 与全程管理分子诊断 (集成精准）精准医学多学科会诊Sciences 2013十大科学突破之首 Harness
8、ing the immune system to battle tumors Silvia et al.J Natl Cancer Inst.2013免疫指标CD8+TILs预测PFS和OS过度放化疗破坏机体免疫过度放化疗破坏机体免疫Clin Cancer Res 2009；J.Radiat Oncol Biol Phys.2012;放疗或化疗放疗或化疗强度不足强度不足放疗或化疗放疗或化疗强度过度强度过度放疗或化疗放疗或化疗强度适宜强度适宜Check-point Signaling in Check-point Signaling in CaCa Immunotherapy Immunothe
9、rapyJames AllisonJames Allison LASKER 2015LASKER 2015Check Mate-017&057Check Mate-017&057晚期晚期NSCLC:Success or NotNSCLC:Success or NotqEarly palliative care:Early palliative care:2.72.7 monsmons(11.6(11.6 vsvs 8.9)8.9)Early supportive care:Early supportive care:$6000/6000/yryr(N (N EnglEngl J Med)J M
10、ed)qBevacizumabBevacizumab(ECOG 4599):(ECOG 4599):2 2 monsmons(14(14 vsvs 12)12)BevacizumabBevacizumab:$115,000/115,000/yryrqNivolumabNivolumab(ASCO 2015):(ASCO 2015):3.33.3 monsmonsNivolumab:$140,000/yr 新免疫治疗药价是黄金4000倍,治疗费100万美元/年:Saltz;2015 ASCO Most ExpensiveBest Care:2015 ASCO SBRTSBRT Abscopal
11、Effect;Postow et al.N Engl J Med.2012 Combine SBRT with Immunotherapy可手术可手术I I期期NSCLC:SBRT NSCLC:SBRT VsVs 手术手术STARS&ROSELSTARS&ROSEL Pooled Analysis of 58 Pooled Analysis of 58 ptsptsChang JY et al.Lancet Oncol,2015无复发生存总生存SBRT(31 pts)SBRT(31 pts)Surgery(27 pts)Surgery(27 pts)HRHRP-valueP-value3-yr
12、 RFS3-yr RFS86%86%80%80%0.690.690.540.543-yr OS3-yr OS95%95%79%79%0.140.140.0370.037RTOG 3502 Schema:ongoingSchema:ongoing PI:PI:JinmingJinming Yu,MD,PhD;Yu,MD,PhD;目前该研究已经成功入组目前该研究已经成功入组1010例病人例病人仅供医学交流使用 放射免疫治疗放射免疫治疗:远隔效应远隔效应 The abscopal effect:RT-induced tumor regression in lesions distant from a
13、 targeted site Kamrava M,et al,Mol Biosyst.2009 Nov;5:1262-70单纯放疗对区域淋巴结及远隔效应影响研究各组单纯放疗均未见明显的远隔效应 不同分割模式放疗对肿瘤的局控率不同，引发的免疫反应也不同，但均未见明显的远隔效应 大分割较常规分割对肿瘤的局控率更高，进一步激活局部肿瘤、引流淋巴结及全身免疫反应Local plus Systemic Control Lead to Local plus Systemic Control Lead to CaCa Cure Cure没有没有100%100%Stage I;Stage I;其中其中5-10
14、%5-10%患者在血液中发现患者在血液中发现CTCCTCImmunotherapyImmunotherapyBernstein and Chang.Nature Rev Clin OncoI-SBRTPhase III Trial-StudyPhase III Trial-Study DesignDesignOligometastatic NSCLCChemo and IT naveECOG PS 0-1Pre-tr PD-L1 analysisMPDL3280A(1200mg q3w)+SBRT(50Gy in 4 fraction)Primary Endpoint -OS Addition
15、al Endpoint -ORR -PFS -Safety -PD-L1 expressionPemetrexed/Docetaxel/Gemcitabin+Cisplatin/Caboplatin探讨寡转移者SBRT联合免疫治疗代替化疗可行性Hypothesis:Radiation combined immunotherapy will lead to enhanced anti-tumor immune responses&improved clinical outcomeNot All Stage IV Lung Cancer Are Equal Some stage IV could
16、be curable&some elective olig-mets mOS20monsSelective pts with mets responded to ChT/TT survive for years Stage Iv=a/b/c disease and gene profiling or CTC based stage in the futureSingle/olig-metsDiffused metsTr sensitive metsCan Can S Stage IV tage IV L Lung ung C Ca a:Have Have 5 5 yryr OS?Yes OS?
17、Yes p If we have targetable genes or If we have targetable genes or C Ch hT T sensitive sensitive C Ca ap If we can activate immune responseIf we can activate immune responsep If resistant/residual lesion can be wipedIf resistant/residual lesion can be wiped out byout by radiation especially by SBRT
18、 radiation especially by SBRT p If personalized combine modalityIf personalized combine modality or precision or precision medisionmedision is is delivereddeliveredp If we could cIf we could combine immunotherapy ombine immunotherapy&SBR SBRT T 免疫与靶向之比较免疫与靶向之比较q两者都是有划时代意义的革命性贡献q靶向治疗可作一线而免疫目前尚不能q靶向敏感
19、性高治愈率低而免疫则相反免疫的ORR 仅为20%,但存在拖尾现象q都需要靶点检测而靶向的标准更成熟q价格超贵及病人不敏感和耐药及损伤 免疫治疗自身免疫与间质肺炎等损伤q与其他治疗手段的联合目前都有争议TKI TKI VsVs Immunotherapy Immunotherapy个性化治疗方案大数据组学研究精准治疗提高疗效、减轻损伤、降低费用分子影像精准肿瘤学精准肿瘤学:最终目标最终目标?临床队列和生物样本库临床队列和生物样本库Hypoxia PET/CT ImagingHypoxia PET/CT Imaging Hypoxia FETNIM PET/CT imaging in basic
20、and clinical studies Predict the radiosensitivity and OS using hypoxia imaging Am J Clin Oncol 2006;29:628 Cancer Biol Ther 2006;5:1320 Clin Lung Cancer.2010;11:335 First reported in 2008 ASCO,be commented in ASCO Daily News“The first study using FETNIM PET to detect the clinical hypoxia&optimize th
21、e treatment”A significant correlation between lung cancer hypoxia and overall survival of radiotherapyFETNIM PET/CT uptake positively correlating with expression of hypoxia markersOverall Survival,%Time,Months HV23.85HV 23.85P=0.041Cancer Sci 2007;98:1413 J Nucl Med 2009;50:303 J Nucl Med 2011 EGFRE
22、GFR受体显像研究获受体显像研究获JNMJNM年度最佳论文年度最佳论文q通过细胞-动物-临床系列研究，创建PD153035 PET/CT EGFR显像技术q应用于临床，指导肺癌分子靶向治疗、疗效预测及放疗靶区勾画意大利博洛尼亚大学Pantaleo教授在国际影像学排名第一的J Nucl Med专题评述:“国际率先的临床研究，在核医学和肿瘤学研究方面取得突破”EGFR系统显像技术15.012.09.06.03.00.0随访时间（月）1.00.80.60.40.20.0总 生 存率SUV 2.92SUV 2.92P=0.001EGFR显像预测靶向治疗疗效Dear Shuanghu Yuan,MD,P
23、hD,On behalf of the Annual Meeting Scientific Program Committee of the American Society for Radiation Oncology,I am pleased to inform you that you have been selected as one of the recipients of a 2015 Annual Meeting Abstract Award.You have won the International Abstract Award for your abstract title
24、d,“Noninvasive Evaluation of Metabolic Tumor Volume in LLC Tumor Bearing C57 Mice With PET and the Radiotracers 18F-Alfatide and 18F-FDG:A Comparative Analysis.”To honor your achievement,you will receive a$4,000 award and a complimentary registration to the Annual Meeting.All award winners will be f
25、eatured in the Annual Meeting Proceedings and in the Final Program,and you will be given a Certificate onsite at the meeting during the International Breakfast.Your attendance at the meeting is required in order to receive the award benefits.Your award check will be available for pick-up at the Facu
26、lty/VIP office at the Henry B.Gonzalez Convention Center when you arrive in San Antonio.The Annual Meeting dates are:October 17 21,2015Location:Henry B.Gonzalez Convention Center,San Antonio Texas USAAttendance Required-International Breakfast:Sunday,October 18 6:45am 8:00amCongratulations on your e
27、xcellent work and we look forward to your presentation in San Antonio.Sincerely,Benjamin Movsas,MD,FASTROChairman,Annual Meeting Scientific Committee Lisa Kachnic,MD,FASTROVice-chair,Annual Meeting Scientific Committee Johanna VanArsdall|Sr.Manager,Scientific and Educational Programs|direct line:703
28、.839.7358 American Society for Radiation Oncology8280 Willow Oaks Corporate Drive,Suite 500Fairfax,VA 22031Main#:703.502.1550 肺癌研究需要肺癌研究需要 Advances of Lung Advances of Lung CaCaq转化医学转化医学q个体医学个体医学q整合医学整合医学q精准医学 肺癌研究需要肺癌研究需要 Precision Oncologyq个体个体q实时实时q动态动态q多点多点q定量定量q集成集成Sequencing Buccal swab or Blo
29、od Sequencing Tumor Board Disclosure of Results Genetic Counselor Analysis 1)Actionable Results?2)Incidental Results?Informed Consent Tumor Biopsy Genetic Counseling MI-ONCOSEQ:The Michigan Oncology Sequencing Center Precision Medicine Tumor Board 肺癌精准治疗的流程Sequencing Buccal swab or Blood Sequencing
30、Tumor Board Disclosure of Results Genetic Counselor Analysis 1)Actionable Results?2)Incidental Results?Informed Consent Tumor Biopsy Genetic Counseling MI-ON COSEQ:The Michig an Oncolog y Sequencing Center Precision Medicine Tumor Board Datacollection精准医学挑战精准医学挑战 Challenge:Challenge:PresicionPresicion Medicine Medicineq检测方法不精确带来的治疗不精确q监测不到靶点或监测到也无药可用q也将和循证及转化医学一样被淡化q精准医学一定不是唯一版和终极版 肿瘤的病因仍是未知的和多因素的 是不断发展完善:3DCRT;IMRT;IGRTq解决老的价格贵又带来新价格毒性 从统计学到个体的精确但针对少数
