2009ASCO结肠癌进展.ppt

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1、2009ASCO结肠癌进展结肠癌进展南昌大学第一附属医院肿瘤科南昌大学第一附属医院肿瘤科 黎军和黎军和n n分子指标预测期结肠癌高危复发n n大型研究结果n nCeteximab疗效的预测n n结肠癌辅助化疗终点n nOxaliplatin相关n nsynchronous stage IV colorectal cancer n n化疗策略和方案的调整n n其它分子指标预测结肠癌高危复发及指导化疗分子指标预测结肠癌高危复发及指导化疗n nAbr4000 高通量高通量 n nAbr4001MSIn nAbr 4002 n nAbr 4012 18q LOHn nBackground:Backgr

2、ound:NSABP C-01/C-02 NSABP C-01/C-02、CCF CCF、C-04 C-04、C-06C-06 48 genes significantly associated with recurrence risk and 66 genes predictive of 48 genes significantly associated with recurrence risk and 66 genes predictive of 5FU/LV benefit.Multivariate analysis yielded 18 genes(7 prognostic genes

3、,6 5FU/LV benefit.Multivariate analysis yielded 18 genes(7 prognostic genes,6 predictive genes,5 reference genes)and separate predictive genes,5 reference genes)and separate prognostic recurrence score(RS)prognostic recurrence score(RS)and and predictive treatment score(TS)predictive treatment score

4、(TS)algorithms.algorithms.n nMethods:Methods:Gene expression was quantitated by RT-PCR.Recurrence-free interval Gene expression was quantitated by RT-PCR.Recurrence-free interval(RFI),disease-free survival(DFS),and overall survival(OS)were analyzed using Cox(RFI),disease-free survival(DFS),and overa

5、ll survival(OS)were analyzed using Cox regression regression n nResults:Results:In the QUASAR validation study the RS predicted recurrence risk(p=0.004).In the QUASAR validation study the RS predicted recurrence risk(p=0.004).The RS also predicted DFS(p=0.01)and OS(p=0.04).Recurrence risk increased

6、The RS also predicted DFS(p=0.01)and OS(p=0.04).Recurrence risk increased monotonically with increasing RS.In multivariate analyses,RS retained prognostic monotonically with increasing RS.In multivariate analyses,RS retained prognostic significance(p=0.008)independent of mismatch repair(MMR),T stage

7、,nodes significance(p=0.008)independent of mismatch repair(MMR),T stage,nodes examined,grade,and lymphovascular invasion.MMR deficiency(p0.001)and T4 examined,grade,and lymphovascular invasion.MMR deficiency(p12,500 Impact of older age on the efficacy of newer adjuvant therapies in 12,500 patients(p

8、ts)with stage II/III colon cancer:Findings from the ACCENT patients(pts)with stage II/III colon cancer:Findings from the ACCENT Database.Database.n nBackground:Background:to determine the impact of pts age 70 v 70 yrs on colon cancer to determine the impact of pts age 70 do not receive the same bene

9、fit from combination and/or pts 70 do not receive the same benefit from combination and/or oral FU as those 70.Any benefit,if present,compared to IV FU/LV would oral FU as those 70.Any benefit,if present,compared to IV FU/LV would not be clinically meaningful.not be clinically meaningful.Tejpar etl.

10、2009ASCO Abstract LBA4n nInternational randomized phase III study of capecitabine(Cap),bevacizumab International randomized phase III study of capecitabine(Cap),bevacizumab(Bev),and mitomycin C(MMC)in first-line metastatic colorectal cancer(Bev),and mitomycin C(MMC)in first-line metastatic colorecta

11、l cancer(mCRC):Final results of the AGITG MAX trial.(mCRC):Final results of the AGITG MAX trial.n npatients:patients:either unfit for or who do not require initial oxaliplatin/irinotecan.either unfit for or who do not require initial oxaliplatin/irinotecan.n nMethods:Methods:arm A Cap(Cap 2000mg/m2/

12、d or 2500mg/m2 d1-14 q21d),arm A Cap(Cap 2000mg/m2/d or 2500mg/m2 d1-14 q21d),arm B Cap Bev(Bev 7.5mg/kg q3w)arm B Cap Bev(Bev 7.5mg/kg q3w)arm C Cap Bev MMC(MMC 7mg/m2 q6w).arm C Cap Bev MMC(MMC 7mg/m2 q6w).n nResultsResultsn nConclusions:Conclusions:The addition of BevMMC to Cap significantly impr

13、oved PFS The addition of BevMMC to Cap significantly improved PFS without significant additional toxicity.OS was similar for all arms.Cap without significant additional toxicity.OS was similar for all arms.Cap BevMMC is an active,low toxicity regimen that may be considered as a BevMMC is an active,l

14、ow toxicity regimen that may be considered as a treatment option for pts with mCRC.treatment option for pts with mCRC.Tebbutt etl.2009ASCO Abstract 4023n nIn phase III CRYSTAL trialIn phase III CRYSTAL trial，QoL was a secondary endpoint QoL was a secondary endpoint n nMethods:Methods:EORTC QLQ-C30(v

15、3.0)questionnaire EORTC QLQ-C30(v3.0)questionnaire n nResults Results：In pts with mCRC,cetuximab plus FOLFIRI first-line In pts with mCRC,cetuximab plus FOLFIRI first-line significantly prolongs PFS compared with FOLFIRI alone while significantly prolongs PFS compared with FOLFIRI alone while preser

16、ving QoL.The PFS benefit is even more pronounced for pts preserving QoL.The PFS benefit is even more pronounced for pts with KRAS wt tumors.with KRAS wt tumors.Folprecht etl.2009ASCO Abstract 4076n nmFOLFOX-bevacizumab or XELOX-bevacizumab then mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizum

17、ab(B)alone or with erlotinib(E)in first-line bevacizumab(B)alone or with erlotinib(E)in first-line treatment of patients with metastatic colorectal cancer treatment of patients with metastatic colorectal cancer(mCRC):Interim safety analysis of DREAM study.(mCRC):Interim safety analysis of DREAM stud

18、y.n nResults:Results:induction with mFOLFOX-B or XELOX-B as induction with mFOLFOX-B or XELOX-B as well as maintenance with B or B+E appears to be well-well as maintenance with B or B+E appears to be well-tolerated,without unexpected side effects tolerated,without unexpected side effects Tournigand

19、etl.2009ASCO Abstract 4077Ceteximab疗效的预测疗效的预测n nEGFR ligand:amphiregulin epiregulin n ninsulin-like growth factor 1(IGF-1)n nBRAF-1n n皮疹n nEGFR polymorphismsn nBackground:Background:Gene expression of the EGFR ligand epiregulin(Gene expression of the EGFR ligand epiregulin(EREGEREG)may further predi

20、ct benefit from cetuximab may further predict benefit from cetuximab n nMethods:Methods:CRC tumour samples were analyzed from a phase III clinical CRC tumour samples were analyzed from a phase III clinical trial of cetuximab plus BSC vs BSC alone(NEJM 2007;357(20)trial of cetuximab plus BSC vs BSC a

21、lone(NEJM 2007;357(20)n nResults:Results:In the In the K-rasK-ras WT subset,OS was better for cetuximab than BSC WT subset,OS was better for cetuximab than BSC among patients with high EREG(HR 0.43;p0.0001)but not for low among patients with high EREG(HR 0.43;p0.0001)but not for low EREG patients(HR

22、 0.77,p=0.28).High EREG patients(HR 0.77,p=0.28).High EREGEREG AND AND K-rasK-ras WT status WT status(Combimarker)was present in 139(36%).Within the Combimarker(Combimarker)was present in 139(36%).Within the Combimarker positive group the median PFS was 5.4 vs 1.9 months(HR,0.31;positive group the m

23、edian PFS was 5.4 vs 1.9 months(HR,0.31;p0.0001),and median OS 9.8 vs 5.1 months(HR,0.43;p0.001)in the p0.0001),and median OS 9.8 vs 5.1 months(HR,0.43;p0.001)in the cetuximab vs BSC arms cetuximab vs BSC arms n nConclusions:Conclusions:patients with both high patients with both high EREGEREG gene e

24、xpression and gene expression and K-rasK-ras wild-type status may benefit from cetuximab therapy.Determination of wild-type status may benefit from cetuximab therapy.Determination of EREGEREG gene expression levels should be prospectively evaluated in gene expression levels should be prospectively e

25、valuated in patient selection for EGFR targeted therapy.patient selection for EGFR targeted therapy.Jonker et al.2009ASCO Abstract 4016n nBackground:Background:70%to 40%of patients with K-RAS wild type does not seem 70%to 40%of patients with K-RAS wild type does not seem to benefit from Cetuximab.Co

26、lorectal cancer cells with IGF-1 system to benefit from Cetuximab.Colorectal cancer cells with IGF-1 system activation may escape anti-EGFR mediated cell death activation may escape anti-EGFR mediated cell death n nMethods:Methods:IGF-1 expression and K-RAS mutational status was assessed in IGF-1 ex

27、pression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab advanced colorectal cancer patients receiving irinotecan/cetuximab n nResults:Results:IGF-1 was overexpressed in 41 cases(66%).IGF-1 was overexpressed in 41 cases(66%).IGF-1 negati

28、ve IGF-1 positive IGF-1 negative IGF-1 positive progressive disease 6(29%)26(63%)progressive disease 6(29%)26(63%)Median TTP 7.7 months 2.3 months Median TTP 7.7 months 2.3 months Among K-RAS wild type patients,IGF-1 negative and positive tumors Among K-RAS wild type patients,IGF-1 negative and posi

29、tive tumors showed a partial response to cetuximab-irinotecan in 7(50%)and 1(5%)showed a partial response to cetuximab-irinotecan in 7(50%)and 1(5%)cases respectively(p=0.004).Median TTP in IGF-1 negative tumors was 11 cases respectively(p=0.004).Median TTP in IGF-1 negative tumors was 11 months and

30、 3.2 months in IGF-1 positive colorectal cancers(p=0.03).months and 3.2 months in IGF-1 positive colorectal cancers(p=0.03).Conclusions:Conclusions:IGF-1 proved to be a reliable predictive factor for resistance to IGF-1 proved to be a reliable predictive factor for resistance to anti-EGFR monoclonal

31、 antibodies in K-RAS wild type colorectal cancer anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer Scartozzi et al.2009ASCO Abstract 4017n nBackground:Background:To study the power of epiregulin(EREG)and amphiregulin To study the power of epiregulin(EREG)and amphiregulin(AREG)expr

32、ession in primary tumors to predict the outcome in patients(AREG)expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer(cmCRC)treated with the with chemorefractory metastatic colorectal cancer(cmCRC)treated with the combination of cetuximab

33、plus bination of cetuximab plus irinotecan.n nMethods:Methods:amphiregulin and epiregulin mRNA expression amphiregulin and epiregulin mRNA expression n nResults:Results:In In KRASKRAS wild-type wild-type(WT)patients,there was a significant association between (WT)patients,there was a significant ass

34、ociation between log-transformed ligand expression and response In a Cox-regression model log-transformed ligand expression and response In a Cox-regression model log-transformed ligand expression was significantly associated to progression-log-transformed ligand expression was significantly associa

35、ted to progression-free survival(PFS)and overall survival(OS)free survival(PFS)and overall survival(OS)There was no predictive power of ligand expression in There was no predictive power of ligand expression in KRASKRAS mutant mutant patients.patients.n nConclusions:Conclusions:Expression of EGFR li

36、gands in primary tumors significantly Expression of EGFR ligands in primary tumors significantly predicts favorable outcome in predicts favorable outcome in KRASKRAS WT mCRC treated with cetuximab and WT mCRC treated with cetuximab and irinotecan irinotecan Prenen et al.2009ASCO Abstract 4019nAbstra

37、ct 4021 retrospectively assessed KRAS mutational status and Amphiregulin expression by immunohistochemistry(IHC)in 86 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan,n nResults:Results:AR-low patients reported a significantly worse RR(2/22,AR-low patients rep

38、orted a significantly worse RR(2/22,9%)compared with AR-high(10/27,37%)(p=0.024)and a 9%)compared with AR-high(10/27,37%)(p=0.024)and a trend toward shorter PFS(3.5 vs 5.3 months,HR 0.88 95%CI:trend toward shorter PFS(3.5 vs 5.3 months,HR 0.88 95%CI:0.46-1.60,p=0.628)and OS(8.8 vs 15.1 months,HR 0.6

39、0 0.46-1.60,p=0.628)and OS(8.8 vs 15.1 months,HR 0.60 95%CI:0.30-1.10,p=0.106).95%CI:0.30-1.10,p=0.106).n nConclusions:Conclusions:Absent or low AR expression at IHC may be related Absent or low AR expression at IHC may be related to resistance to cetuximab plus irinotecan.to resistance to cetuximab

40、 plus irinotecan.Loupakis et al.2009ASCO Abstract 4021n nBackground:Background:re-assessing the impact of KRAS status and other re-assessing the impact of KRAS status and other possible predictive factors for OS possible predictive factors for OS n nResults:Results:OS in pts with KRAS wt tumors was

41、significantly improved OS in pts with KRAS wt tumors was significantly improved compared to pts with KRAS mt tumors(median 20.8 vs 15.9 compared to pts with KRAS mt tumors(median 20.8 vs 15.9 mo;hazard ratio(HR)=1.62;p=0.0296).mo;hazard ratio(HR)=1.62;p=0.0296).Cox proportional hazard analysis showe

42、d that as well as KRAS Cox proportional hazard analysis showed that as well as KRAS wt status(vs KRAS mt),an acne-like rash of grade 2/3(vs grade wt status(vs KRAS mt),an acne-like rash of grade 2/3(vs grade 0/1)in the first 6 weeks and no prior treatment(vs prior neo-0/1)in the first 6 weeks and no

43、 prior treatment(vs prior neo-/adjuvant treatment)were the strongest independent predictors/adjuvant treatment)were the strongest independent predictors for prolonged survival(each p0.005).for prolonged survival(each p1xULN levels of LDH,have major and 1xULN levels of LDH,have major benefit to anti-

44、EGFR therapy in second-third line therapy.benefit to anti-EGFR therapy in second-third line therapy.n nAbstract 4063Abstract 4063：Co-expression of pIGF-1R and MMP7 is Co-expression of pIGF-1R and MMP7 is associated with resistance to anti-EGFR therapy in associated with resistance to anti-EGFR thera

45、py in WTRASWTRAS pts.pts.n n结肠癌辅助化疗观测终点Abstract 4011n nObject Object (1)2yr DFS predicts 5yr OS?(2)a stronger relationship between DFS and OS (1)2yr DFS predicts 5yr OS?(2)a stronger relationship between DFS and OS in stage III pts?(3)6 or 7 yrs are necessary to demonstrate DFS and OS?association in

46、 in stage III pts?(3)6 or 7 yrs are necessary to demonstrate DFS and OS?association in future trials due to extended survival following recurrence future trials due to extended survival following recurrence n n12,676 patients from MOSAIC,X-ACT,PETACC-3,NSAPB C-06 and C-07,and 12,676 patients from MO

47、SAIC,X-ACT,PETACC-3,NSAPB C-06 and C-07,and C89803C89803n nMethods:Methods:Concordance between 2 and 3yr DFS,and 5 and 6yr OS was examined in 6 Concordance between 2 and 3yr DFS,and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997-2002.randomized phase III trials from 1997-2002.n

48、 nResults Results n nConclusions:Conclusions:In recent trials in stage III pts,DFS HRs based on 2yr median f-up are In recent trials in stage III pts,DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs.In all pts the association between DFS and OS highly predictive of 5 and 6y

49、r OS HRs.In all pts the association between DFS and OS HRs is stronger for 6yr OS,but 7yr follow-up may be required.These data support 3yr HRs is stronger for 6yr OS,but 7yr follow-up may be required.These data support 3yr DFS as a primary endpoint for modern stage III trials,and indicate that 2yr D

50、FS would DFS as a primary endpoint for modern stage III trials,and indicate that 2yr DFS would also be an appropriate primary endpoint.also be an appropriate primary endpoint.Sargent et al.2009ASCO Abstract 4011OxaliplatinOxaliplatin相关相关n nTo define the sensitivity to oxaliplatin reintroduction n nC