肺癌驱动基因研究总结

Current Standard of NSCLC Care
ຫໍສະໝຸດ Baidu
Figure: Massachusetts General Hospital, data on file.
Horn L, Pao W. J Clin Oncol. 2009;26:4232–4235.
NSCLC肿瘤驱动基因
2010：7类肿瘤驱动基因，未知55%
Previously untreated stage IIIB/IV NSCLC,
PS 0/1 (n=451)
EGFR TKI组
Gefitinib trials
IPASS*1
9.5
(n= 261)
NEJ0022 N=194
10.8
WJTOG34053
9.2
N=172
Erlotinib trials
OPTIMAL4 N= 154
13.7
EURTAC5 N=174
10.4
Afatinib trial
LUX-LUNG- 3
13.6
N=345
PFS
化疗组 6.3 5.4 6.3
4.6 5.4
6.9
HR
EGFR TKI组
0.48
21.6
p<0.001
0.36
27.7
P<0.001
0.49
36
P<0.0001
0.16
22.7
p<0.0001
0.47
19.3
p<0.0001
0.47 p<0.0001
OS
化疗组
HR
21.9
1.00(0.76-1.33)
2010 Targeting oncogenic
drivers*
Evolution of NSCLC treatment
Adenocarcinoma
Non-squamous
Squamous
EGFR Mu
EGFR WT
2008
Squamous
Squamous-cell carcinoma
KRAS EGFR
No mutation detected KRAS (22%) EGFR (17%) EML4-ALK (7%) Double mutants (3%) BRAF (2%) AKT1
NRAS
MEK1 MET AMP HER2 PIK3CA
Frequency of driver genes in subgroups of NSCLC in Chinese
An SJ, Wu YL. PLoS One June 2012
91%抗肿瘤药物的敏感性与基因变异相关
Garnett MJ, et al. Nature 2012; 483:570-577.
分析了130种抗肿瘤 药物与肿瘤基因变异 之间的关系，证实 91% (118/130)的抗 肿瘤药物敏感性与至 少一种基因变异相关
NSCLC
FGER2 0.6%
DDR2 1% BRAF 2% PIK3CA 4%
unknown 30%
EGFR 28%
STK11
KRAS
8%
5%
c-MET
EML4-ALK
5%
6%
PTEN 10%
An SJ, Wu YL. PLoS One June 2012
Frequency of driver genes in subgroups of NSCLC in Chinese
PIK3CA ALK
BRAF HER2
MET Unknown
EGFR Mu
ALK+
KRAS Mu
Other non-
Today
squamous Squamous
WT
Large cell carcinoma *Incidence of mutations in adenocarcinoma provided as an example
Significantly Mutated Genes in Squamous Cell Lung Cancer
178/500鳞癌完成分析
Govindan et al. The Cancer Genome Atlas (TCGA) Project . 2012 ASCO
Therapeutic targets in squamous cell lung carcinoma
26.6
0.89(0.63-1.24)
39
1.19(0.77-1.83)
28.8
1.04(0.69-1.58)
19.5
1.04(0.65-1.68)#
FASTACT-2 (MO22201; CTONG0902) study design
Screening
Study treatment
Maintenance phase
2011：10类肿瘤驱动基因，未知46%
Unknown
K-ras EGFR B-raf Her2 PIK3CA ALK MET
Unknown
Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01. Massachusetts General Hospital, data on file; Horn L, Pao W. J Clin Oncol 2009; 26:4232–4235.
Amplification Mutation Mutation Amplification Mutation
16% 15% 15% 9% 9%
8% 4% 4% 4% 3%
Govindan R et al. ASCO 2012
第一个有临床意义的NSCLC驱动基因：
EGFR
EGFR mutant 1st line trials : PFS and OS
Gene
Event Type
Frequency
CDKN2A
Deletion/Mutation/Methylation
72%
PI3KCA PTEN FGFR1 EGFR PDGFRA
CCND1 DDR2 BRAF ERBB2 FGFR2
Mutation Mutation/Deletion Amplification Amplification Amplification/Mutation
非小细胞肺癌驱动基因研究
吴一龙 广东省肺癌研究所
广东省人民医院 广东省医学科学院
Treatment selection is moving from histologybased to targeting oncogenic drivers
1999 Histology-driven
selection