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癌症的个体化治疗: 现实还是梦境?. 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 2010.05.21 上海. 2010. Sir William Osler (1849-1919). 1892 年的医学实践. 1892 年的医学实践. “ 假如个体之间没有如此大的不同,医学就是科学而不是艺术”. 目前的临床实践 – 问题多多. 选择和不选择. Lung adeno EGFR M+ : 44.1% (113/256) * Non-smoker M+ : - PowerPoint PPT Presentation
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2010.05.21
1892 1892
Intron1 allele16 MST20 >16 MST11 P=0.039SNP Iressa
Exon 19& MET30 Exon 21 &T790M 55 Exon 19PRT790M TKI
TKIc-MET was amplified in 3.8% (2/53) of 25 the TKI-nave NSCLC Chen HJ, Wu YL,Pathol. Oncol. Res.2009,unpublished data
EGFRTKIEGFREGFR EGFR Her3c-Met kRasPTENPI3K/Akt
EGFR TKI
NSCLC EGFREGFR Richard L Schilsky, ASCO
NSCLC Phase IIIMMP-Is FT-Is PKC-Is HDA-Is HER2 moabsCOX-2 Is P53 Gene Th.SORAFENIB VEGF TrapIGF-1R
EGFR-TKIs - Erlotinib /Gefitinib* in 2nd-3rd line (FDA/EMEA approval)* Only for Asiatic CountriesAnti-EGFR-mABs - Cetuximab in 1st-line EGRF + (+ CT P-based)Anti-VEGF-mABs - Bevacizumab in 1st-line non Squamous (+ CT P-based)(FDA/EMEA approval)Multiple TK Is -Vandetanib -Sunitinib Proteasome IsHDACmTOR Is
EGFR: epidermal growth factor receptor; TKI: tyrosine kinase inhibitorVEGF: vascular epidermal growth factor
EML4-ALKALK
EML4-ALK 12/10511.4%10/62 16.1% 2/29 0.7%
WuZhang et al. 2009
3
(SCLC)
(NSCLC)
KRAS1987: KRAS
KRASEGFR2004: EGFR
Chart8
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80
10
Sheet1
Adenocarcinoma50
Squamous20
Large Cell10
Small20
KRAS20
Unknown80
EGFR10
Sheet1
Sheet2
Sheet3
KRASEGFRHER2BRAFALK fusionPIK3CAMEK1ROS fusionPDGFR amp2009:
Chart10
20
80
10
2
1
2
2
4
1
1
Sheet1
Adenocarcinoma50
Squamous20
Large Cell10
Small20
KRAS20
Unknown80
EGFR10
BRAF2
MEK11
HER22
ALK fusion2
PIK3CA4
ROS fusion1
PDGFRa amp1
Sheet1
Sheet2
Sheet3
KRASEGFRHER2BRAFALK fusionPIK3CAMEK1ROS fusionPDGFR amp G719X, exon 19 del, L858R, L861Q 1exon 20 dup2L747S, D761Y, T854A, T790MMET amplification2009:
Chart10
20
80
10
2
1
2
2
4
1
1
Sheet1
Adenocarcinoma50
Squamous20
Large Cell10
Small20
KRAS20
Unknown80
EGFR10
BRAF2
MEK11
HER22
ALK fusion2
PIK3CA4
ROS fusion1
PDGFRa amp1
Sheet1
Sheet2
Sheet3
EGFR exon 19 del/L858RSens to EGFR TKIsKRASRes to EGFR TKIsEGFR T790M/D761Y/T854ARes to EGFR TKIs; sens to new TKIs?MET amplificationSens to MET TKIsMEK1Sens to MEK inhibitorsHER2Sens to HER2 TKIsBRAFSens to BRAF inhibitorsALK fusionsSens to ALK inhibitorsPDGFRa amplificationSens to PDGFR inhibitorsPIK3CAPIK3CA inhibitors?ROS fusionSens to ROS inhibitors?
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Oncotype offers a Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer21 genes are investigated in paraffin-embedded tumor tissue via RT-PCRGoals Predicting distant disease recurrenceIdentify patients best benefiting from treatmentsAvoiding adverse events in those who will not benefit
2: UGT1A1 Irinotecan 10%UGT1A1UGT1A1
PGx Based on data from Innocenti et al (2004)
(IHC)enzyme-linked immunosorbent assay (ELISA)assessed by microarray technology or reverse transcription-polymerase chain reaction (RT-PCR)fluorescent/chromogenic in-situ hybridisation (FISH/CISH)DNA sequencing (other methods possible for known mutations)IHC FISH ELISA
RRM1 ERCC1 NSCLC.
NSCLCERCC1ERCC1
4
:? ? , , , , 2D6 cypP450 genotype []plasma(free)90% PET, MRI,..
NSCLC
*ADCC, antibody-dependent cellular cytotoxicity; EGFR, epidermal growth factor receptorWithin treatment group comparison showed that progression-free survival was significantly longer in mutation positive patients receiving gefitinib (HR 0.19; 95% CI 0.13, 0.26; p