2010.05.21

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EGFR mutation IPD meta-analysis in Chinese NSCLCLung adeno EGFR M+44.1% (113/256) *Non-smoker M+43.3% (84/194) *Female M+42.7% (76/178) *Lung non-adeno EGFR M+ 8.9% (18/202)Smoker M+15.3% (37/242)Male M+22.8% (76/334)Wu et al, JTO 2007; 5: 430* P

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 Res.2009,unpublished data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

Comparison of PFS by mutation status within treatment armsGefitinib, HR=0.19, 95% CI 0.13, 0.26, p

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

20

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