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Multiplex Genotyping and the 
Treatment of Lung Cancers 
Mark G Kris, MD The William and Joy Ruane Chair of Thoracic Oncology 
Attending Physician, Thoracic Oncology Service 
Lead Physician, MSK-IBM Watson Oncology Project 
Memorial Sloan Kettering Cancer Center 
Professor of Medicine 
Weill Cornell Medical College
13%
2003: Discovery of EGFR exon 19 deletion at MSK 
1 JUL 2002 29 JUL 2002 23 OCT 2003 
ATP-binding site 
EGF binding Tyrosine kinase 
TM K Y Y Y Y 
Auto-phos 
Exon 19 
PVAIKELREATSPKAN 
6 aa del 
* 
Serial radiographs of a 73-year old never smoking woman with adenocarcinoma, mixed cell-type with BAC 
features, who demonstrated radiographic regression while on gefitinib. She took gefitinib from July 2002 until 
October 2003. B. Schematic of the EGFR protein and the 6 amino acid (aa) deletion detected in A.G.’s tumor. 
(K-lysine residue, Y-tyrosine). C. Immunoblotting analyses demonstrate that compared to wild type (WT) 
EGFR, the A.G. mutant has less autophosphorylation activity but may be more stable in transient transfections. 
(2 identical but individual WT clones and 3 identical but individual A.G. mutant clones were assessed. 
Pao PNAS 2004
Frequency of Oncogenic Drivers in 
3026 Lung Adenocarcinomas at MSK 
Dogan Clin Cancer Res, 2012
Marc Ladanyi 
“Looking for a Target on Every Tumor” Science 2009; 326: 218-220 www.science mag.org
LCMC: Frequency of Oncogenic Drivers 
in Lung Adenocarcinomas 
Kris and Johnson JAMA 2014
Survival with the five most frequent oncogenic drivers 
0 1 2 3 4 5 
0.0 0.2 0.4 0.6 0.8 1.0 
YEARS 
SURVIVAL 
group=ALK 
group=Doub 
group=EGFR(o) 
group=EGFR(s) 
group=KRAS 
p=0.001 
Altered Gene N Median Survival (95% CI) 
EGFR (sensitizing) 140 4.0 years (2.7 to 5.4) 
EGFR (other) 50 3.3 years (2.2 to 6.2) 
ALK 73 4.3 years (3.0 to NA) 
KRAS 231 2.4 years (1.9 to 3.6) 
Two Drivers 32 2.0 years (1.6 to 4.6)
Survival of Patients with Drivers: Targeted 
Therapy vs No Targeted Therapy 
(C) 
(B) 
(A) 
(C) 264 233 146 80 40 25 
(B) 361 255 123 61 44 27 
(A) 313 200 109 64 45 23 
0 1 2 3 4 5 
0.0 0.2 0.4 0.6 0.8 1.0 
YEARS 
SURVIVAL 
(A) 
(B) 
(C) 
Group N Median Survival (95% CI) 
Driver, no targeted therapy (A) 313 2.4 years (1.8 to 2.9) 
No driver (B) 361 2.1 years (1.8 to 2.5) 
Driver, targeted therapy (C) 264 3.5 years (3.2 to 4.6) 
S U R V IV AL 
Driver with targeted therapy 
Driver with NO targeted therapy 
Kris 
JAMA 2014
Krisk 
k
Response to Vemurafenib 
BRAF V600E Mutant Lung Cancer 
baseline 6 weeks on vemurafenib
Evolution of Multiplexed Testing Platforms 
Now-Gen 
MSK LC-MAP 
8 genes 
Point mutations only 
Next-Gen 
MSK IMPACT 
341 genes 
Point mutations plus deletions, insertions, 
amplifications 
Comparable time and cost
MSK-IMPACT: Assay of 341 Cancer Genes 
ABL1 BRAF CSF1R ETV6 H3F3C KLF4 MYD88 PIK3CB RECQL4 SPEN 
AKT1 BRCA1 CTCF EZH2 HGF KRAS MYOD1 PIK3CD REL SPOP 
AKT2 BRCA2 CTLA4 FAM123B HIST1H1C LATS1 NBN PIK3CG RET SRC 
AKT3 BRD4 CTNNB1 FAM175A HIST1H2BD LATS2 NCOR1 PIK3R1 RFWD2 STAG2 
ALK BRIP1 CUL3 FAM46C HIST1H3B LMO1 NF1 PIK3R2 RHOA STK11 
ALOX12B BTK DAXX FANCA HNF1A MAP2K1 NF2 PIK3R3 RICTOR STK40 
APC CARD11 DCUN1D1 FANCC HRAS MAP2K2 NFE2L2 PIM1 RIT1 SUFU 
AR CASP8 DDR2 FAT1 ICOSLG MAP2K4 NKX2-1 PLK2 RNF43 SUZ12 
ARAF CBFB DICER1 FBXW7 IDH1 MAP3K1 NKX3-1 PMAIP1 ROS1 SYK 
ARID1A CBL DIS3 FGF19 IDH2 MAP3K13 NOTCH1 PMS1 RPS6KA4 TBX3 
ARID1B CCND1 DNMT1 FGF3 IFNGR1 MAPK1 NOTCH2 PMS2 RPS6KB2 TERT 
ARID2 CCND2 DNMT3A FGF4 IGF1 MAX NOTCH3 PNRC1 RPTOR TET1 
ARID5B CCND3 DNMT3B FGFR1 IGF1R MCL1 NOTCH4 POLE RUNX1 TET2 
ASXL1 CCNE1 DOT1L FGFR2 IGF2 MDC1 NPM1 PPP2R1A RYBP TGFBR1 
ASXL2 CD274 E2F3 FGFR3 IKBKE MDM2 NRAS PRDM1 SDHA TGFBR2 
ATM CD276 EED FGFR4 IKZF1 MDM4 NSD1 PRKAR1A SDHAF2 TMEM127 
ATR CD79B EGFL7 FH IL10 MED12 NTRK1 PTCH1 SDHB TMPRSS2 
ATRX CDC73 EGFR FLCN IL7R MEF2B NTRK2 PTEN SDHC TNFAIP3 
AURKA CDH1 EIF1AX FLT1 INPP4A MEN1 NTRK3 PTPN11 SDHD TNFRSF14 
AURKB CDK12 EP300 FLT3 INPP4B MET PAK1 PTPRD SETD2 TOP1 
AXIN1 CDK4 EPCAM FLT4 INSR MITF PAK7 PTPRS SF3B1 TP53 
AXIN2 CDK6 EPHA3 FOXA1 IRF4 MLH1 PALB2 RAC1 SH2D1A TP63 
AXL CDK8 EPHA5 FOXL2 IRS1 MLL PARK2 RAD50 SHQ1 TRAF7 
B2M CDKN1A EPHB1 FOXP1 IRS2 MLL2 PARP1 RAD51 SMAD2 TSC1 
BAP1 CDKN1B ERBB2 FUBP1 JAK1 MLL3 PAX5 RAD51B SMAD3 TSC2 
BARD1 CDKN2A ERBB3 GATA1 JAK2 MPL PBRM1 RAD51C SMAD4 TSHR 
BBC3 CDKN2B ERBB4 GATA2 JAK3 MRE11A PDCD1 RAD51D SMARCA4 U2AF1 
BCL2 CDKN2C ERCC2 GATA3 JUN MSH2 PDGFRA RAD52 SMARCB1 VHL 
BCL2L1 CHEK1 ERCC3 GNA11 KDM5A MSH6 PDGFRB RAD54L SMARCD1 VTCN1 
BCL2L11 CHEK2 ERCC4 GNAQ KDM5C MTOR PDPK1 RAF1 SMO WT1 
BCL6 CIC ERCC5 GNAS KDM6A MUTYH PHOX2B RARA SOCS1 XIAP 
BCOR CREBBP ERG GREM1 KDR MYC PIK3C2G RASA1 SOX17 XPO1 
BLM CRKL ESR1 GRIN2A KEAP1 MYCL1 PIK3C3 RB1 SOX2 YAP1 
BMPR1A CRLF2 ETV1 GSK3B KIT MYCN PIK3CA RBM10 SOX9 YES1 
Ladanyi 
Berger 
Solit 
Acila
Using Driver Mutations to Classify 
and Treat All Lung Cancers 
Carcinoid 
Large Cell 
Large Cell Neuroendocrine 
5%
Oncogenic Drivers In Lung Cancers
Impact of MSK IMPACT 
MSK Patients with Thoracic Cancers 
Many Targets, Drugs, and Protocols 
Gene Targets in NCCN Guidelines 7 
Targeted Drugs in NCCN Compendia 12 
Gene Targets for Investigational Agents 17 
Trials of Targeted Therapies for Specific Genes 30
Multiplex Genotyping and the Treatment of Lung Cancers 
Conclusions 
• The “one size fits all” treatment era of lung cancers is over 
• Advances in cancer biology have changed care. Targeted 
therapies are biology-based and patient specific 
• Precise pathologic diagnoses a must. Tissue needed. 
• Test …. Don’t Guess. No “patient profile” adequate to select 
• Do multiplexed testing at diagnosis. Tissue needed. 
• Targeted therapies are standard for patients with stage IV. 
Results justify use with local therapies in stages I-III 
• Personalized care for lung cancers is here. A model for other 
cancers.
2005 2012 
“ Here's my sequence...” 
Kris 
Kris 
XXXXXXXXXXXXXXXXX

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Multiplex Genotyping Guides Precision Lung Cancer Treatment

  • 1. Multiplex Genotyping and the Treatment of Lung Cancers Mark G Kris, MD The William and Joy Ruane Chair of Thoracic Oncology Attending Physician, Thoracic Oncology Service Lead Physician, MSK-IBM Watson Oncology Project Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Cornell Medical College
  • 2. 13%
  • 3. 2003: Discovery of EGFR exon 19 deletion at MSK 1 JUL 2002 29 JUL 2002 23 OCT 2003 ATP-binding site EGF binding Tyrosine kinase TM K Y Y Y Y Auto-phos Exon 19 PVAIKELREATSPKAN 6 aa del * Serial radiographs of a 73-year old never smoking woman with adenocarcinoma, mixed cell-type with BAC features, who demonstrated radiographic regression while on gefitinib. She took gefitinib from July 2002 until October 2003. B. Schematic of the EGFR protein and the 6 amino acid (aa) deletion detected in A.G.’s tumor. (K-lysine residue, Y-tyrosine). C. Immunoblotting analyses demonstrate that compared to wild type (WT) EGFR, the A.G. mutant has less autophosphorylation activity but may be more stable in transient transfections. (2 identical but individual WT clones and 3 identical but individual A.G. mutant clones were assessed. Pao PNAS 2004
  • 4. Frequency of Oncogenic Drivers in 3026 Lung Adenocarcinomas at MSK Dogan Clin Cancer Res, 2012
  • 5. Marc Ladanyi “Looking for a Target on Every Tumor” Science 2009; 326: 218-220 www.science mag.org
  • 6. LCMC: Frequency of Oncogenic Drivers in Lung Adenocarcinomas Kris and Johnson JAMA 2014
  • 7. Survival with the five most frequent oncogenic drivers 0 1 2 3 4 5 0.0 0.2 0.4 0.6 0.8 1.0 YEARS SURVIVAL group=ALK group=Doub group=EGFR(o) group=EGFR(s) group=KRAS p=0.001 Altered Gene N Median Survival (95% CI) EGFR (sensitizing) 140 4.0 years (2.7 to 5.4) EGFR (other) 50 3.3 years (2.2 to 6.2) ALK 73 4.3 years (3.0 to NA) KRAS 231 2.4 years (1.9 to 3.6) Two Drivers 32 2.0 years (1.6 to 4.6)
  • 8. Survival of Patients with Drivers: Targeted Therapy vs No Targeted Therapy (C) (B) (A) (C) 264 233 146 80 40 25 (B) 361 255 123 61 44 27 (A) 313 200 109 64 45 23 0 1 2 3 4 5 0.0 0.2 0.4 0.6 0.8 1.0 YEARS SURVIVAL (A) (B) (C) Group N Median Survival (95% CI) Driver, no targeted therapy (A) 313 2.4 years (1.8 to 2.9) No driver (B) 361 2.1 years (1.8 to 2.5) Driver, targeted therapy (C) 264 3.5 years (3.2 to 4.6) S U R V IV AL Driver with targeted therapy Driver with NO targeted therapy Kris JAMA 2014
  • 9.
  • 10.
  • 12. Response to Vemurafenib BRAF V600E Mutant Lung Cancer baseline 6 weeks on vemurafenib
  • 13. Evolution of Multiplexed Testing Platforms Now-Gen MSK LC-MAP 8 genes Point mutations only Next-Gen MSK IMPACT 341 genes Point mutations plus deletions, insertions, amplifications Comparable time and cost
  • 14. MSK-IMPACT: Assay of 341 Cancer Genes ABL1 BRAF CSF1R ETV6 H3F3C KLF4 MYD88 PIK3CB RECQL4 SPEN AKT1 BRCA1 CTCF EZH2 HGF KRAS MYOD1 PIK3CD REL SPOP AKT2 BRCA2 CTLA4 FAM123B HIST1H1C LATS1 NBN PIK3CG RET SRC AKT3 BRD4 CTNNB1 FAM175A HIST1H2BD LATS2 NCOR1 PIK3R1 RFWD2 STAG2 ALK BRIP1 CUL3 FAM46C HIST1H3B LMO1 NF1 PIK3R2 RHOA STK11 ALOX12B BTK DAXX FANCA HNF1A MAP2K1 NF2 PIK3R3 RICTOR STK40 APC CARD11 DCUN1D1 FANCC HRAS MAP2K2 NFE2L2 PIM1 RIT1 SUFU AR CASP8 DDR2 FAT1 ICOSLG MAP2K4 NKX2-1 PLK2 RNF43 SUZ12 ARAF CBFB DICER1 FBXW7 IDH1 MAP3K1 NKX3-1 PMAIP1 ROS1 SYK ARID1A CBL DIS3 FGF19 IDH2 MAP3K13 NOTCH1 PMS1 RPS6KA4 TBX3 ARID1B CCND1 DNMT1 FGF3 IFNGR1 MAPK1 NOTCH2 PMS2 RPS6KB2 TERT ARID2 CCND2 DNMT3A FGF4 IGF1 MAX NOTCH3 PNRC1 RPTOR TET1 ARID5B CCND3 DNMT3B FGFR1 IGF1R MCL1 NOTCH4 POLE RUNX1 TET2 ASXL1 CCNE1 DOT1L FGFR2 IGF2 MDC1 NPM1 PPP2R1A RYBP TGFBR1 ASXL2 CD274 E2F3 FGFR3 IKBKE MDM2 NRAS PRDM1 SDHA TGFBR2 ATM CD276 EED FGFR4 IKZF1 MDM4 NSD1 PRKAR1A SDHAF2 TMEM127 ATR CD79B EGFL7 FH IL10 MED12 NTRK1 PTCH1 SDHB TMPRSS2 ATRX CDC73 EGFR FLCN IL7R MEF2B NTRK2 PTEN SDHC TNFAIP3 AURKA CDH1 EIF1AX FLT1 INPP4A MEN1 NTRK3 PTPN11 SDHD TNFRSF14 AURKB CDK12 EP300 FLT3 INPP4B MET PAK1 PTPRD SETD2 TOP1 AXIN1 CDK4 EPCAM FLT4 INSR MITF PAK7 PTPRS SF3B1 TP53 AXIN2 CDK6 EPHA3 FOXA1 IRF4 MLH1 PALB2 RAC1 SH2D1A TP63 AXL CDK8 EPHA5 FOXL2 IRS1 MLL PARK2 RAD50 SHQ1 TRAF7 B2M CDKN1A EPHB1 FOXP1 IRS2 MLL2 PARP1 RAD51 SMAD2 TSC1 BAP1 CDKN1B ERBB2 FUBP1 JAK1 MLL3 PAX5 RAD51B SMAD3 TSC2 BARD1 CDKN2A ERBB3 GATA1 JAK2 MPL PBRM1 RAD51C SMAD4 TSHR BBC3 CDKN2B ERBB4 GATA2 JAK3 MRE11A PDCD1 RAD51D SMARCA4 U2AF1 BCL2 CDKN2C ERCC2 GATA3 JUN MSH2 PDGFRA RAD52 SMARCB1 VHL BCL2L1 CHEK1 ERCC3 GNA11 KDM5A MSH6 PDGFRB RAD54L SMARCD1 VTCN1 BCL2L11 CHEK2 ERCC4 GNAQ KDM5C MTOR PDPK1 RAF1 SMO WT1 BCL6 CIC ERCC5 GNAS KDM6A MUTYH PHOX2B RARA SOCS1 XIAP BCOR CREBBP ERG GREM1 KDR MYC PIK3C2G RASA1 SOX17 XPO1 BLM CRKL ESR1 GRIN2A KEAP1 MYCL1 PIK3C3 RB1 SOX2 YAP1 BMPR1A CRLF2 ETV1 GSK3B KIT MYCN PIK3CA RBM10 SOX9 YES1 Ladanyi Berger Solit Acila
  • 15. Using Driver Mutations to Classify and Treat All Lung Cancers Carcinoid Large Cell Large Cell Neuroendocrine 5%
  • 16. Oncogenic Drivers In Lung Cancers
  • 17. Impact of MSK IMPACT MSK Patients with Thoracic Cancers Many Targets, Drugs, and Protocols Gene Targets in NCCN Guidelines 7 Targeted Drugs in NCCN Compendia 12 Gene Targets for Investigational Agents 17 Trials of Targeted Therapies for Specific Genes 30
  • 18.
  • 19. Multiplex Genotyping and the Treatment of Lung Cancers Conclusions • The “one size fits all” treatment era of lung cancers is over • Advances in cancer biology have changed care. Targeted therapies are biology-based and patient specific • Precise pathologic diagnoses a must. Tissue needed. • Test …. Don’t Guess. No “patient profile” adequate to select • Do multiplexed testing at diagnosis. Tissue needed. • Targeted therapies are standard for patients with stage IV. Results justify use with local therapies in stages I-III • Personalized care for lung cancers is here. A model for other cancers.
  • 20. 2005 2012 “ Here's my sequence...” Kris Kris XXXXXXXXXXXXXXXXX