Lung cancer in Never-smokers A clinical entity with increasing clinical relevance in Southern California The role of chemo...
Patient case <ul><li>56 yo Chinese never-smoking female, mother of 2, no PMHx </li></ul><ul><li>Routine health check-up (a...
Global Cancer deaths Sun Nature  Review cancer 2007; 7 : 778-790
Global distribution of never-smokers Sun Nature  Review cancer 2007; 7 : 778-790
NSCLC Epidemiology   (Orange, San Diego, & Imperial County 1995 to 2003; N=11,969) Variable Number Percent Age 68.3 years ...
Characteristics of NSCLC according to smoking status
Characteristics of Asian subgroups Total Ever-smoker Never-smoker P N (%)^ 891 (73.9) 314 (26.1) Median age [years] (95% C...
Proportion of NSCLC patients by  gender & smoking status * percentage calculated across the row
Percentages of Never-smokers in Southern California
Proportion of NSCLC who were never-smokers 5 major Asian subgroups and period of diagnosis
Effect of Smoking on overall survival
Major EGFR signaling pathways
Expression pattern of EGFR in NSCLC
EFGR Expression by IHC and Survival Meta-analysis Meert et al, Eur Respir J 2002; 20: 975-981
Structures of EGFR-TK Inhibitors  (Quinazolines) Gefitinib [Iressa ®  (ZD1839)] MW=446 CI F N O NH N O O N Erlotinib [Tarc...
BR21 OS Shepherd NEJM 2005; 353: 123-132 Erlotinib  (N=488) Placebo   (N=243) Median Survival 6.7 mo 4.7 mo 1-Year Surviva...
ISEL OS At 7.2 months median follow-up OS: 5.6 months vs 5.1 months 1 yr survival rate: 27% vs 21% HR 0.89, [0.77-1.02]; P...
ISEL Adenocarcinoma OS At 7.2 months median follow-up OS: 6.3 months vs 5.4 months 1 yr survival rate: 30% vs 18% HR 0.84,...
Overall Survival of ISEL Asian vs. non-Asian Chang JTO 2006; 1: 847-855
1. Asians have higher proportion of never-smokers with lung cancer 2. Asian seems to response and have better survival to ...
Discovery of activating EGFR mutations in NSCLC
List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
Distribution of EGFR mutations Shigematsu Gazdar Int J Cancer 2006; 118: 257-262
EGFR mutation incidence by cigarette-smoking status Pham et al JCO 2006; 24: 1700-1704 Pham et al JCO 2006; 24: 1700-1704
How would you treat the patient? <ul><li>Tarceva? </li></ul><ul><li>Chemotherapy? </li></ul><ul><ul><li>which combination?...
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not all mutations are the same!!!
List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
Differential response of exon 19 deletions & L858R point mutation to TKIs Riely et al, Clin Cancer Res 2006; 12: 839-844
Differential response of exon 19 deletions & L858R point mutation to TKIs Jackman et al, Clin Cancer Res 2006; 12: 3908-39...
 
 
 
 
Acquired resistance to oral EGFR TKI <ul><li>T790M mutation (70%) </li></ul><ul><li>c-met over-expression (8%) </li></ul>A...
List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
BIBW2992 <ul><li>Orally available </li></ul><ul><li>Irreversible inhibitor of EGFR1 and EGFR2 </li></ul><ul><ul><li>Binds ...
EGFR-TKIs Selectivity IC 50  (nM) EGFR-1 HER-2 Erlotinib (Tarceva) 2 350 Gefitinib (Iressa) 23 3700 BIBW2992 (Tovok) 0.5 1...
EGFR-TKIs In vitro EGFR activity IC 50  (nM) Cell line BIBW2992 Gefitinib NCI-H1666 (EGFR WT) 7 100 NCI-H3255 (L858R) 6 50...
1200.22 Patient 1 46 yo Hispanic Female Never-smoker Exon19 deletion 8/20/2008 9/15/2008
1200.22 Patient 1  46 yo Hispanic Female Never-smoker  Exon19 deletion 3/2/2009
1200.22 Patient 2 63 yo Vietnamese Female Never-smoker Exon19 deletion 12/16/2008 1/9/2009
1200.22 Patient 2 63 yo Vietnamese Female Never-smoker Exon19 deletion 2/9/2009 3/9/2009
Global trial registration trial of BIBW2992 <ul><li>EGFR mutation positive patients </li></ul><ul><li>BIBW2992 versus  Pem...
How would you treat the patient now? <ul><li>EGFR mutation analysis is negative (wild-type) </li></ul>
Clinical Activity Observed in a Phase 1 Dose-Escalation Trial of an Oral MET and ALK Inhibitor PF-02341066  EL Kwak 1 , DR...
PF-02341066 <ul><li>Potent & selective ATP competitive inhibitor of MET and ALK kinases and their oncogenic variants  </li...
Initial characterization of EML4-ALK fusion in NSCLC Soda  Nature 2007; 448:561-566
Schema of EML4-ALk NSCLC translocations Wong Cancer 2009; 115; 1723-1733
EML4-ALK NSCLC Adenocarcinoma comparisons (N = 209) Wong Cancer 2009; 115; 1723-1733 EML4-ALK positive EML4-ALK negative T...
Break-Apart FISH Assay  for ALK Fusion Genes <ul><li>Potential Fusion  </li></ul><ul><li>Partners: </li></ul><ul><li>EML4 ...
EML4-ALK Patients: Waterfall Plot Tumor Responses to PF-02341066 for NSCLC Patients with EML4-ALK Fusions For 2 patients w...
48 YO Female Non-Smoker with EML4-ALK NSCLC Pre-Treatment   After 2 Cycles PF-02341066
My own pt 51 yo Caucasian Male NSCLC Failed Tarceva, on 6 th  line Rx before enrolling in c-met trial Before and After c-m...
Planned Global  registration  trial for PF-02341066 <ul><li>EML4-ALK positive NSCLC patients </li></ul><ul><li>PF-02341066...
1 st  & 2 nd  -line treatment for Never-smoker with NSCLC EGFR Mutation  Positive (~60%) EML4-ALK  translocation  Positive...
The End
 
 
 
 
Proportion of male NSCLC never-smoker By period of diagnosis and 5 Asian subgroups
Proportion of female NSCLC never-smoker By period of diagnosis and 5 ethnicities
1 st  & 2 nd  line Rx of NSCLC in ever-smokers <ul><li>First line </li></ul><ul><ul><li>ATTRACT-1 (UCI-07-72) </li></ul></...
Adjuvant Rx <ul><li>ECOG1505 </li></ul><ul><ul><li>Cisplatin + gemcitabine /navelbine/alimta/taxotere +/- avastin </li></u...
Cox models for Never-smokers and Smokers Never-smoker Smoker HR 95% CI P HR 95% CI P Ethnicity* Caucasian Asian African-Am...
Place of birth-North America Smoker (%)* Never-smoker (%)* Canada All (N=176) Male Female 162 (92.1%) 79 (95.2%) 83 (89.2%...
Interplay between CA repeats and promoter polymorphism in EGFR gene Nomura PLoS Med 2007; 4 (4):e125
California Cancer Registry http://statecancerprofiles.cancer.gov/
Birthplace of Asian patients Filipino Vietnamese Chinese Japanese Koreans All Never-smoker Smoker All Never-smoker Smoker ...
Proportion of never-smokers by Asian subgroups
OS according to stage stratified by smoking status
Pharmodynamic blockade of EGFR pathway
Positions of Mutations Detected in HER1/EGFR Tyrosine Kinase Domain in NSCLC 747-750 Activation  loop L858 G719 Autophosph...
 
 
 
Upcoming SlideShare
Loading in …5
×

Never-smoker with lung cancer in Southern California

3,100 views

Published on

Never-smoker with Lung cancer in Southern California. Never-smokers with lung cancer have distinct genetic changes. Chao Family Comprehensive Cancer Center at UCI Irvine offers cutting edge clinical trials. Please call 1-714-456-8000

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
3,100
On SlideShare
0
From Embeds
0
Number of Embeds
504
Actions
Shares
0
Downloads
53
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • In total, there were 11,969 incident cases of non-small-cell lung cancer during the defined study period detected in our database. Mean age was 68.3 years, and 54% of the group was male. The majority of patients were caucasian (80.4%).
  • Structures of EGFR-TK Inhibitors (Quinazolines) IRESSA  (gefitinib [ZD1839]) and Tarceva  (erlotinib [OSI-774]) are low molecular weight quinazolines that are highly selective and specific inhibitors of EGFR-TK The ATP-mimetic portions of these molecules are highlighted in white
  • This is a schematic view of EGFR and its key domains. The extracellular ligand-binding domain The transmembrane domain The tyrosine kinase domain The autophosphorylation domain The tyrosine kinase domain (exons 18 through 24) is expanded, showing the sites of described point mutations at G719, S752, R776, H835, L858, and L861, and in-frame deletions at L747-A750. In the 3-dimensional ribbon structure of the intracellular domain shown on the right of the slide, the positions of 3 of these mutations are shown relative to the activation loop. Pao et al. Proc Natl Acad Sci U S A . 2004;101:13306. Lynch et al. N Engl J Med . 2004;350:2129; Paez et al. Science . 2004;304:1497.
  • Never-smoker with lung cancer in Southern California

    1. 1. Lung cancer in Never-smokers A clinical entity with increasing clinical relevance in Southern California The role of chemotherapy and updates from ASCO2009 Sai-Hong Ignatius Ou, MD PhD Associate Clinical Professor [email_address] Chao Family Comprehensive Cancer Center Department of Medicine, Division of Hematology-Oncology University of California Irvine Medical Center, Orange, CA 92868 Genetic Epidemiology Research Institute Department of Epidemiology School of Medicine University of California Irvine, Irvine, CA92697
    2. 2. Patient case <ul><li>56 yo Chinese never-smoking female, mother of 2, no PMHx </li></ul><ul><li>Routine health check-up (asymptomatic) right chest opacity on CXR </li></ul><ul><li>CT-PET fusion revealed RML mass 1.8 cm (SUV 5.2) and right mediastinal and subcarinal LN involvement </li></ul><ul><li>VAT revealed pleural nodules (Lobectomy + mediastinal LN resection aborted, RML mass wedge resection and pleural nodules biopsy performed) </li></ul><ul><li>Lung mass & pleural nodules: well-differentiated adenocarcinoma with BAC features </li></ul><ul><li>MRI of brain negative </li></ul><ul><li>Stage: T4 N2 M0 (current staging) or T1 N2 M1 (new staging) </li></ul>
    3. 3. Global Cancer deaths Sun Nature Review cancer 2007; 7 : 778-790
    4. 4. Global distribution of never-smokers Sun Nature Review cancer 2007; 7 : 778-790
    5. 5. NSCLC Epidemiology (Orange, San Diego, & Imperial County 1995 to 2003; N=11,969) Variable Number Percent Age 68.3 years +/- 0.1 SE --- Gender Male Female 6470 5497 54.1 45.9 Smoking status Smoker Non-smoker 8762 942 90.3 9.7 Stage Localized Regional Metastatic 2399 3071 5907 21.1 27.0 51.9
    6. 6. Characteristics of NSCLC according to smoking status
    7. 7. Characteristics of Asian subgroups Total Ever-smoker Never-smoker P N (%)^ 891 (73.9) 314 (26.1) Median age [years] (95% CI) 68 (47-83) 66 (44-86) .0359* Sex Male Female 671 (75.3) 220 (24.7) 83 (26.4) 231 (73.6) < .0001 Histology Adenocarcinoma BAC Large cell Squamous cell Undifferentiated 361 (40.5) 25 (2.8) 55 (6.2) 183 (20.5) 267 (30.0) 178 (56.7) 23 (7.3) 18 (5.7) 16 (5.1) 79 (25.2) < .0001 AJCC stage Stage 1 Stage 2 Stage 3 Stage 4 Unknown 92 (10.3) 42 (4.7) 203 (22.8) 420 (47.1) 134 (15.0) 31 (9.9) 5 (1.6) 49 (15.6) 190 (60.5) 39 (12.4) .0003
    8. 8. Proportion of NSCLC patients by gender & smoking status * percentage calculated across the row
    9. 9. Percentages of Never-smokers in Southern California
    10. 10. Proportion of NSCLC who were never-smokers 5 major Asian subgroups and period of diagnosis
    11. 11. Effect of Smoking on overall survival
    12. 12. Major EGFR signaling pathways
    13. 13. Expression pattern of EGFR in NSCLC
    14. 14. EFGR Expression by IHC and Survival Meta-analysis Meert et al, Eur Respir J 2002; 20: 975-981
    15. 15. Structures of EGFR-TK Inhibitors (Quinazolines) Gefitinib [Iressa ® (ZD1839)] MW=446 CI F N O NH N O O N Erlotinib [Tarceva ™ (OSI-774)] MW=430 O O H 3 C H 3 C O O NH N N NH N O O N
    16. 16. BR21 OS Shepherd NEJM 2005; 353: 123-132 Erlotinib (N=488) Placebo (N=243) Median Survival 6.7 mo 4.7 mo 1-Year Survival 31.2% 21.5%
    17. 17. ISEL OS At 7.2 months median follow-up OS: 5.6 months vs 5.1 months 1 yr survival rate: 27% vs 21% HR 0.89, [0.77-1.02]; P = 0.087 At 10.2 months median follow-up HR 0.89, [0.79-1.01]; P = 0.074 Thatcher et al, Lancet 2005; 366: 1527-1537
    18. 18. ISEL Adenocarcinoma OS At 7.2 months median follow-up OS: 6.3 months vs 5.4 months 1 yr survival rate: 30% vs 18% HR 0.84, [0.68-1.03]; P = 0.089 At 10.2 months median follow-up HR 0.84, [0.70-1.02]; P = 0.072 Thatcher et al, Lancet 2005; 366: 1527-1537
    19. 19. Overall Survival of ISEL Asian vs. non-Asian Chang JTO 2006; 1: 847-855
    20. 20. 1. Asians have higher proportion of never-smokers with lung cancer 2. Asian seems to response and have better survival to inhibitors of Epidermal Growth Factor Receptor (EGFR) Why?
    21. 21. Discovery of activating EGFR mutations in NSCLC
    22. 22. List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
    23. 23. Distribution of EGFR mutations Shigematsu Gazdar Int J Cancer 2006; 118: 257-262
    24. 24. EGFR mutation incidence by cigarette-smoking status Pham et al JCO 2006; 24: 1700-1704 Pham et al JCO 2006; 24: 1700-1704
    25. 25. How would you treat the patient? <ul><li>Tarceva? </li></ul><ul><li>Chemotherapy? </li></ul><ul><ul><li>which combination? </li></ul></ul><ul><li>Screen for EGFR mutation? </li></ul>
    26. 44. Not all mutations are the same!!!
    27. 45. List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
    28. 46. Differential response of exon 19 deletions & L858R point mutation to TKIs Riely et al, Clin Cancer Res 2006; 12: 839-844
    29. 47. Differential response of exon 19 deletions & L858R point mutation to TKIs Jackman et al, Clin Cancer Res 2006; 12: 3908-3914 No K-ras mutation identified RR: gefitinib (78%) vs erlotinib (33%) (P = 0.035) Exon 19 deletion L858R mutation P N 22 10 CR 9% 0% PR 64% 50% ORR 73% 50% 0.25 Median OS 38 mo 17 mo 0.0384 Median TTP 24 mo 10 mo 0.04 Median Duration of Rx for CR/PR 16 mo 13 mo 0.46 Median duration of RX for SD 26 mo 10 mo 0.01
    30. 52. Acquired resistance to oral EGFR TKI <ul><li>T790M mutation (70%) </li></ul><ul><li>c-met over-expression (8%) </li></ul>Arcila PASCO 2009
    31. 53. List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
    32. 54. BIBW2992 <ul><li>Orally available </li></ul><ul><li>Irreversible inhibitor of EGFR1 and EGFR2 </li></ul><ul><ul><li>Binds covalently to Cys773 within the catalytic cleft of the ATP-binding pocket of EGFR </li></ul></ul><ul><li>Inhibits to a significant level in vitro phosphorylation of EGFR in NSCLC cell lines with T790M mutation </li></ul>
    33. 55. EGFR-TKIs Selectivity IC 50 (nM) EGFR-1 HER-2 Erlotinib (Tarceva) 2 350 Gefitinib (Iressa) 23 3700 BIBW2992 (Tovok) 0.5 14 Lapatinib (GW572016) 11 9
    34. 56. EGFR-TKIs In vitro EGFR activity IC 50 (nM) Cell line BIBW2992 Gefitinib NCI-H1666 (EGFR WT) 7 100 NCI-H3255 (L858R) 6 50 NCI-H1975 (L858R + T790M) 93 resistant
    35. 57. 1200.22 Patient 1 46 yo Hispanic Female Never-smoker Exon19 deletion 8/20/2008 9/15/2008
    36. 58. 1200.22 Patient 1 46 yo Hispanic Female Never-smoker Exon19 deletion 3/2/2009
    37. 59. 1200.22 Patient 2 63 yo Vietnamese Female Never-smoker Exon19 deletion 12/16/2008 1/9/2009
    38. 60. 1200.22 Patient 2 63 yo Vietnamese Female Never-smoker Exon19 deletion 2/9/2009 3/9/2009
    39. 61. Global trial registration trial of BIBW2992 <ul><li>EGFR mutation positive patients </li></ul><ul><li>BIBW2992 versus Pemetrexed/Cisplatin </li></ul><ul><li>Primary endpoint: Progression-Free survival </li></ul>
    40. 62. How would you treat the patient now? <ul><li>EGFR mutation analysis is negative (wild-type) </li></ul>
    41. 63. Clinical Activity Observed in a Phase 1 Dose-Escalation Trial of an Oral MET and ALK Inhibitor PF-02341066 EL Kwak 1 , DR Camidge 2 , J Clark 1 , GI Shapiro 3 , RG Maki 4 , MJ Ratain 5 , B Solomon 6 , Y-J Bang 7 , S-H Ou 8 , R Salgia 5 1. Massachusetts General Hospital 5. University of Chicago Cancer Center 2. University of Colorado Cancer Center 6. Peter MacCallum Cancer Centre 3. Dana-Farber Cancer Institute 7. Seoul National University 4. Memorial Sloan-Kettering Cancer Center 8. University of California at Irvine
    42. 64. PF-02341066 <ul><li>Potent & selective ATP competitive inhibitor of MET and ALK kinases and their oncogenic variants </li></ul>PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases. MET/HGFR ALK   Y Y P P Y Y P P TM TM Y Y P P Y Y P P Y Y P P Y Y P P SEMA TM TM Extracellular Intracellular Y Y P P Y Y P P Kinase Y Y P P Y Y P P Y Y P P Y Y P P Cytoplasmic Fusion Variants of ALK NPM-ALK EML4-ALK Y Y P P Y Y P P TM TM Y Y P P Y Y P P Y Y P P Y Y P P TM TM Extracellular Intracellular Y Y P P Y Y P P Kinase Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Kinase Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Y Y P P Kinase
    43. 65. Initial characterization of EML4-ALK fusion in NSCLC Soda Nature 2007; 448:561-566
    44. 66. Schema of EML4-ALk NSCLC translocations Wong Cancer 2009; 115; 1723-1733
    45. 67. EML4-ALK NSCLC Adenocarcinoma comparisons (N = 209) Wong Cancer 2009; 115; 1723-1733 EML4-ALK positive EML4-ALK negative Total P Median age 59 (51-61) 64 (55-71) 64 (54.5-71) 0.018 Smoking status Never-smoker Ever-smoker 10 (90.9) 1 (9.1) 117 (59.1) 81 (40.9) 127 (60.8) 82 (39.2) 0.053 EGFR Mutated Wildtype 0 (0) 11 (100) 121 (61.10 77 (38.9) 121 (57.9) 88 (42.1) < 0.001
    46. 68. Break-Apart FISH Assay for ALK Fusion Genes <ul><li>Potential Fusion </li></ul><ul><li>Partners: </li></ul><ul><li>EML4 </li></ul><ul><li>KIF5B </li></ul><ul><li>TGF </li></ul>~ 250 kb ~ 300 kb t(2;5) ALK gene breakpoint region 2p23 region Telomere Centromere 3’ 5 ’
    47. 69. EML4-ALK Patients: Waterfall Plot Tumor Responses to PF-02341066 for NSCLC Patients with EML4-ALK Fusions For 2 patients whose best response was PD, patients discontinued prior to first on-study scan 2 16 20 40 8+ 12 4+ 13+ 15+ 8+ 23+ 15+ 2+
    48. 70. 48 YO Female Non-Smoker with EML4-ALK NSCLC Pre-Treatment After 2 Cycles PF-02341066
    49. 71. My own pt 51 yo Caucasian Male NSCLC Failed Tarceva, on 6 th line Rx before enrolling in c-met trial Before and After c-met inhibitor Before After 2 months of c-met
    50. 72. Planned Global registration trial for PF-02341066 <ul><li>EML4-ALK positive NSCLC patients </li></ul><ul><li>PF-02341066 versus Pemetrexed/Cisplatin </li></ul><ul><li>Primary endpoint: PFS </li></ul>
    51. 73. 1 st & 2 nd -line treatment for Never-smoker with NSCLC EGFR Mutation Positive (~60%) EML4-ALK translocation Positive (~5%) EGFR WT EGFR Unknown EGFR not tested (~35%) 06-62 08-01 07-40 A8081007 A8081005 08-49 PF-00299804 1200.32 1200.42
    52. 74. The End
    53. 79. Proportion of male NSCLC never-smoker By period of diagnosis and 5 Asian subgroups
    54. 80. Proportion of female NSCLC never-smoker By period of diagnosis and 5 ethnicities
    55. 81. 1 st & 2 nd line Rx of NSCLC in ever-smokers <ul><li>First line </li></ul><ul><ul><li>ATTRACT-1 (UCI-07-72) </li></ul></ul><ul><ul><ul><li>Carboplatin/paclitaxel +/- ASA402 </li></ul></ul></ul><ul><ul><li>CP13-0811 (UCI-09-05) </li></ul></ul><ul><ul><ul><li>Carboplatin/gemcitabine/Erbitux +/- IMC-A12 </li></ul></ul></ul><ul><li>Second line </li></ul><ul><ul><li>UCI-04-60 </li></ul></ul><ul><ul><ul><li>Docetaxel or alimta +/- erbitux </li></ul></ul></ul><ul><ul><li>UCI-09-04 </li></ul></ul><ul><ul><ul><li>Tarceva +/- CP-751,871 </li></ul></ul></ul><ul><ul><li>ATTRACT-2 (UCI-08-66) </li></ul></ul><ul><ul><ul><li>Docetaxel +/- ASA404 </li></ul></ul></ul>
    56. 82. Adjuvant Rx <ul><li>ECOG1505 </li></ul><ul><ul><li>Cisplatin + gemcitabine /navelbine/alimta/taxotere +/- avastin </li></ul></ul><ul><li>MARGRIT (UCI-07-57) </li></ul><ul><ul><li>Adjuvant MAGE vaccine </li></ul></ul>
    57. 83. Cox models for Never-smokers and Smokers Never-smoker Smoker HR 95% CI P HR 95% CI P Ethnicity* Caucasian Asian African-American Hispanic 1.000 0.866 1.126 0.843 (0.751-0.999) (0.796-1.592) (0.714-0.996) .0483 .8938 .0446 1.000 0.866 0.987 0.981 (0.807-0.928) (0.901-1.081) (0.923-1.043) < .0001 .7800 .5450 Gender Male Female 1.000 0.786 (0.707-0.874) < .0001 1.000 0.841 (0.814-0.868) < .0001 AJCC stage 1 2 3 4 1.00 2.788 2.242 3.033 (2.053-3.785) (1.784-2.818) (2.465-3.731) < .0001 < .0001 < .0001 1.00 1.675 2.009 2.893 (1.537-1.826) (1.885-2.142) (2.729-3.068) < .0001 < .0001 < .0001 Age 1.015 (1.011-1.019) < .0001 1.012 (1.010-1.013) < .0001
    58. 84. Place of birth-North America Smoker (%)* Never-smoker (%)* Canada All (N=176) Male Female 162 (92.1%) 79 (95.2%) 83 (89.2%) 14 (7.9%) 4 (4.8%) 10 (10.8%) Mexico All (N=647) Male Female 516 (79.8%) 373 (91.6%) 143 (59.6%) 131 (20.3%) 34 (8.4%) 97 (40.4%)
    59. 85. Interplay between CA repeats and promoter polymorphism in EGFR gene Nomura PLoS Med 2007; 4 (4):e125
    60. 86. California Cancer Registry http://statecancerprofiles.cancer.gov/
    61. 87. Birthplace of Asian patients Filipino Vietnamese Chinese Japanese Koreans All Never-smoker Smoker All Never-smoker Smoker All Never-smoker Smoker All Never-smoker Smoker All Never-smoker Smoker N 446 113 333 396 114 282 137 47 90 148 22 126 78 18 60 Native-born Yes (%) No (%) 410 (91.9) 36 (8.1) 107 (94.7) 6 (5.3) 303 (91.0) 30 (9.0) 342 (86.4) 54 (13.6) 101 (88.6) 13 (11.4) 241 (85.5) 41 (14.5) 111 (81.0) 26 (19.0) 36 (76.6) 11 (23.4) 75 (83.3) 15 (16.7) 73 (49.3) 75 (50.7) 14 (63.6) 8 (36.4) 59 (46.8) 67 (53.2) 57 (73.1) 21 (26.9) 12 (66.7) 6 (33.3) 45 (75.0) 15 925.0)
    62. 88. Proportion of never-smokers by Asian subgroups
    63. 89. OS according to stage stratified by smoking status
    64. 90. Pharmodynamic blockade of EGFR pathway
    65. 91. Positions of Mutations Detected in HER1/EGFR Tyrosine Kinase Domain in NSCLC 747-750 Activation loop L858 G719 Autophosphorylation Tyrosine kinase EGF ligand binding K R H DFG GXGXXG L L Y 718 745 776 835 858 861 869 964 18 19 20 21 22 23 24 757-750 Exon: Paez: Lynch: Pao: Tumor with point mutation (amino acid substitution) Tumor with in-frame deletion EGF = endothelial growth factor; TM = transmembrane. Adapted from: Pao et al. Proc Natl Acad Sci U S A. 2004;101:13306; Lynch et al. N Engl J Med . 2004;350:2129; Paez et al. Science . 2004;304:1497. 719 858 TM K DFG Y Y Y Y

    ×