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Personalized Therapy of
Lung Cancer
2011 Winter Lung Cancer Conference
Thomas J. Lynch, Jr., M.D.
Jonathan and Richard Sackler Professor of Internal Medicine
Director, Yale Cancer Center
Physician-in-Chief, Smilow Cancer Hospital
Lung Cancer 2011
• USA
–
–
–
–
–
190,000 cases of lung cancer
165,000 deaths
165,300 cases of NSCLC
115,000 cases of adenocarcinoma
28,500 cases of lung cancer in never smokers
• Global
– 1.4 million deaths from lung cancer
NCI SEER Cancer Statistics, WHO Fact Sheet.
Cancer 2011
• Cancer is a disease caused by abnormal
genes that “drive” either excessive cell growth
or inadequate cell destruction
• Imbalance of growth and death signals leads
to growth of cancer cells into tumors
• Tumors then proceed to grow and
metastasize
• Understanding which genes drive which
cancers will provide a “roadmap” to curing
cancer
Major Classes of Genomic
Alterations that Give Rise to Cancer
• Point mutations
• Copy number alterations
 Deletions
 Amplifications
• Translocations
 Examples: BCR-ABL, EML4, ALK
MacConall LE and Garraway LA. J Clin Oncol 2010;28:5219-28.
Kate’s Story
• March 2002: Shortness of breath
• April 2002: Lung cancer in brain, lung and lymph
nodes
• Summer 2002: Chemotherapy
• November 2002: Progression in liver
Kate November 2002 Pre Rx
Kate April 2003
INTACT Trials:
1-Year Overall Survival
INTACT 1
• Gefitinib 500 mg + gemcitabine/cisplatin, 9.9 months
• Gefitinib 250 mg + gemcitabine/cisplatin, 9.9 months
• Placebo, 11.1 months
INTACT 2
• Gefitinib 500 mg + paclitaxel/carboplatin, 8.7 months
• Gefitinib 250 mg + paclitaxel/carboplatin, 9.8 months
• Placebo, 9.9 months
Giaccone G et al. J Clin Oncol 2004;22:777-84. Herbst RS et al. J Clin Oncol 2004;22:785-94.
First-Line Gefitinib in Patients with
Advanced NSCLC Harboring Somatic
EGFR Mutations
• Mutations detected in 34/98 patients who underwent
direct DNA sequencing of tumor tissue EGFR exons
18 to 21
– In-frame deletions of 11-15 bp, 53%
– L858R, 26%
– Atypical, 21%
• Objective response rate, 55%
• Median progression-free survival, 9.2 months
Sequist LV et al. J Clin Oncol 2008;26(15):2442-9.
Resistance
 There are 2 robustly described TKI-resistance
mechanisms: T790M in EGFR and MET amplification
 1 patient with both T790M and L858R had a best
response of SD and remained on treatment for 55 days
Source: Sequist LV et al. Proc ASCO 2007. Abstract 7504
T790M
• Gatekeeper mutation present in nearly 60%
of acquired resistance
• Rare familial germline mutations found
• Detected at diagnosis in CTCs and circulating
DNA in 30% of patients using highly sensitive
methods
• Efforts to target T790M are emerging
T790M
• Irreversible Dual (EGFR, Her-2) kinases
have not yet proven effective in this setting
• Novel T790M specific inhibitor (Nathanael
Gray-DFCI) under development
• Combination therapy might hold best hope
2011: Lung AdenocaMultiple Molecular Subsets
ALK fusion
ROS fusion
BRAF PIK3CAPDGFR amp
MEK1
KRAS
HER2
EGFR
Squam
Large
Adeno
Unknown
Small
Courtesy William Pao
2011: Never Smoker Lung Adenoca (US)Almost All Molecular Subsets Defined!
ALK fusion
KRAS
Squam
Unknown
HER2
Large
Adeno
EGFR
Small
Pham D et al. J Clin Oncol 2006;24(11):1700.
Stephens P et al. Nature 2004;431(7008):525.
Shaw AT et al. J Clin Oncol 2009;27(26):4247.
Riely GJ et al. Clin Cancer Res 2008;14(18):5731.
Somatic Mutations Affect Key
Pathways in Lung Adenocarcinoma
• Discovery of more than 1,000 somatic mutations after
sequencing 623 genes with known or potential
relationships to cancer
• Identified 26/623 genes that are mutated at a significantly
high frequency
– Most frequent: TP53, KRAS, STK11, EGFR
– Less frequent: LRP1B, KDR, RB1, LTK, SLC38A3,
NRAS
• Genetic alterations frequently occur in genes of the
MAPK, p53, Wnt and mTOR pathways
Ding L et al. Nature 2008;455:1069-75.
McDermott U et al. N Engl J Med 2011;364:340-50.
Tumor Tissue Heterogeneity and Microdissection
A. H&E micrograph
of prostate carcinoma
showing epithelial tissue
(red arrows) and stroma
(black arrow).
B. Area of epithelial
tissue to be dissected outlined by etching with
laser.
C. Tissue section after
removal of outlined tissue.
D. Removed tissue.
EGFR mutation assay on normal
tonsil DNA
EGFR mutation assay on DNA of a
formalin-fixed, paraffin-embedded
sample of lung tumor with a
heterozygous mutation
Gene
EGFR
KRAS
Mutations tested
G719A, G719S, G719C
E746_A750del, E746_S752>V
L747_T751, L747_P753>S
T790M
L858R
L861Q
G12S, G12R, G12D, G12V,
G12C, G12A
G13C, G13S, G13R, G13D
Q61K, Q61L, Q61R, Q61H
BRAF
V600E, V600K
NRAS
G12C, G12S, G12R, G12D,
G12V, G12A
G13R, G13C, G13V, G13D,
G13A
Q61K, Q61L, Q61R, Q61H,
Q61P
PIK3CA
PTEN
Cancer type
Lung (26%)
(adenocarcinoma)
TKIs: erlotinib, gefitinib
11
14
Lung (17%), colon (15%)
pancreas, biliary tract,
endometrium, ovary
Erlotinib, gefitinib;
cetuximab
Melanoma (50%), thyroid,
biliary tract, colon (12%)
PLX4032,
GSK2118436
17
Melanoma (15%),
leukemia, colon (3%)
Drugs targeting
RAS/RAF/MEK
pathway
12
Breast, urinary tract,
endometrium, colon (13%),
stomach, melanoma (5%)
2
R88Q
E542K
E545K, E545A, E545G
Q546K, Q546R
H1047Y, H1047L, H1047R
G1049S, G1049R
R130*
R173C
R233*
K267fs*
Targeted therapy
4
Endometrium, brain,
prostate, colon (10%),
melanoma (10-30%)
Total = 60 mutations
Drugs targeting
PI3K/AKT/mTOR
pathway
Genome Statistics
• 29,000 human genes
• Average gene 3000 bases but wide
variation exists
• 99.9% of our bases are exactly the
same from person to person
• Functions are unknown for 50% of the
discovered genes
Progress in Sequencing the Human
Genome
• 2000
– 12 years
– 1,800,000,000 USD
• 2010
– 12 days
– 20,000 USD
• 2011
– 5 days
– 5,000 USD
Yale Genome Statistics
• Human genome 3.2 billion bases or 3.2
Gbases
• Sept 2010 Yale sequences 1.8 trillion
bases or 1800 Gbases
• In September Yale sequenced the
equivalent of 562 human genomes!
• In January Yale sequenced 1300
human genomes!
Post Genome World
• 2008 - EGFR and Ras mutation testing
routine
• 2009 - Molecular genotyping - snapshot
• 2010 - Whole genome sequencing begins
experimentally
• 2012 - Routine WGS available to patients
Will we be ready?