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TCOS, Shanghai, May 20 2010
Cancer Biomarkers: Opportunities and Challenges
Cancer Biomarkers: Opportunities and Challenges
Ann-Lii Cheng M.D., Ph.D.
Department of Oncology and Department of Internal Medicine, National Taiwan University Hospital;
Taipei, Taiwan.
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Cancer Biomarkers- the opportunities
• A new era in which physicians no longer make treatment choices that are based on population-based statistics but rather on the specific characteristics of individual patients and their tumors.
Dalton W Science 2006
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First-line study of gefitinib vs carboplatin / paclitaxel in patients with advanced non-small cell lung cancer (IPASS)
EGFR mutation-positive EGFR wild-type
Pro
bab
ilit
y o
f P
FS
1.0
0.8
0.6
0.4
0.2
0P
rob
abil
ity
of
PF
S
1.0
0.8
0.6
0.4
0.2
00 4 8 12 16 20 24 0 4 8 12 16 20 24
Months Months
132 108 71 31 11 3 0129 103 37 7 2 1 0
At risk:GefitinibC/P
91 21 4 2 1 0 085 58 14 1 0 0 0
Gefitinib (n=132)Carboplatin/paclitaxel (n=129)
HR (95% CI) = 0.48 (0.36, 0.64)p<0.0001
Gefitinib (n=91)Carboplatin/paclitaxel (n=85)
HR (95% CI) = 2.85 (2.05, 3.98)p<0.0001
Mok et. al. ESMO 2008
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First-line treatment of mCRC with FOLFOX cetuximab (OPUS Study)
K-Ras mutant K-Ras wild-type
Progression-free time (months)
Kap
lan
-Mei
er
esti
ma
te
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Cetuximab + FOLFOX
FOLFOX
Cetuximab + FOLFOX
FOLFOX
HR=1.83; p=0.0192 FOLFOX: 8.6 m Cetuximab + FOLFOX: 5.5 m
Progression-free time (months)
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
HR=0.57; p=0.016 FOLFOX: 7.2 mCetuximab + FOLFOX: 7.7 m
Bokemeyer C, et al. JCO 2009
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Cancer Biomarkers- the challenges
• Clinically a must in an increasing number of cancer types.
• Cost, workload, and workflow.
• Technic issues – reliability of methods
• Ethnic and geographic issues – how far can data be extrapolated from area to area ?
Non-Small cell lung cancerColorectal cancer
Breast cancerGastric cancer
Renal cell carcinomaGI stromal tumor
LeukemiaLymphomaMelanoma
Basal cell carcinomaMedulloblastoma
…………
Non-Small cell lung cancerColorectal cancer
Breast cancerGastric cancer
Renal cell carcinomaGI stromal tumor
LeukemiaLymphomaMelanoma
Basal cell carcinomaMedulloblastoma
…………
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Reliability of Biomarkers on Surgically Resected Tumor Specimens
1. Ischemia during operation – unknown in most specimens
2. Unknown processing of specimens
Warm ischemia
Specimen aging
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Comparison of Biopsy vs. Hepatectomy HCC Tissues
Study design:• 46 paired HCC tissues (‘03~’08)
– Biopsy taken within 3 months before hepatectomy
– Hepatectomy• IHC studies:
– p-Akt (S473): rabbit antibody (Santa Cruz)– p-ERK1/2 (T202/Y204): rabbit antibody
(Santa Cruz)
~ Shao YY et al: AACR 2010, Abstract 3759.
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Comparison of Biopsy vs. Hepatectomy HCC Tissues
• Poor correlation• Higher expression in biopsy tissues
phospho-Aktphospho-Aktphospho-ERKphospho-ERK
~ Shao YY et al: AACR 2010, Abstract 3759.
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p-ERKBiopsy tissue Hepatectomy tissue
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Tissue Ischemia Affects Gene Expression within Minutes Following CRC Excision
─ Microarray analysis
Spruessel A, et al. BioTechniques 2004;36:1030-1037
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Tissue Ischemia Affects Protein Expression within Minutes Following CRC Excision
─ SELDI-TOF MS analysis
Spruessel A, et al. BioTechniques 2004;36:1030-1037
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Slide Aging Affects Immunohistochemistry
HER2 ER E-Cadherin
Mirlacher M, et al. Mod Pathol, 2004;17:1414-1420
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Figure 2. Influence of slide aging on the fraction of positive cases. For each antibody, the frequency of positive cases is shown as separate bars for old (O) and fresh (F) sections.
Slide Aging Affects Immunohistochemistry
Mirlacher M, et al. Mod Pathol, 2004;17:1414-1420
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Slide Aging Affect p53 Immunostaining of Breast Cancer Tissues
Jacob TW et al J, Natl Cancer Inst 1996;88:1054-09
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The Problems of Genomic Biomarkers- minimal reproducibility
• Numerous gene signatures have been reported.
• Only marginal overlap of reports– poor study design
lack of a standard technology platform
different ways of tumor collection
different statistical methods
• Only few validated into clinic practice.
Dalton W. science 2006;312:1165-8
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Toward Robust Genomic Biomarkers
• Share samples
• Common technology platform
• Ask similar questions
• Use similar criteria for patient enrollment
• Partnership among academic groups, pharmaceutical and biotechnology companies, as well as government agencies.
Dalton W. Science 2006;312:1165-8
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Challenges of Cancer Biomarkers- ethnic and geographic issues -
East vs West
Lung cancer
Breast cancer
Hepatocelluar carcinoma
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Asian (n=342) Non-Asian (n=1350)
Pro
po
rtio
n s
urv
ivin
g
Time (months)
0.0
1.0
0.8
0.6
0.4
0.2
0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16
GefitinibPlacebo
Importance of Ethnicity for MTT ─ the lessons of ISEL trial
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EGFR mutation rates in each subgroup
Study CentreNo. of
patients
AdenoCa
(+BAC) (%) M (%)
F (%)
Smokers (%)
n-smokers (%)
Taiwan1 NTUH 62 49 25 61 29 56
Taiwan2 VGH-T 37 67.4 52 72 44 69
Korea3 Seoul NU 90 21 9 33 13 26
Japan4 NCC Tokyo 66 61 53 69 35 68
Japan5 Aichi CCH 59 64 44 70 42 71
HK6 Chinese U 72 32 — — — —
China7 Pek UMCH 76 48.6 32.3 34.8 — —
Italy8* U Chieti 375 10 6 30 7 25
1. Shih et al, IJC 20052. Chou et al, CCR 20053. Han et al, JCO 20054. Takano et al, JCO 2005
5. Mitsudomi et al, JCO 20056. Lung et al, PAACR 20057. Mu et al, CCR 20058. Machetti et al, JCO 2005
*only AdenoCa
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EGFR Mutations in NSCLC Patients Born or Domiciled in the USA
• Other ethnicities 14/159 (9%)
• East Asians 12/22 (55%)
Adi Gazdar, 2005
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Ethnic Difference in Mutational Pattern of Lung Adenocarcinoma
EGFR mutationKRAS mutation
EML4-ALKBRAF mutation
HER2 mutataionPIK3CA
MET amplificationMEK1 mutation
Unknown
East Asians Other Countries
EGFR mutation
KRAS mutation
EGFR mutation
KRAS mutation
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• Incidence of breast cancer has been increasing around the world including Latina America, Middle East and Asia
– Incidence now stabilizing in some Western populations– Incidence continues to increase in many Asian
populations
Trends in Breast Cancer Incidence
Country Incidence Incidence % 1973–77 1993–97 Increase
Japan (Miyagima) 17.5 34.4 97Japan (Osaka) 12.7 28.7 126Singapore (Chinese) 21.9 45.9 110 China (Shanghai) 19.6 27.2 39
Cancer Incidence in Five Continents (Vol. IV, VIII)
Katanoda et al, Jpn J Clin Oncol. 2007 Aug;37(8):638-9
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Age-specific Breast Cancer Incidence in Taiwan
0.0
100.0
200.0
300.0
400.0
500.0
600.0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 8085+年齡
AmericanCaucasion
台灣1994
台灣1998
台灣2002
台灣2005
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Population(study period, y)
Patient no.
Luminal A (%)
Luminal B (%)
HER2+/ER- (%)
Basal-like (%)
Unclassified (%)
USA (1993-1996) 496
African American 196
Premenopausal 97 36 9 9 39 6
Postmenopausal 99 59 16 7 14 4
Non-African American 300
Premenopausal 164 51 18 6 16 10
Postmenopausal 136 58 16 6 16 4
Taiwan (2004-2006) 1028
≦50 y 515 66 11 10 9 4
>50 y 513 56 8 14 17 6
Comparison of Molecular Subtypes between American and Taiwanese
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High frequency of ER expression in Taiwanese YFBC: validated by Taiwan Cancer Database
TCDB (n=3899)
<35 35-49 ≧50 P value
ER+ 194 (63) 1837 (66) 1868 (57) <0.001
ER- 114 (37) 927 (34) 1399 (43)
PR+ 160 (52) 1744 (63) 1596 (49) <0.001
PR- 148(48) 1020 (37) 1671 (51)
Taiwan Cancer DataBase 2005
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0
10
20
30
40
50
60
70
80
90
100
<36 36-50 >50
1st cohort 2nd cohort
Preliminary data
(1992-2000) (2004-2006)
54
74
62
75
5861
Time Trend of Increase Frequency of ER expressions in Young Breast Cancer at NTUH
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IBCSG data Lancet 2000
ER expression : a poor prognostic factor for DFS among very young patients receiving adjuvant
chemotherapy alone in Western Countries
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178 very young (<35 years) breast cancer patients diagnosed at NTUH in 1997-2006
ER expression : a favorable prognostic factor for OS among very young (<35y)
patients in Taiwan
Proceeding ASCO 2009
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Hepatocellular Carcinoma— Distinct Geographic Distribution
Risk Factors
Hepatitis B virus
Hepatitis C virus
Alcohol
Tobacco
Oral contraceptives
Aflatoxin
Other and emerging risk factors/cofactors
Estimate Range
22 4~-58
60 12~72
45 8~57
12 0~14
--- 10~50
Limited exposure
< 5 ---
Estimate Range
20 18~-44
63 48~94
20 15~33
40 9~51
--- --- Limited exposure
--- ---
Estimate Range
60 40~90
20 9~56
--- 11~41
22 ---
8 ---
Important exposure
< 5 ---
Bosch FX et al. Gastroenterology 2004;127:S5-16.
Europe and United States (%)
Japan (%) Asia and Africa (%)
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Viral Proteins And Signal Transduction Pathways
Axin
APC
Cytokine receptor
Growth factor receptor
Toxins, other stress
AKT PI3K
PTEN
RAS
Raf
MEK
ERK
IKK
NFKBNFKB
Fork-head
BADmTOR
Src
PKC
IkBIkB
SHP2SHP2
GRB2
SHCSOS1
Proteasome
ER stress
Pre-S mutant
HBxHBx
HBxHBx
Cell survival Angiogenesis Metastasis
Cell cycle Cell survival Metabolism DNA damage Metabolism
Cell cycle
Cell survival Cell cycle Protein translation Nutrient response
Protein degradation
Cell survival Cell cycle Angiogenesis Metastasis
GSK3
: Targeted agents in pre-clinical development
: Targeted agents in clinical development
: Dys-regulated in HCC
Wnt
β-catenin
HCV core
HCV core
By Hsu C, Shen YC, Cheng AL
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Transcriptome classification of HCC
~ Boyault S et al: Hepatol 2007;45:42. based on120 surgically resected HCC, including transcriptome analysis on 57 HCCs and 3 adenomas, and qRT-PCR validation in additional 63 HCCs
Over-expressionIGF1R Akt p-GSK3β HBV(+) HCV(+)
G1-group (N=11) 64% 75% 78% 8 3G2-group (N=17) 25% 42% 7 4Others (N= 92) 9% 8% 9% 22 23
31
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Is HBV-related HCC a more aggressive tumor ?
Is HBV-related HCC associated with molecular changes which affect molecular therapy ?
HBV-related HCC
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HCC ─ East vs West
Long-term results after surgical treatment were similar in West and East when clinicopatnologic factors were accounted for.
Pawlik TM et al Liver Transplantation 2004;10(suppl 1) 74-80
Taeck D et al Liver Transplantation 2004;10(suppl 1) 58-63
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HBV vs. HCV HCCItalian Liver Cancer group
Survival in patients with advanced HCC. HBV-HCC patients had a lower survival than HCV-HCC patients (p=0.025)
• Patients with HBV-HCC tended to have poor prognosis;
~ Cantarini MC et al: Am J Gastroenterol 2006;101:91-8.
and the difference became statistically significant among patients with advanced HCC
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HBV vs. HCV HCC in NTUHSurvival for patients with advanced ds.
• 927 patients receiving supportive care or chemotherapy.
Etiology
Median survival
(M)1 year (%)3 year (%)5 year (%)10 year (%)
HBV
2.5
12.43.40.80.5
HCV
3.4
21.78.52.21.1
B+C
3.4
10.83.11.50
NBNC
2.6
11.23.11.01.0
HCV-HCC patients had better survival than HBV-HCC patients
Chen CH et al. Eur J Cancer. 2006 Oct;42(15):2524-9. Epub 2006 Aug 22
HCV+
HBV+
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Sorafenib phase II HCC studyHCV- vs. HBV-related HCC
~ Huitzil-Melendez FD et al: ASCO-2007 GI Symposium Abstract# 173.A retrospective analysis
HCV+ HBV+ P
P’t No. 33 13
Median age 71 66
Race (%)
Caucasians 82 54
Clinical benefit (%) 75 53
PFS (median, M) 6.5 3.5 .27
TTP (median, M) 6.5 4 .05
OS (median, M) 12.4 7.3 .29
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Thalidomide phase II HCC studyHCV- vs. HBV-related HCC
P’t No.Median age
Objective response+AFP response (%)
TTP (median)OS (median)
HCV+
3367.5
27.314.1 W32.6 W
HBV+
6153.6
13.18.3 W
21.4 W
~ Hsu C et al: Proc. ASCO 2004: Abs#4198.
P
61< .001
.09
.03
.08
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Conclusions─ Cancer biomarkers
• Provide excellent opportunity for personalized care.
• Cost, workload, and workflow remain a problem.
• Technic issues should not be overlooked.
• Significant ethnic and geographic difference exist.
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TCOS, Shanghai, May 20 2010
Cancer Biomarkers: Opportunities and Challenges
Cancer Biomarkers: Opportunities and Challenges