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CANCER BIOMARKERS: SELECTING THE RIGHT DRUG
FOR THE RIGHT PATIENT
Dr Ravindra Chhabra
Scientist
Molecular Medicine Laboratory
What is Cancer?• Broad group of diseases involving unregulated cell growth
• In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered.
• Cancer is a genetic disorder involving dynamic changes in the genome leading to uncontrolled cell growth, ability to invade and metastasize
Types of cancer genes
Types of proteinsMutated functionNormal functionType of gene
Enzymes for mismatch or excision repair
Fail to repair DNA mutations
Repair DNA mutations
DNA repair gene mutation
Checkpoint molecules
Fails to suppress division
Suppresses cell division
Tumor suppressor gene
Growth factorsPromotes division - abnormal time or cell type
Promotes divisionOncogene
Challenge in Treating Cancer:
• Every tumor is different• Every cancer patient is different
• One drug fit all• Personalized strategy
Cancer biomarkers• There are different types of cancer biomarkers;
• Prognostic,
• Pharmacodynamic
• Predictive
Prognostic Biomarker• Anticipates the likely outcome of illness• or dictate whether further therapy is required or not
• Oncotype Dx test: Forecast the probability of Breast cancer recurring after surgical intervention (www.oncotypedx.com/)
• Clin Chem. 2007 Jun;53(6):1084-91
Pharmacodynamic Biomarker
• Measure the effect of a drug on the disease
• For example, the level of proliferation and apoptosis in the tumor upon delivery of a drug,
• or the degree of change on a substrate regulated by an enzymatic drug target (such as phosphorylation after inhibition of a protein kinase
Predictive Biomarkers• Assess the likelihood
that the tumor will respond to the drug,
• Thereby allow a level of personalization to be introduced into the treatment regimen
The need for predictive biomarkers• Cost effectiveness of the therapy, and go hand-in-hand
with improved clinical benefit and safer drugs • Certain chemotherapy regimens result in death rates in
the range of 0.5–2.0%, and 30–40% of patients experience grade 3 or 4 toxic effects,
• representing a large burden of morbidity, especially if a significant fraction of this population do not benefit from treatment.
• Predictive biomarker-driven cancer therapy reduces the unnecessary treatment and adverse effects.
CML and BCR-ABL• Philadelphia chromosome (t 9:22)• BCR-ABL• Fusion protein have high tyrosine kinase activity.• Imatinib: Tyrosine Kinase Inhibitor
Monitoring of Minimal Residue Disease
• Resistance to imatinib occurs in about 10–15% of patients • 30–50% of patients with secondary resistance to imatinib
have a catalytic domain mutation • dasatinib and nilotinib • The level of resistance to imatinib, nilotinib and dasatinib
depends on the mutation identified• some mutations that result in amino acid substitutions,
such as Tyr315Ile impart resistance to all three agents
PML- RARα and all trans retinoic acid• APL 5–8% of acute myeloid leukemia (AML)• 99% of APL has t(15;17)(q22;q12)• All-trans-retinoic acid targets RARα • Arsenic trioxide targets PML• Anthracycline based Chemotherapy
KRAS in colorectal cancer• Key element in the MAPK, JAK–STAT and PI3K cell-
signaling pathways• Mutations in the gene lead to abnormal cellular growth,
proliferation and differentiation• 35–40% of colorectal tumors• Activated KRAS mutations are strongly associated with a
resistance to anti–epidermal growth factor receptor (EGFR) therapies
(A) Progression-free survival and (B) overall survival of the 88 patients in the independent series according to the presence or absence of KRAS mutation (P = .0001 and P = .026,
respectively).
Lièvre A et al. JCO 2008;26:374-379
RTK
Vemurafenib(PLX4032, RO5185426)
RAS BRAFV600E MEK ERKGene
transcription
Melanoma accounts for about 80% of deaths from skin cancer, with a 5‑year survival rate of 15%.40-60% of cutaneous melanomas are positive for mutations in the BRAF geneBRAF V600E mutation comprises approximately 90% of BRAF mutations
Chapman PB et al. Proc ASCO 2011;Abstract LBA4.
Cellular proliferation
Vemurafenib Inhibits BRAFV600E Kinase
Approved by FDA for BRAF V600E mutated Melanoma patients on Aug 2011
Pro
gre
ssio
n-f
ree
su
rviv
al(
%)
Months
Hazard ratio 0.26(95% CI; 0.20–0.33)Log-rank p < 0.001
Vemurafenib (N = 275)
Dacarbazine (N = 274)
Median 5.3 moMedian 1.6 mo
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Chapman PB et al. N Engl J Med 2011;364(26):2507-16.
Progression-Free Survival
EML4–ALK in NSCLC• EML4–ALK inv(2)(p21p23)• 5% IN NSCLC• 1.3 million new cases of NSCLC worldwide each year,• This translates into more than 60,000 patients with ALK-
positive NSCLC annually• EML4–ALK inhibitor, Crizotinib• Overall response rate of 57% and rate of stable disease
of 33% • Historically, the response rate in NSCLC in the second-
line setting is approximately 10%• Approved by US FDA on November, 2013
Progression free survival
7.7 month
3.0month
Shaw et al NEJM 2013; 368;25
EGFR And Gefitinib• EGF receptor (EGFR) is a transmembrane protein• cytoplasmic kinase activity that• transduces important growth factor signals• 10% NSCLC have EGFR Mutation• EGFR inhibitor----Gefitinib
EGFR M+HR=0.48, 95% CI 0.36, 0.64
p<0.0001
EGFR M-
HR=2.85, 95% CI 2.05, 3.98
p<0.0001
0 4 8 12 16 20 24
Time from randomisation (months)
0.0
0.2
0.4
0.6
0.8
1.0Probabilityof PFS
Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)
M+, mutation positive; M-, mutation negative
Treatment by
subgroup interaction
test, p<0.0001
Mok 2009
HER2: breast cancer
• Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and part of the HER family of 4 growth factor receptors (HER1 to HER4)
• Overexpression of HER2 and/or amplification of the HER2 gene occurs in up to 30% of breast cancers
• HER2 positivity is associated with aggressive disease• a high risk of relapse
• poor survival
Trastuzumab: targeting HER2• Recombinant humanised monoclonal antibody directed against the
extracellular domain of HER2
• Attacks HER2-positive tumours via 4 distinct mechanisms of action• Activation of antibody-dependent cellular
cytotoxicity (ADCC)
• Prevention of the formation of p95HER2, a truncated and very active form of HER2
• Inhibition of cell proliferation by preventing HER2-activated intracellular signalling
• Inhibition of HER2-regulated angiogenesis
• Multicenter randomized studies have reported significant benefit from the addition of trastuzumab to adjuvant therapy with up to 50% reduction in the relapse of breast cancer
J Clin Oncol. 2011
AC, doxorubicin and cyclophosphamide; H, trastuzumab; T, paclitaxel.
PARP inhibitors and BRCA deficiency• BRCA1 and BRCA2 encode proteins that are components
of the homologous recombination (HR) DNA-repair pathway
• poly-ADP(ribose) polymerase (PARP) is a DNA-damage-sensing nuclear enzyme involved in DNA repair
• inhibitors of PARP in BRCA1/2 deficient tumors• breast cancer cells defective in BRCA1 or BRCA2 are
highly sensitive to PARP inhibition
Examples of predictive biomarkers for drug response
Biomarker Cancer type Drug therapy Drug target HER2 (gene amplification)
Breast Trastuzumab HER2
Estrogen receptor (protein expression)
Breast Tamoxifen Estrogen receptor
BCR–ABL (gene translocation)
CML Imatinib, dasatinib, nilotinib
BCR–ABL
EGFR ± KRAS (KRAS mutation)
CRC Cetuximab, panitumumab
EGFR
EGFR (kinase domain mutation)
NSCLC Erlotinib, gefitinib EGFR
PML–RAR (gene translocation)
APL All trans retinoic acid PML–RAR
BRCA1/2 (mutation) Breast Olaparib, veliparib PARP
BRAF V600E (mutation)
Melanoma Vemurafenib BRAF
ALK (rearrangements)
NSCLC Crizotinib ALK
Thank You….!!