This document discusses the importance of cancer biomarkers for selecting effective targeted drug therapies. It provides examples of predictive biomarkers such as BCR-ABL for CML treated with tyrosine kinase inhibitors, EGFR mutations for NSCLC treated with EGFR inhibitors, and HER2 overexpression for breast cancer treated with trastuzumab. The use of predictive biomarkers can help personalize cancer treatment by identifying patients most likely to respond to a specific drug and avoid unnecessary toxicity for those who will not benefit.

1. CANCER BIOMARKERS:
SELECTING THE RIGHT DRUG
FOR THE RIGHT PATIENT
Dr Ravindra Chhabra
Scientist
Molecular Medicine Laboratory

2. 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

3. Types of cancer genes
Types of proteins
Mutated
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

4. Challenge in Treating Cancer:
• Every tumor is different
• Every cancer patient is different
• One drug fit all
• Personalized strategy

5. Cancer biomarkers
• There are different types of cancer biomarkers;
• Prognostic,
• Pharmacodynamic
• Predictive

6. 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

7. 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

8. 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

9. 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.

10. CML and BCR-ABL
• Philadelphia chromosome (t 9:22)
• BCR-ABL
• Fusion protein have high tyrosine kinase activity.
• Imatinib: Tyrosine Kinase Inhibitor

11. Monitoring of Minimal Residue Disease

13. • 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

14. 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

15. 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

16. (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

17. RTK
Vemurafenib
(PLX4032, RO5185426)
RAS BRAFV600E MEK ERK
Gene
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 gene
BRAF 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

18. Progression-free
survival(%)
Months
Hazard ratio 0.26
(95% CI; 0.20–0.33)
Log-rank p < 0.001Vemurafenib (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

19. 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

20. Progression free survival
7.7 month
3.0month
Shaw et al NEJM 2013; 368;25

21. 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

22. 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
1.0Probability
of 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

23. 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

24. 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

25. J Clin Oncol. 2011
AC, doxorubicin and cyclophosphamide; H, trastuzumab; T, paclitaxel.

26. 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

28. 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