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

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Page 1: Cancer Biomarkers

CANCER BIOMARKERS: SELECTING THE RIGHT DRUG

FOR THE RIGHT PATIENT

Dr Ravindra Chhabra

Scientist

Molecular Medicine Laboratory

Page 2: Cancer Biomarkers

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

Page 3: Cancer Biomarkers

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

Page 4: Cancer Biomarkers

Challenge in Treating Cancer:

• Every tumor is different• Every cancer patient is different

• One drug fit all• Personalized strategy

Page 5: Cancer Biomarkers

Cancer biomarkers• There are different types of cancer biomarkers;

• Prognostic,

• Pharmacodynamic

• Predictive

Page 6: Cancer Biomarkers

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

Page 7: Cancer Biomarkers

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

Page 8: Cancer Biomarkers

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

Page 9: Cancer Biomarkers

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.

Page 10: Cancer Biomarkers

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

Page 11: Cancer Biomarkers

Monitoring of Minimal Residue Disease

Page 12: Cancer Biomarkers
Page 13: Cancer Biomarkers

• 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

Page 14: Cancer Biomarkers

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

Page 15: Cancer Biomarkers

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

Page 16: Cancer Biomarkers

(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

Page 17: Cancer Biomarkers

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

Page 18: Cancer Biomarkers

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

Page 19: Cancer Biomarkers

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

Page 20: Cancer Biomarkers

Progression free survival

7.7 month

3.0month

Shaw et al NEJM 2013; 368;25

Page 21: Cancer Biomarkers

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

Page 22: Cancer Biomarkers

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

Page 23: Cancer Biomarkers

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

Page 24: Cancer Biomarkers

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

Page 25: Cancer Biomarkers

J Clin Oncol. 2011

AC, doxorubicin and cyclophosphamide; H, trastuzumab; T, paclitaxel.

Page 26: Cancer Biomarkers

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

Page 27: Cancer Biomarkers
Page 28: Cancer Biomarkers

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

Page 29: Cancer Biomarkers

Thank You….!!