Precision  medicine

Manit Sae-­teaw
B.Pharm,  BCP,  BCOP                                            
Grad  dip  in  pharmacotherapy
Faculty  of  pharmaceutical  sciences
Ubon Ratchathani University
1
 Outline
l Introduction  to  precision  medicine
l Introduction  to  pharmacogenomics
l Pharmacogenomics  effect
l Novel  precision  medicine  trial  designs
l Precision  medicine  limitation

2
Interindividual Variability  in  Drug  
Response

Disease Drug  Class Rate  of  Poor  Response

Asthma Beta-­agonists 40-­75%
Hypertension Various 30%
Solid  Cancers Various 70%
Depression SSRIs,  tricyclics 20-­40%
Diabetes Sulfonylureas,  others 50%
Arthritis NSAIDs,  COX-­2  inhibitors 30-­60%
Schizophrenia Various 25-­75%

3
Factors  Contributing  to  Interindividual
Variability  in  Drug  Disposition  and  Action

l Age
l Race/ethnicity
l Weight
l Gender PERSONALIZED
l Concomitant  Diseases MEDICINE
l Concomitant  Drugs
l Social  factors
l GENETICS

4
 Precision  medicine
l Prevention  and  treatment  disease
l Application  of  patient  specific  profile
l Gene

l Environment

l Lifestyle

Ref  :  National  Institutes  of  Health  (NIH),  2019 5

 Personalized  medicine
l Older  term  according  to  National  research  
council
l Personalized  could  be  misinterpreted  to  imply  
prevent  and  treatment  uniquely
l May  not  focusing  based  on  genetic  

Ref  :  National  Institutes  of  Health  (NIH),  2019 6

 Benefit  of  precision  medicine
l Improve  medical  decision-­making
l Delivery  of  appropriate  therapies
l Optimized  disease  prevention  
l Reduced  exposure  to  lower  efficacy  or  
potential  toxicity
l Reduced  healthcare  cost
l Enhanced  patient  satisfaction

7
 Genetic  testing  result  in  behavioral  health  change
Prospective  study  design  

Normal                              
(N=117)
Stratified  by  
199  identified   alpha-­1   Carrier                                
smokers  from  large   antitrypsin   (N=65)
genetic  testing       deficiency  
test
Severe  deficient  
(N=17)

l Endpoint:  attempt  to  quite  smoking

Ref  :  Carpenter  MJ,  et  al.  Ann  Behav  Med.  2007;;33(1):22-­8. 8

 Genetic  testing  result  in  behavioral  health  change
Prospective  study  design  

Ref  :  Carpenter  MJ,  et  al.  Ann  Behav  Med.  2007;;33(1):22-­8. 9

 Prescription  medication  changes  following                    
direct-­to-­consumer  (DTC)  testing
Prospective  study  design  

• 961  participants  using  DTC  testing

Ref  :  Carere DA,  et  al.  Genet  Med.  2017;;19(5):537-­545. 10

 Pharmacogenetics vs  
pharmacogenomics
l Pharmacogenetics
l Role  of  genetic  variation  response  to  drug
l Specific  DNA  polymorphism  or  coding  variant
l Pharmacogenomics
l Role  of  various  component  of  genome  on  response  
to  drug
l Multiple  genes  influence  on  drug  response

11
 Pharmacogenetics vs  
pharmacogenomics

Ref  :  Roden DM,  et  al.  Ann  Intern  Med  2006;;145:749.     12

 Historical  of  pharmacogenomics

l The  6th century  BC

l Pythagoras  recognized  eating  fava  bean  caused  
illness  in  individual
l 1940s  
l William  Boyd  noted  that  hemolytic  anemia  from  fava  
beans  is  cause  from  genetic  different
l Recent,  G6PD  (X-­linked  disease)  was  identified
l 1957
l Motulsky 1st suggested  different  drug  efficacy  and  
ADRs  attributable  to  genetic  different

13
 Historical  of  pharmacogenomics

l 1959
l Frederich Vogel  (1925-­2006),  German  geneticist,  
introduced  the  term  “pharmacogenetics”

Ref  :  Vogel  F.  Ergeb Inn  Med  Kinderheilkd 1959;;12:52.     14

15
Human  Genome  Project
l Determine  the  sequence  of  the  3  billion  
nucleotides  that  make  up  human  DNA
l Characterize  variability  in  the  genome
l Complete  sequence  in  year  2000                                      
(complete  project  in  year  2003)  
l Identify  all  the  genes  in  human  DNA
l The  Era  of  Genomic  Medicine:  
l Improve  prediction  of  drug  efficacy  or  toxicity  
l Improve  the  diagnosis  of  disease
l Earlier  detection  of  genetic  predisposition  to  
disease
16
 Composition  of  the  Human  Genome

l Mutation/Polymorphism 1  bp
l Unit  of  genetic  code 3  bp
l Coding  sequence  (exons) 3,000  bp
l Gene  (exons  and  introns) 50,000  bp
l Chromosome 150,000,000  bp
l Human  genome 3,000,000,000  bp

17
The  Foundation  of  Pharmacogenomics:    
Differences  in  the  Genetic  Code  
Between  People
l Mutation:    difference  in  the  DNA  code  that  
occurs  in  less  than 1%  of  population
l Often  associated  with  rare  diseases
l Cystic  fibrosis,  sickle  cell  anemia,  Huntington’s  disease
l Polymorphism:    difference  in  the  DNA  code  
that  occurs  in  more  than 1%  of  the  
population
l A  single  polymorphism  is  less  likely  to  be  the  
main  cause  of  a  disease
l Polymorphisms  often  have  no  visible  clinical  
impact
18
Single  Nucleotide  Polymorphisms  
(SNP)

l Pronounced  “snip”
l Single  base  pair  difference  in  the  DNA  
sequence
l Over  2  million  SNPs  in  the  human  genome
l Other  polymorphisms:
l Insertion/deletion  polymorphisms
l Gene  duplications
l Gene  deletions

19
 Types  of  genetic  testing
l Specific  single  gene  tests
l Eg.  BRCA1  ,  BRCA2
l Multiple  gene  testing
l Complex  SNP  cause  same  phenotype
l Whole  Genome  Sequencing  (WGS)  or                                  
Whole  Exome  Sequencing  (WES)
l High  throughput  sequencing  platform
l Next  Generation  Sequencing  (NGS)

20
Roche  AmpliChip:    FDA-­Approved

21
Roche  AmpliChip P450  Test
l Identify a patient's CYP2D6 and CYP2C19 genotype from
genomic DNA extracted from a whole blood sample

l Information about CYP2D6 and CYP2C19 genotype aid to

clinicians in determining therapeutic strategy and
treatment dose for therapeutics that are metabolized by
the CYP2D6 or CYP2C19 gene product.

22
Next  Generation  Sequencing
 Sequencing  technologies
Techniques Definition
Transcriptomics Analysis  of  mRNA
Gene  Expression  Profiling  (GEP)
Proteomics Analyzed  of  expressed  protein  in  cell
Characterize  panel  of  metabolites  
Metabolomics
related  to  specific  pathway
Profile  of  modification  DNA  (caused by  
Epigenomics environment)  that  control gene  
expression
 Pharmacogenomics  effect
l Effect  on  drug  pharmacokinetics
l Effect  on  drug  pharmacodynamics
l Effect  on  idiosyncratic  reactions
l Effect  on  disease  pathology                      
l Determine  prevention  and  treatment

25
Pharmacogenomics  and  
pharmacokinetics

26
 Pharmacogenomics  and  
pharmacokinetics
l 2  phases  of  metabolism  are  corresponding  
genes
l Phase  I  metabolism  (modification)
l Oxidation,  reduction,  hydrolysis  to  facilitate  water-­
solubility
l Catalyzed  by  the  cytochrome  P450
l Phase  II  metabolism  (conjugation)
l Conjugate  with  another  substance  facilitate  water-­
solubility

27
Pharmacogenomics  and  
pharmacokinetics

28
Clopidogrel and  CYP2C19  variant
 Clopidogrel and  CYP2C19  variant

Ref  :  Xie  HG,  et  al.  Annu  Rev  Pharmacol  Toxicol.  2001;;41:815-­50. 31
 Clopidogrel and  CYP2C19  variant
l Meta-­analysis  from  9  studies  (9685  patients)
l Outcome:  CV  death,  MI,  ischemic  stroke

Ref  :  Mega  JL,  et  al.  JAMA.  2010;;304(16):1821-­30. 32

 Clopidogrel and  CYP2C19  variant
l 1524  patients  undergoing  PCI

Ref  :  Sibbing  D,  et  al.  Circulation.  2010;;121(4):512-­8. 33

 CYP2D6  variants  
l CYP2D6  responsible  for  metabolism  of  variety  drugs
l Codeine

l Nortriptyline

l Metoprolol

l Selective  serotonin  reuptake  inhibitors  (SSRIs)

l Tamoxifen

l CYP2D6  is  highly  polymorphic  (>  90  allelic  variants)

l Poor  metabolizer  or  ultra-­rapid  metabolizer  may  alter  
drug  efficacy  and  toxicity

34
 CYP2D6  Phenotypes
NEJM 2003; 348:529

Ref  :  Roden DM,  et  al.    Ann  Intern  Med  2006;;  145:749-­57 35
 Global  Distribution  of  Major  CYP2D6  Variant  Alleles
Allele  Frequency  (%)

Black  
Enz. America Black   Saudi  
Allele Activity Cauc.  EU Cauc  US n Africans Arabia Japan China Turkey
*1 Normal 33-­37 37-­40 29-­34 28-­56 * 42-­43 23 37
*2 Normal 22-­33 26-­34 30-­27 11-­45 * 9-­13 20 35
*3 None 1 <2 <1 <1 * * 1 0
*4 None 12-­23 18-­23 7-­9 1-­7 4 <1 0-­1 11
*5 None 2-­7 2-­4 6-­7 1-­6 <1 5-­6 6 15
*6 None <2 1 <1 0 * * * 7
*9 Redc’d 0-­3 2-­3 <1 0 * * * <1
*10 Redc’d 1-­2 4-­8 3-­8 3-­9 <1 39-­41 50-­70 6
*17 Redc’d <1 * 15-­26 9-­34 <1 * * <1
*41 Redc’d 20 * * * * * * *
*1xN Incrs’d <1 <1 1 3 * <1 * <1
*2xN Incrs’d <2 <1 1 3 10 <1 1 <1
*4xN None <1 <1 2 1 * * * <1
*No  data  reported.  
Percentages  represent  ranges  of  allelic  frequencies  reported  in  published  studies  
AmpliChip  Package  Insert,  Roche  Diagnostics,  2006. 36
 Prevalence  of  genotype 2D6  
in  Thai  Population

other wt/wt
27% 9%
wt/*10
31%

*10/*10
33%

Ref  : Prevalence  in  check  up  group  at  Phyathai II  in  2007 37
238
 Tamoxifen metabolism

Singh  MS,  et  al.  The  Breast  2011;;20:111.   39

 Tamoxifen  and  CYP2D6  variant
l 202  patients  treated  with  tamoxifen
l 202  pts  for  plasma  level                                                                                                                    
(21  pts  metastasis for  clinical  outcome)

Ref  :  Lim  HS,  et  al.  J  Clin Oncol.  2007;;25(25):3837-­45. 40

 Tamoxifen  and  CYP2D6  variant
l 202  patients  treated  with  tamoxifen
l 202  pts  for  plasma  level                                                                                                                    
(21  pts  metastasis for  clinical  outcome)

Ref  :  Lim  HS,  et  al.  J  Clin Oncol.  2007;;25(25):3837-­45. 41

 Tamoxifen  and  CYP2D6  variant
l 67  patients  treated  with  adjuvant  tamoxifen

Ref  :  Kiyotani  K,  et  al.  Cancer  Sci.  2008;;99(5):995-­9. 42

Roche  AmpliChip P450  Test
l Identify a patient's CYP2D6 and CYP2C19 genotype from
genomic DNA extracted from a whole blood sample

l Information about CYP2D6 and CYP2C19 genotype aid to

clinicians in determining therapeutic strategy and
treatment dose for therapeutics that are metabolized by
the CYP2D6 or CYP2C19 gene product.

43
 Pharmacogenomics  and  
pharmacodynamics
l Pharmacodynamics  refers  to  individual’s  body  
therapeutic  response  to  drug
l Genetic  variation  may  lead  to  individual  
differences  in  therapeutic  response
l Genetic  variation  has  more  effect  with  PK  than  
PD  because  
l Drug  target  pathways  is  complex
l Multiple  genetic  variations  are  required    

44
 Warfarin  and  VKORC1  polymorphism
l VKORC1  encodes  the  vitamin  K-­epoxide  reductase  
protein  (the  target  warfarin  enzyme)
l The  common  G  allele  is  replaced  by  A  allele
l Produce  less  VKORC1  (reduce  ability  to  clot)

45
Warfarin  and  VKORC1  polymorphism

2
46
Stable  INR  frequency  vs  warfarin  dose  (mg/week)

GG  :  Normal
GA  :  Heterozygous
AA  :  Homozygous
 Recommended  daily  warfarin  dose  
(mg/day)

VKORC1     CYP2C9 CYP2C9 CYP2C9 CYP2C9 CYP2C9* CYP2C9

-­1639G>A *1/*1 *1/*2 *1/*3 *2/*2 2/*3 *3/*3

GG 5-­7 5-­7 3-­4 3-­4 3-­4 0.5-­2

GA 5-­7 3-­4 3-­4 3-­4 0.5-­2 0.5-­2

AA 3-­4 3-­4 0.5-­2 0.5-­2 0.5-­2 0.5-­2

48
Ref  :  Johnson  JA,  et  al.  Clin Pharmacol Ther.  2011;;90(4):625-­9.
 Pharmacogenomics  and  
idiosyncratic  reactions
l Idiosyncratic  ADRs  can  not  be  anticipated  
based  on  known  drug  target
l Genetic  variants  are  associated  with  ADRs  
ADRs Medication Genetic variant
Hypersensitivity Abacavir HLA-­B*5701
Severe  cutaneous  
Allopurinol HLA-­B*5801
reaction
Musculoskeletal Aromatase  
TCL1A
side  effect inhibitors
HLA-­A*3101  or  
Hypersensitivity Carbamazepine
B*1502
 Allopurinol  and  HLA-­B*5801
l Allopurinol  is  xanthine  oxidase  inh using  for  
hyperuricemia  in  gouty  arthritis  or  TLS
l Inheritance  of  HLA-­B*5801  associated  with  
severe  cutaneous  reactions  (SCARS)
l Including  SJS/TEN
l Asian  population  (Han  Chinese  and  Thai)

50
 Association  between  allopurinol  and  
HLA-­B*5801
l Meta-­analysis  include  6  studies
l Compare  HLA-­B*5801  with  matched-­control  or  
population  control  (odd  ratio)

OR  =  96.60

OR  =  79.25

2
51
Ref  :  Somkrua  R,  et  al.  BMC  Med  Genet.  2011;;12:118.
 Association  between  allopurinol  and  
HLA-­B*5801

52
Ref  :  Lee  HY,  et  al.  Dermatologica  sinica.  2013;;31:217.
 Carbamazepine  and                                                                
HLA-­A*3101  or  HLA-­B*1502

l Carbamazepine  is  an  anticonvulsant

l Can  cause  hypersensitivity  reaction  (SJS/TEN)  
especially  in    patient  carrying  1  of  2  allele
l HLA-­B*1502  :  Asian  population
l HLA-­A*3101  :  European  population
l US.FDA.  Recommended  testing  HLA-­B*1502
allele  before  using  carbamazepine  and  
oxcarbamazepine in  Asian  population

53
 Association  between  carbamazepine  
and  HLA-­B*1502
l Meta-­analysis  include  16  studies

OR  =  79.84

Ref  :  Tangamornsuksan W,  et  al.  JAMA  Dermatol.  2013;;149(9):1025-­32. 54

 Association  between  carbamazepine  
and  HLA-­B*1502

55
Ref  :  Lee  HY,  et  al.  Dermatologica  sinica.  2013;;31:217.
 Pharmacogenomics  and  
disease  pathogenesis
l Genetic  variations  can  influence  disease  
pathogenesis
l Associated  with  prevention  and  treatment
l Determine  severity  of  disease  and  response  to  
specific  therapy    

56
Drug  Target  Pharmacogenomics
l Direct  protein  target  of  drug  
l Receptor
l Enzyme
l Proteins  involved  in  pharmacologic  response  
l Signal  transduction  proteins  or  downstream  
proteins
l Polymorphisms  associated  with  disease  risk  
l “Disease-­modifying”  polymorphisms
l “Treatment-­modifying”  polymorphisms
l POLYGENIC

57
Signal  Transduction  Inhibitors

Mutation

58
Etiology
l HER2  (erbB-­2)
l Human  Epidermal  Growth  Factor  Receptor-­2
l Proto-­oncogene
l Amplified/overexpression 20-­25%  of  breast  CA
l Should  determined  in  invasive  breast  cancer
l Immunohistochemistry (IHC)  :  Scale  0-­3
§ Measure  protein  expression  at  cell  surface
l In-­situ  hybridization  (ISH,  FISH)  :  positive,  negative
§ Measure  gene  amplification
l Positive  result  :  IHC  3+  or  2+  with  positive  ISH

59
Trastuzumab
l Humanized  monoclonal  antibodies  to  
HER2  receptor  protein
l Indication  :  HER2  positive
l Stage  I,  II,  III  for  adjuvant
l Stage  IIA,  IIB,  III  for  neoadjuvant
l Stage  IV  for  other  primary  treatment
l Dose  :  
l 4  mg/kg  (load)  then  2  mg/kg  weekly
l 8  mg/kg  (load)  then  6  mg/kg  every  3  wks
61
 Comparison  trastuzumab regimen  (BCIRG  006)

Ref  :  Slamon D,  et  al.  N  Engl J  Med  2011;;365:1273. 62

 Comparison  trastuzumab regimen  (BCIRG  006)

Ref  :  Slamon D,  et  al.  N  Engl J  Med  2011;;365:1273. 63

Signal  Transduction  Inhibitors

Mutation

Mutation
 Non-­small  cell  lung  cancer  target

Ref  :  https://oncohemakey.com/new-­targets-­in-­non-­small-­cell-­lung-­cancer/ 64
 NSCLC  treatment

NCCN  Clinical  practice  guideline  in  oncology,  2019.   65

 Role  of  chemotherapy  in  metastatic  disease
First-­line  therapy
l Single  agent  targeted  therapy  is  recommended  for  
l Patient  with  ALK  or  ROS1  rearrangement  (Crizotinib)
l Patient  with  EGFR  mutation  (Erlotinib,  Gefitinib,  Afatinib)
l Patient  with  BRAF  mutation  (Dabrafenib +  trametinib)
l Patient  with  PD-­L1  expression  ≥  50%  (Pembrolizumab or  
PEM  +  CMT  or  Atezolizumab +  CMT)
l Platinum-­based  regimen  for  PS2  or  elderly
l Doublet  chemotherapy  are  recommended  over  
single  agents
l All  platinum-­based  chemotherapy  regimens are  preferred
l Non-­squamous cell  :  Cisplatin/pemetrexed
l Non-­squamous cell  (optional)  :  Bevacizumab/chemotherapy
l Squamous cell  :  Cisplatin/gemcitabine
l Carboplatin can  be  switched
NCCN  Clinical  practice  guideline  in  oncology,  2019.   66
Drug  Target  Pharmacogenomics
l Direct  protein  target  of  drug  
l Receptor
l Enzyme
l Proteins  involved  in  pharmacologic  response  
l Signal  transduction  proteins  or  downstream  
proteins
l Polymorphisms  associated  with  disease  risk  
l “Disease-­modifying”  polymorphisms
l “Treatment-­modifying”  polymorphisms
l POLYGENIC
Breast  Cancer  Gene  (BRCA)
l BRCA  1  and  BRCA  2
l Tumor  suppressor  gene  
l Relative  rare  in  general  population  (1:500)
l Probability  for  breast  and  ovarian  CA  by  70  yr
§ BRCA  1  :  57%  (breast)  and  40%  (ovary)
§ BRCA  2  :    49%  (breast)  and  18%  (ovary)

l Non  carrier  have  cancer  risk  as  normal  

population
l Individual  likely  to  get  benefit  for  testing

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 BRCA  screening

Ref  :  Burstein  HJ,  et  al.  in:  Devita VT,  et  al.  Cancer:  principle  and  practice  of  
oncology.  9th ed.  1401-­1446. 68
 Survival  probability  at  age  70
(Normal  population  84%)

OS:  Overall  survival,  BCD:  Breast  cancer  death,  OCD:  ovarian  cancer  death
RRSO:  risk  reduction  bilateral  salpingo-­oophorectomy
RRM:  risk  reduction  bilateral  total  mastectomy
Ref:  Kurian  AW,  et  al.  J  Clin  Oncol.  2010;;28(2):222-­31. 69
 Risk-­reduction  surgery
l Risk  reducing  mastectomy
l Meta-­analysis  of  4  studies  (2635  patients)

l BRCA1  and  BRCA2  mutation

Ref:  De  Felice  F,  et  al.  Ann  Surg  Oncol.  2015;;22(9):2876-­80. 70
 l Bilateral  oophorectomy
l Meta-­analysis  of  10  studies  (5703  patients)

l BRCA1  or  BRCA2  mutation

Ovarian  cancer Breast  cancer  (BRCA1/2)

Breast  cancer  (BRCA1) Breast  cancer  (BRCA2)

Ref:  Rebbeck TR,  et  al.  J  Natl  Cancer  Inst.  2009;;101(2):80-­7. 71

 NCCN  risk-­reduction  guideline
l Management
l Lifestyle  modification
l Risk-­reduction  surgery
l Bilateral  total  mastectomy
§ Consider  only  in  women  with  genetic  mutation  for  high  
risk  breast  cancer  (BRCA,  p53,  PTEN)
§ Compelling  family  history
§ Prior  thoracic  RT  at  <  30  years
l Bilateral  salpingo-­‐oophorectomy  (BSO)  with  
peritoneal  washings
§ For  BRCA  mutation  typical  btw  35-­40  years,  and  upon  
completion  of  child  bearing  
Ref:  NCCN.  Breast  cancer  risk  reduction  V.1  2019.  www.nccn.org 72
 Outline
l Introduction  to  precision  medicine
l Introduction  to  pharmacogenomics
l Pharmacogenomics  effect
l Novel  precision  medicine  trial  designs
l Precision  medicine  limitation
 Novel  precision  medicine  trial  designs

Ref  :  West  HJ.  JAMA  Oncol.  2017;;3(3):423. 73

 Novel  precision  medicine  trial  designs

Ref  :  Herbst RS,  et  al.  Clin  Cancer  Res.  2015;;21(7):1514-­24. 74

Precision  medicine  limitation
l Limited  predictive  value  of  most  test  
l Limited  number  of  testing
l Lack  of  physician  knowledge
l Information  providence  and  patient  privacy  
issues
l Inconsistent  standardization
l Reimbursement  issues  

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This  is  your  future  prescription!
Thank you for your attention

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