primer on personalized medicined2j7fjepcxuj0a.cloudfront.net/wp-content/uploads/2014/08/14acg...•...

Sandeep K. Gupta, MD, FACG

Primer On Personalized Medicine

Sandeep Gupta MD FACG FASGE AGAFp pPrashanth Porayette MD PhD

Pediatric Gastroenterology, Hepatology, Nutrition,Riley Hospital for Children,

Indianapolis, IN 46202

Disclosures: Dr Gupta is a consultant for Abbott, Meritage, Nestle, QOL and Receptos

Objectives

• Concepts of Personalized Medicine (PM)

• Clinical examples of Personalized Medicine

• A disease condition that encompasses Personalized Medicine

ACG Midwest Regional Postgraduate Course - Indianapolis, IN Copyright 2014 American College of Gastroenterology

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Personalized Medicine

• DefinitionEmerging practice using individual’s genetic profile for decision-making in

prevention, diagnosis, and treatment

• FutureHelp predict disease susceptibility/course and treatment-response based on

clinical and genomic informationclinical and genomic information


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Traditional One-Size-Fits-All Approach to Treatment

Disease Classification based on Genetic Makeup

Genetic Profile AStandard Therapy

Genetic Profile B/C/D….Targeted Therapy

Multi-faceted Approach to Patient Care in Personalized Medicine

ASPECT OF PM WHAT IT ENTAILS

Risk Assessment Genetic tests for disease predisposition

Prevention Lifestyle interventions to prevent disease

Detection Early detection of disease at molecular level

Diagnosis Tests to individualize care plan

TreatmentTargeted treatments to reduce side effects, improve outcomes

Monitoring Treatment response/disease progression


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Using PM: Hereditary Pancreatitis Risk Assessment

PRSS1 mutation ABSENT PRSS1 mutation PRESENT

Acute Pancreatitis (AP)-Incidence 12-18/100,000/ year 60%- 80%- will get AP

4% with AP get chronic pancreatitis (CP) 50% with AP will get CP

0 6-4 9% of CP get pancreatic cancer 40% CP -> pancreatic cancer (x50-87 risk)0.6 4.9% of CP get pancreatic cancer 40% CP > pancreatic cancer (x50 87 risk)

Tobacco smoking increases risk of CP x2 Same risk

-Bang UC, Benfield T et al. Gastroenterology 2014 April;146(4):989-94.-Whitcomb DC. Gut 2004 Nov;53(11):1710-7.

Using PM: Hereditary Pancreatitis Risk Assessment

• SPINK1 mutation

• SPINK1 mutation incidence- 1% • Acts as a modifier gene• No AP if SPINK1 mutation alone as independent risk factor

TYPE OF MUTATION RISK FOR CP- FOLD INCREASECFTR- 2 mutations x40CFTR- 2 mutations AND SPINK1 mutation x900

-Pfutzer RH, Barmada MM et al. Gastroenterology 2000 Sep;119(3):615-23.-Noone PG, Zhou Z et al Gastroenterology2001 Dec;121(6):1310-9.


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Using PM: Beyond Serologies in Celiac Disease (CD)

• HLA-DQ2/DQ8 molecules is necessary but not sufficient

• 30-40% Caucasians carry HLA-DQ haplotype but only 1% develop CD

• Disease risk x5 higher if HLA-DQ2 homozygote vs. heterozygote

• HLA testing has a strong negative predictive value• HLA testing has a strong negative predictive value

• Can use HLA testing to evaluate at-risk population

-Husby S, Koletzko S et al. J Pediatr Gastroenterol Nutr 2012 Jan; 54(1):136-60.-Megrioni F, Pizzuti A. J Biomedical Science 2012 19:88-93.

Using PM: - Diagnosis of Celiac DiseaseHLA typing for CD risk gradient

-Megiorni F, Mora B et al. Human Immunology 2009 70:55-9.


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Using PM: Diagnosis of Celiac DiseaseHLA typing for CD risk-gradient

-Megiorni F, Mora B et al. Human Immunology 2009 70:55-9.

Using PM: Personalizing H. pylori Treatment

PPI-

PPI L H l i di ti i PPI t i t b li (CYP2C19 ti it )• PPI: Lower H. pylori eradication in PPI extensive metabolizers (CYP2C19 activity)

Antibiotics-

• ACG guidelines- Culture guided Rx if fail 2 courses of Rx

• Newer PCR techniques with faster/accurate clarithromycin resistance testing• Newer PCR techniques with faster/accurate clarithromycin resistance testing

-Schwab M, Schaeffeler E et al. Clin PharmacolTherapy 2004;76:201–209; -Cammarota G, Ianiro C. World J Gastroenterol 2014 May 14; 20(18): 5205-5211;-Chey WD, Wong B et al. Am J Gastroenterol 2007;102:1808-1825.


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Empiric vs. Tailored treatment Regimens- Eradication RatesEMPIRIC TREATMENT REGIMEN DURATION ERADICATION RATES

Standard Therapy-PPI, clarithromycin,

amoxicillin/metronidazole10–14 70–85%

Salvage Therapy- 7 68%Bismuth Quadraple Therapy 7 68%

LINE OF TAILORED THERAPY REFERENCES TYPE OF

THERAPYERADICATION

RATES

First Toracchio et al Triple 98%

Molina-Infante et al Quadruple 92%

Cosme et al Triple 88%Furuta et al Triple 97%K i l T i l 94%Kawai et al Triple 94%

Second Yahav et al Triple 86%Third Gasbarrini et al Quadruple 77%

Cammarota et al Quadruple 92%Cammarota et al Triple 80%Gomollón et al Quadruple 36%-52%Vicente et al Quadruple 47%-74%






THERAPYERADICATION

RATES







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THERAPYERADICATION

RATES











THERAPYERADICATION

RATES



Cosme et al Triple 88%Furuta et al Triple 97%K i l T i l 94%

Pharmacogenomics Based Tailored Treatment Strategy-

CYP2C19 genotyping and 23S rRNA gene polymorphisms vs. standard therapy-

higher eradication and cost-effective

Kawai et al Triple 94%Second Yahav et al Triple 86%Third Gasbarrini et al Quadruple 77%



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IBD Case Presentation

• 22yo male with Crohn disease- Inflammatory phenotype with perianal diseaseoPredicting risk for needing surgery-Stricturing disease= HR of 4.91Penetrating disease= HR of 3 53Penetrating disease= HR of 3.53NOD2 risk allele and perianal disease= OR of 3.84

o Initiating Azathioprine-TPMT enzyme checkGST-M1 mutation and changing to 6-MP

o Fistulizing disease-Therapeutic Drug Monitoring (TDM) for anti-TNF therapyPredicting primary failure to anti-TNF therapy

oNatalizumab and JC virus sero-negativity

ASPECT OF PM CLINICAL USE IN IBD

Risk Assessment • Need for Surgery

Various Aspects of PM in IBD

Detection • HLAB27 and ankylosing spondylitis

Diagnosis• Panel to differentiate-

- IBD from non-IBD- UC from CD

Treatment • TPMT for AZA

Monitoring• TDM for AZA • TDM for IFX

-Alvarez-Lobos M et al. Ann Surg. 2005;242:693-700-Cosnes et al. Inflamm Bowel Dis 2002; 8:244-50-Beaugerie et al. Gastroenterology. 2006;130:650-6


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Indication for thiopurine treatment

TPMT genotype or phenotype testing

Normal or high TPMT

IntermediateTPMT

Low or Absent TPMT

Therapeutic Drug Monitoring Algorithm for Thiopurines

Alternative treatment (e.g. MTX)

Reduce dose by 50% and monitor CBC and

LFT

Full dose 6-MP or AZA

ResponseResponse Toxicity or Non-response

Monitor CBC and LFT

Monitor CBC and LFT

Check 6TG and 6MMP levels

Low 6TG and low 6MMP levels

High or optimal 6TG levels

Low 6TG and high 6MMP levels

Low dose Non Compliance

Increase dose or check Compliance

Alternative Treatment

-Mosli et al. Am J Gastro 2014 109(7):994-1004

Therapeutic Drug Monitoring Algorithm for Infliximab

ATI Negative ATI Positiveg

Low IFX level Normal IFX level Low IFX level Normal IFX level

IFX escalation Endoscopy vs. switch Optimize Dose Switch drug

Mild Disease Significant Disease

Monitor Switch Drug

-Mosli et al. Am J Gastro 2014 109(7):994-1004


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Summary• Personalized Medicine- One-size does not fit all• Multiple Aspects of Personalized Medicine involved in clinical decision p p

making-• Risk Assessment• Detection• Therapy

• Rapidly evolving field with role for guidelines-based algorithms• Bioethics and Legal framework lagging behind and needs evolving

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