Primer On Personalized Medicine

Transcription

1 Primer On Personalized Medicine Sandeep Gupta MD FACG FASGE AGAF Prashanth Porayette MD PhD Pediatric Gastroenterology, Hepatology, Nutrition, Riley Hospital for Children, Indianapolis, IN 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 1

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3 Personalized Medicine Definition Emerging practice using individual s genetic profile for decision-making in prevention, diagnosis, and treatment Future Help predict disease susceptibility/course and treatment-response based on clinical and genomic information 3

4 Traditional One-Size-Fits-All Approach to Treatment Disease Classification based on Genetic Makeup Genetic Profile A Standard Therapy Genetic Profile B/C/D. Targeted Therapy Multi-faceted Approach to Patient Care in Personalized Medicine ASPECT OF PM Risk Assessment Prevention Detection Diagnosis Treatment Monitoring WHAT IT ENTAILS Genetic tests for disease predisposition Lifestyle interventions to prevent disease Early detection of disease at molecular level Tests to individualize care plan Targeted treatments to reduce side effects, improve outcomes Treatment response/disease progression 4

5 Using PM: Hereditary Pancreatitis Risk Assessment PRSS1 mutation ABSENT Acute Pancreatitis (AP)- Incidence 12-18/100,000/ year PRSS1 mutation PRESENT 60%- 80%- will get AP 4% with AP get chronic pancreatitis (CP) 50% with AP will get CP % 9%ofCPget 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): Whitcomb DC. Gut 2004 Nov;53(11): 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 CFTR- 2 mutations CFTR- 2 mutations AND SPINK1 mutation RISK FOR CP- FOLD INCREASE x40 x900 -Pfutzer RH, Barmada MM et al. Gastroenterology 2000 Sep;119(3): Noone PG, Zhou Z et al Gastroenterology2001 Dec;121(6):

6 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 Can use HLA testing to evaluate at-risk population -Husby S, Koletzko S et al. J Pediatr Gastroenterol Nutr 2012 Jan; 54(1): Megrioni F, Pizzuti A. J Biomedical Science : Using PM: - Diagnosis of Celiac Disease HLA typing for CD risk gradient -Megiorni F, Mora B et al. Human Immunology :

7 Using PM: Diagnosis of Celiac Disease HLA typing for CD risk-gradient -Megiorni F, Mora B et al. Human Immunology :55-9. Using PM: Personalizing H. pylori Treatment PPI: Lower H. pylori eradication in PPI extensive metabolizers (CYP2C19 activity) it PPI- Antibiotics- ACG guidelines- Culture guided Rx if fail 2 courses of Rx Newer PCR techniques with faster/accurate clarithromycin resistance testing -Schwab M, Schaeffeler E et al. Clin PharmacolTherapy 2004;76: ; -Cammarota G, Ianiro C. World J Gastroenterol 2014 May 14; 20(18): ; -Chey WD, Wong B et al. Am J Gastroenterol 2007;102:

8 Empiric vs. Tailored treatment Regimens- Eradication Rates EMPIRIC TREATMENT REGIMEN DURATION ERADICATION RATES Standard Therapy- PPI, clarithromycin, amoxicillin/metronidazole Salvage Therapy- Bismuth Quadraple Therapy LINE OF TAILORED REFERENCES % 7 68% TYPE OF ERADICATION RATES First Toracchio et al Triple 98% Molina-Infante et al Quadruple 92% Cosme et al Triple 88% Furuta et al Triple 97% Kawai et al Ti 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% Empiric vs. Tailored treatment Regimens- Eradication Rates EMPIRIC TREATMENT REGIMEN DURATION ERADICATION RATES Standard Therapy- PPI, clarithromycin, % amoxicillin/metronidazole Salvage Therapy- Bismuth Quadraple Therapy 7 68% LINE OF TAILORED REFERENCES TYPE OF ERADICATION RATES First Toracchio et al Triple 98% Molina-Infante et al Quadruple 92% Cosme et al Triple 88% Furuta et al Triple 97% Kawai et al Ti 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% 8

9 Empiric vs. Tailored treatment Regimens- Eradication Rates EMPIRIC TREATMENT REGIMEN DURATION ERADICATION RATES Standard Therapy- PPI, clarithromycin, amoxicillin/metronidazole Salvage Therapy- Bismuth Quadraple Therapy LINE OF TAILORED REFERENCES % 7 68% TYPE OF ERADICATION RATES First Toracchio et al Triple 98% Molina-Infante et al Quadruple 92% Cosme et al Triple 88% Furuta et al Triple 97% Kawai et al Ti 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% Empiric vs. Tailored treatment Regimens- Eradication Rates EMPIRIC TREATMENT REGIMEN DURATION ERADICATION RATES Standard Therapy- PPI, clarithromycin, % amoxicillin/metronidazole Salvage Therapy- Bismuth Quadraple Therapy 7 68% Pharmacogenomics Based Tailored Treatment Strategy- LINE OF TAILORED REFERENCES TYPE OF ERADICATION RATES First Toracchio et al Triple 98% Molina-Infante et al Quadruple 92% Cosme et al Triple 88% Furuta et al Triple 97% Kawai et al Ti 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% CYP2C19 genotyping and 23S rrna gene polymorphisms vs. standard therapyhigher eradication and cost-effective 9

10 IBD Case Presentation 22yo male with Crohn disease- Inflammatory phenotype with perianal disease o Predicting risk for needing surgery- Stricturing disease= HR of 4.91 Penetrating disease= HR of 3.53 NOD2 risk allele and perianal disease= OR of 3.84 o Initiating Azathioprine- TPMT enzyme check GST-M1 mutation and changing to 6-MP o Fistulizing disease- Therapeutic Drug Monitoring (TDM) for anti-tnf therapy Predicting primary failure to anti-tnf therapy o Natalizumab and JC virus sero-negativity ASPECT OF PM Risk Assessment Need for Surgery Various Aspects of PM in IBD CLINICAL USE 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: Cosnes et al. Inflamm Bowel Dis 2002; 8: Beaugerie et al. Gastroenterology. 2006;130:

11 Therapeutic Drug Monitoring Algorithm for Thiopurines Indication for thiopurine treatment TPMT genotype or phenotype testing Low or Absent TPMT Normal or high TPMT Intermediate TPMT Alternative treatment (e.g. MTX) Full dose 6-MP or AZA Reduce dose by 50% and monitor CBC and LFT Response Toxicity or Nonresponse Response Monitor CBC and LFT Check 6TG and 6MMP levels Monitor CBC and LFT Low 6TG and low 6MMP levels High or optimal 6TG levels Low 6TG and high 6MMP levels Low dose Non Compliance -Mosli et al. Am J Gastro (7): Increase dose or check Compliance Alternative Treatment Therapeutic Drug Monitoring Algorithm for Infliximab ATI Negative ATI Positive Low IFX level Normal IFX level Low IFX level Normal IFX level IFX escalation Endoscopy vs. switch Optimize Dose Switch drug Mild Disease Monitor Significant Disease Switch Drug -Mosli et al. Am J Gastro (7):

12 Summary Personalized Medicine- One-size does not fit all Multiple Aspects of Personalized Medicine involved in clinical decision making- Risk Assessment Detection Therapy Rapidly evolving field with role for guidelines-based algorithms Bioethics and Legal framework lagging behind and needs evolving 8/28/