Personalized Aspirin Therapy

Transcription

1 Personalized Aspirin Therapy Nadir Arber, MD, MSc, MHA Head - Integrated Cancer Prevention Center Tel Aviv Medical Centre and Tel Aviv University Heidelberg 2014

2 CRC is Preventable Early detection Chemoprevention Life style & nutrition

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5 Colonoscopy is the Best Screening Modality to Prevent CRC

6 Low Public Compliance and Acceptance Rates Colon Exam Adapted from Jack Tippit, Saturday Evening Post

7 hemoprevention is Plausible ADENOMAS CRC ADENOMAS MORTALITY *72 Epidemiological Studies, Modified from Arber and Levin, Gastro 2008

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9 Aspirin Reduces the Risk of Recurrent Colorectal Adenomas Trial Treatment Treatment duration (years) Followup (years) Patients (n) Relative Risk* (95% CI) Baron 81 mg ( ) Sandler 325 mg ( ) Placebo Aspirin 325 mg vs placebo / ( ) Benamouzig 60, 300mg vs placebo / ( ) Logan 300mg vs placebo / ( ) Cole mg vs placebo metanalysis 2.75 (med) 1678/ ( ) Ishikawa 100 mg ( )

10 Relative Risk of CRC in Individuals Using Aspirin Case-Control Cohort Cancer causes Control (2006) 17:

11 Aspirin Reduces CRC Risk (Pooled data: British Doctors & the UK-TIA trials) Regular use of aspirin (300 mg/d) 26% reduction in risk (p=0.02) 37% reduction in risk (p=0.002)when used for 5 years Benefits seen after 10 years Flossmann E, et al. Lancet 2007;369:

12 Nurses Health Study (n=121,700) Diet Aspirin BMI Med. Hist. Tobacco N=1,279 with Stage I, II, III CRC Diet Aspirin BMI Med. Hist. Tobacco Courtesy Andrew Chan Health Professionals Follow-up Study

13 Aspirin Reduces Mortality Colon-Cancer Specific Survival Overall Survival Nonuser Aspirin user CRC-specific mortality risk reduced 29% HR= 0.71 ( ) Overall mortality risk reduced 21% HR= 0.79 ( ) From Chan AT, et al. JAMA. 2009;302(6):

14 Rothwell et al, Lancet 2012 Aspirin Reduces Risk of Metastases in RCT Patients

15 Randomized, Double-Blind Placebo Controlled Study in HNPCC Carriers (CAPP2 FU) Aspirin 600mg 1-4 yrs treatment duration Follow-up 4.25 yrs (avg), up to 10 yrs Reduced risk by 38% HR ( ) CAPPS3 is launched Burn J, et al. GUT, 2011

16 Rothwell et al, Lancet 2011 Aspirin Reduces Risk of All Cancer Death in 8 CV RCTs

17 What Are the GI Side Effects of Aspirin (Aspirin-Gastropathy)? Nuisance symptoms: Heartburn, Nausea, Vomiting, Dyspepsia, Abdominal pain Mucosal lesions: Seen on endoscopy or X-rays Serious GI complications Perforated Ulcers Catastrophic bleeding requiring hospitalization Small and large bowel ulcer & stricture Hepatic toxicity Singh. Am J Med. 1998; 105 (1B): 31S-38S.

18 Multivariate relative risk Dose of Aspirin and Risk of GI Bleeding P < to to 5 6 to 14 > 14 Standard tablets of aspirin per week 1.83 Huang et al. Am J. Med 2011.

19 One Should Takes No Risks

20 Are We Making Progress? Sandler in although aspirin may prevent the disease, it may increase the risk of hemorrhagic strokes or cause other adverse effects. We must accurately balance the benefits and risks of these drugs, based on the results of ongoing randomized studies, before recommending aspirin for prevention of colorectal cancer. andler RS. Important Adv Oncol. 1996:

21 U.S. Preventative Services Task Force 2007 Recommends against routine use of aspirin or NSAIDs to prevent CRC in average risk individuals Harms outweigh the benefits for the primary prevention of CRC

22 Chan AT et al Cancer Prev Res 2012;5: Are We Making Progress? Chan et al 2012 Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with longterm aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation.

23 Personalized Aspirin Therapy

24 Multivariate relative risk Aspirin is Effective if One Takes it Everyday *P < * 0.68* to to 5 6 to 14 > 14 Tablets aspirin per week Chan, JAMA 2005

25 Multivariate relative risk Aspirin is Effective After a Decade of Use *P < * 0.67* 0.68* 0 1 to 5 6 to to 20 > 20 Years of regular aspirin use Chan, JAMA 2005

26 Aspirin Decreases the Long-Term Incidence of Proximal CRC Any aspirin treatment duration 1 Scheduled aspirin treatment 5 years 1 HR (95% CI) P-value HR (95% CI) P-value Total: CRC 0.76 ( ) ( ) Proximal 0.45 ( ) ( ) Aspirin should be combined with screening colonoscopy Distal 1.10 ( ) ( ) Rectum 0.74 ( ) ( ) <

27 Chan et al, JAMA 2009 Aspirin is Effective Only in Adenomas Expressing COX-2 Non-Users Regular Users All CRC ( ) COX-2 positive CRC ( ) COX-2 negative CRC ( ) P=0.04

28 Aspirin is Effective Only in WT BRAF Tumors Non-Users Regular Users All CRC ( ) BRAF wildtype ( ) BRAF mutant ( ) P=0.037 Courtesy: Andrew Chan Nishihara et al, in press

29 Aspirin is Effective in Patients with PIK3CA Mutation Non-Users Regular Users All CRC ( ) PIK3CA mutant CRC ( ) PIK3CA wildtype CRC ( ) P=0.01 Liao et al, NEJM 2012

30 Advanced Adenoma, Aspirin Use and Increase Urine PGE-M Non-Users Regular Users Any PGE-M ( ) High PGE-M (Q 2,3,4) ( ) Low PGE-M (Q1) ( ) Courtesy: Andrew Chan Bezwada et al, 2013

31 Aspirin Use in Populations at Risk for Colorectal Cancer? High Risk: YES, in all subjects Familial Adenomatous Polyposis (FAP) Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Lifetime risk ~ % Moderate Risk: Personal or family history of adenoma or CRC. Lifetime risk ~ 10-20% YES, in some subjects

32 Approaches in the General Population 30-50% incidence of adenomas 1,200,000 CRC cases/year Lifetime risk = 5-6% Diet Exercise Tobacco avoidance Limitation of alcohol Screening Aspirin?

33 Targeting Aspirin to Persons with Risky Phenotypes and/or Behaviors Current smoking RR 1.9 Current Smoking and > 25 pack years RR 3.0 Alcohol, > 14 units per week RR 2.2 Obesity, BMI > 27 RR 1.5 sedentarians RR 1.6 Red meat, > 4 times per week RR 2.7 Specific genetic profile?

34 Development of a simple scoring system for CRC in a cohort of > men Predictor Odds ratio (95%CI) Prediction Score Points Age (y) ( ) ( ) 4 > ( ) 6 Those in the highest risk group (9-10 points) Smoking history (Yes) 1.42 ( ) 1 Body mass Index kg/m ( ) 1 >30 kg/m ( ) 2 had an OR of 15.3 for CRC compared with those with the lowest risk (0-3 points) Alcohol use (>once/week) 1.36 ( ) 1 Driver et al. Am J Med 2007; 120:

35 Arber s Risk Score for CRC Predictor Odds ratio (95%CI) Points Age (y) ( ) ( ) 4 > ( ) 6 Smoking history (Yes) 1.42 ( ) 1 Body mass Index kg/m ( ) 1 >30 kg/m ( ) 2 Sedentery 2 Alcohol use (>once/week)1.36 ( ) 1 APC I1307K APC E1317Q 4 3 CD24 & APC 7 6

36 The Three Major Killing Diseases Cardiovascular disease Cancer Alzheimer's disease

37 % Risk % Risk % Risk % Risk Oesophogeal cancer P< Years to death Colorectal cancer P= Lancet 2011; 377: Risk of death due to cancer during 20-year follow-up of three RCTs of aspirin versus control: 12,659 patients; 1364 cancer deaths Lung cancer P=0.002 A Years to death All solid cancer P=0.003 A 2 1 A 10 5 A Years to death Years to death

38 Personalized Therapy Calculate absolute 10-year risk of IHD, CRC and Alzheimr High risk Cardiovascular Disease (>20% Framingham Study) CRC (FAP, HNPCC, MYH polyposis) Alzheimer Disease (>15% Strong family history, known mutations) Low risk Cardiovascular Disease(<10% Aspirin Framingham Study) CRC- No symptoms, no family Aspirin/NSAIDs history and negative colonoscopy Alzheimer <10% Aspirin?

39 Personalized Therapy Calculate absolute 10-year risk of IHD, CRC and Alzheimr Moderate Risk for IHD (10%-20%) Low risk for CRC Medium risk for CRC Low risk for Alzheimer Medium risk for Alzheimer Preference of the patient No Yes Proximal Colon Cox-2 positive No aspirin Aspirin

40 Impact of Genetic Polymorphisms on Adenoma Recurrence and Toxicity in a COX-2 Inhibitor (Celecoxib) Trial Kraus et al Pharmacogenet Genomics 23, , 2013 It is very exciting but Neli is going to tell you all about it

41 Cumulative Y1 Y3 Cumulative Y1 Y3 Cumulative Y1 Y3 Cumulative PreSAP Study: clinical sites in 32 countries Overall ASA Non-ASA Ad Ad* *Advanced adenoma 1 cm diameter, villous or tubulovillous, high grade dysplasia, intramucosal or invasive carcinoma Arber et al NEJM

42 provide optimum guidance Summary Strong evidence exists for a cancerpreventing effect of low-dose aspirin Particularly if taken everyday, for at least a decade and lesions for right colonic Future benefit>risk balance should take all benefits and risks into account to

43 Summary In particular aspirin can serve as the magic bullet: with its primary and secondary preventive benefits in cancer, vascular and Alzheimer diseases Genomic and neoplastic molecular signature will patients help to chose the right

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45 Thank you