Precision Chemoprevention with Aspirin

Transcription

1 Precision Chemoprevention with Aspirin Andrew T. Chan, MD, MPH Clinical and Translational Epidemiology Unit Division of Gastroenterology Massachusetts General Hospital February 3-5, 2016 Lansdowne Resort, Leesburg, VA

2 Aspirin as a model for prevention Fulfills an unmet need Strength of the evidence Development, testing, follow-up Treating the whole patient Precision approach based on mechanism Prostaglandin pathways Novel genetic approaches Inflammation / immunity Microbiome The future

3 Aspirin as a model for prevention Fulfills an unmet need Strength of the evidence Development, testing, follow-up Treating the whole patient Precision approach based on mechanism Prostaglandin pathways Novel genetic approaches Inflammation / immunity Microbiome The future

4 Colonoscopy: Effective but with limits No screening Colonoscopy screening All CRC ( ) Distal colorectal ( ) Proximal colon ( ) Nishihara et al, NEJM 2013

5 Aspirin as a model for prevention Fulfills an unmet need Strength of the evidence Development, testing, follow-up Treating the whole patient Precision approach based on mechanism Prostaglandin pathways Novel genetic approaches Inflammation / immunity Microbiome The future

6 DA Drew, Y Cao, AT Chan (2016) Nature Rev Cancer, in press

7 Aspirin as a model for prevention Fulfills an unmet need Strength of the evidence Development, testing, follow-up Treating the whole patient Precision approach based on mechanism Prostaglandin pathways Novel genetic approaches Inflammation / immunity Microbiome The future

8 U.S. Preventative Services Task Force 2015 Recommends low-dose aspirin for the primary prevention of cardiovascular disease (CVD) and CRC in adults who have 10% ten-year CVD risk, are not at increased risk of bleeding, have at least a life expectancy of 10 years, and are willing to take low-dose aspirin daily for at least 10 years age years Grade B age years Grade C

9 Study population Nurses Health Study (n=121,700) Diet Aspirin BMI Med. Hist. Tobacco Health Professionals Follow-up Study (n=51,539) Diet Aspirin BMI Med. Hist. Tobacco

10 Regular aspirin use and risk of cancer in 88,084 women and 47,881 men Non-GI Cancer Breast Prostate (Advanced) Lung Other non-gi GI Cancer Colorectum Gastroesophagus Pancreas Other GI Total Cancer Cao et al, in press RR

11 Aspirin as a model for prevention Fulfills an unmet need Strength of the evidence Development, testing, follow-up Treating the whole patient Precision approach based on mechanism Prostaglandin pathways Novel genetic approaches Inflammation / immunity Microbiome The future

12 Can we exploit mechanism to personalize chemoprevention?

13 Aspirin, COX-2, and CRC

14 Aspirin and risk of CRC by intratumoral COX-2 expression Non-Users Regular Users All CRC ( ) COX 2 positive ( ) COX-2 negative ( ) P heterogeneity=0.02 Chan et al, NEJM 2007

15 Aspirin, 15-PGDH, and CRC

16 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) Ubiquitously downregulated in CRC Knockout of 15-PGDH in mice PGE-2, colon tumors, resistance to anti-tumor effect of celecoxib Pilot study in APC Trial 15-PGDH in normal colon = resistance to antiadenoma effect of celecoxib Yan et al, PNAS 2004; Yan et al, PNAS 2009

17 Aspirin and risk of CRC by colonic 15-PGDH Non-Users Regular Users All CRC ( ) High 15-PGDH ( ) Low 15-PGDH ( ) P heterogeneity=0.02 Fink et al, Sci Trans Med 2014

18 Discovery of novel genetic loci for aspirin and CRC Case-control studies nested within U.S. prospective cohorts Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) Women s Health Initiative (WHI) Health Professionals Follow-up Study (HPFS) Nurses Health Study (NHS) VITamins And Lifestyle (VITAL) Case-control studies from the US, Canada and Europe Colon Cancer Family Registry (CCFR) Ontario Familial Colorectal Cancer Registry (OFCCR) Diet, Activity, and Lifestyle Survey (DALS) Darmkrebs: Chancen der Verhutung durch Screening (DACHS) Postmenopausal Hormones Supplementary Study to Colon Cancer Family Registry (PMH-CCFR)

19 Aspirin/NSAID use and risk of CRC by rs at 12p12.3 Non-Users Regular Users All Genotypes ( ) TT (96%) ( ) TA or AA (4%) ( ) P interaction=4.6x10-9 Nan et al, JAMA 2015

20 rs kb downstream from microsomal glutathione S-transferase (MGST1), a member of membrane-associated proteins in eicosanoid and glutathione (MAPEG) metabolism Upregulated in CRC

21 Aspirin/NSAID use and risk of CRC by rs at 15q25.2 Non-Users Regular Users All Genotypes ( ) AA (91%) ( ) AC or CC (9%) ( ) P interaction=8.2x10-9 Nan et al, JAMA 2015

22 rs kb upstream of IL-16 IL-16 stimulates IL-6 and TNF-α Activates COX-2 and Wnt signaling

23 DA Drew, Y Cao, AT Chan (2016) Nature Rev Cancer, in press

24 Inflammatory link between aspirin and the microbiome? Pro-inflammatory environment -adapted from A. Chan AACR 2015

25 Aspirin as a model for prevention Fulfills an unmet need Strength of the evidence Development, testing, follow-up Treating the whole patient Precision approach based on mechanism Prostaglandin pathways Novel genetic approaches Inflammation / immunity Microbiome The future

26 The Future. Can we profile 15-PGDH expression levels in the colon at the time of colonoscopy / polypectomy? Can we genetically profile such individuals to make sure they do not have a risk allele that would predict lack of aspirin efficacy? Can we identify novel molecular mechanisms (e.g. microbiome, immunity) of aspirin efficacy?

27 What is needed? Prospective clinical trials of colonic 15- PGDH expression in relation to outcomes Validation of potential GxE interactions in large populations Cohort studies or RCT data on the effect of aspirin across disease endpoints Cost-effectiveness of aspirin in relation to other cancer prevention strategies Prospective cohort studies of the gut microbiome in relation to cancer outcomes

28 Prospective microbiome collection Baseline Aspirin Nurses Health Study 2 (n=116,430) Stool Collection (n=209)

29 ASPIRED: ASPirin Intervention for the REDuction of CRC risk Three arm, placebo-controlled, double-blind RCT CRC Biomarker Endpoints Primary (efficacy) Urinary PGE-M Secondary Plasma MIC-1 ChIP-Seq (TCF7L2/TCF4 at 8q24) on colonic epithelium Gene expression in colonic epithelium (Wnt signaling/15- PGDH) Oral and gut microbiome Spectral biomarkers