Precision Chemoprevention with Aspirin
Transcript of Precision Chemoprevention with Aspirin
February 3-5, 2016 | Lansdowne Resort, Leesburg, VA
Precision Chemoprevention with
Aspirin
Andrew T. Chan, MD, MPH
Clinical and Translational Epidemiology Unit
Division of Gastroenterology
Massachusetts General Hospital
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
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
Colonoscopy: Effective but with limits
No
screening
Colonoscopy
screening
All CRC 1.0 0.44 (0.38-0.52)
Distal colorectal 1.0 0.24 (0.18-0.32)
Nishihara et al, NEJM 2013
Proximal colon 1.0 0.73 (0.57-0.92)
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
DA Drew, Y Cao, AT Chan (2016) Nature Rev Cancer, in press
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
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 50-59 years – Grade B
age 60-69 years – Grade C
Nurses’ Health Study (n=121,700)
Health Professionals Follow-up Study (n=51,539)
Study population
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012
Diet
Aspirin
BMI
Med. Hist.
Tobacco
Diet
Aspirin
BMI
Med. Hist.
Tobacco
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012
Regular aspirin use and risk of cancer
in 88,084 women and 47,881 men
Total Cancer
GI Cancer
Cao et al, in press
0.5 1 1.5
0.95
0.80
1.01
Colorectum
Gastroesophagus
Pancreas
Other GI
Non-GI Cancer
Prostate (Advanced)
Lung
Breast
Other non-GI
0.75
0.86
0.90
0.98
0.96
0.97
1.00
1.00
RR
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
Can we exploit mechanism to
personalize chemoprevention?
Aspirin, COX-2, and CRC
Aspirin and risk of CRC by
intratumoral COX-2 expression
Non-Users Regular Users
All CRC 1.0 0.73 (0.62-0.86)
COX-2 negative 1.0 0.96 (0.73-1.26)
P heterogeneity=0.02
Chan et al, NEJM 2007
COX–2 positive 1.0 0.64 (0.52-0.78)
Aspirin, 15-PGDH, and CRC
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 anti-
adenoma effect of celecoxib
Yan et al, PNAS 2004; Yan et al, PNAS 2009
Aspirin and risk of CRC by
colonic 15-PGDH
Non-Users Regular Users
All CRC 1.0 0.73 (0.62-0.86)
Low 15-PGDH 1.0 0.90 (0.63-1.27)
P heterogeneity=0.02
Fink et al, Sci Trans Med 2014
High 15-PGDH 1.0 0.49 (0.34-0.71)
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)
Discovery of novel genetic loci for
aspirin and CRC
Aspirin/NSAID use and risk of
CRC by rs2965667 at 12p12.3
Non-Users Regular Users
All Genotypes 1.0 0.69 (0.64-0.74)
TA or AA (4%) 1.0 1.76 (1.16-2.66)
Nan et al, JAMA 2015
TT (96%) 1.0 0.63 (0.59-0.68)
P interaction=4.6X10-9
rs2965667
• 927-971 kB downstream from microsomal
glutathione S-transferase (MGST1), a member
of membrane-associated proteins in eicosanoid
and glutathione (MAPEG) metabolism
• Upregulated in CRC
Aspirin/NSAID use and risk of
CRC by rs16973225 at 15q25.2
Non-Users Regular Users
All Genotypes 1.0 0.76 (0.53-0.99)
AC or CC (9%) 1.0 0.93 (0.75-1.17)
Nan et al, JAMA 2015
AA (91%) 1.0 0.63 (0.59-0.68)
P interaction=8.2X10-9
rs16973225
• 625 kB upstream of IL-16
• IL-16 stimulates IL-6 and TNF-α
• Activates COX-2 and Wnt signaling
DA Drew, Y Cao, AT Chan (2016) Nature Rev Cancer, in press
Inflammatory link between aspirin
and the microbiome?
Pro-inflammatory
environment
-adapted from A. Chan AACR 2015
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
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?
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
Prospective microbiome collection
1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2013 2015
Nurses’ Health Study 2 (n=116,430)
Baseline
Aspirin
Stool Collection
(n=209)
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