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