aspirin as a cancer preventive agent existing evidence & … · 2018-03-27 · nasa -january...

NASA - January 22, 2018

Ernest Hawk, MD, MPHVice President & Head, Division of Cancer Prevention & Population [email protected]

Aspirin as a Cancer Preventive AgentExisting Evidence & Remaining Questions

Disclosure InformationErnest Hawk, MD, MPH

I have the following financial relationships to disclose:Consultant for: Cancer Prevention Pharmaceuticals, PLx Pharma, Inc., Pozen, Inc.Speaker’s Bureau for: N/AGrant/Research support from: NIH/NCI, CPRIT Stockholder in: N/AHonoraria from: Huntsman Cancer Institute, University of Kansas Cancer Center, Mayo Comp. Cancer Center, Ohio State University Comp. Cancer Center, Roswell Park Cancer Institute, University of Nebraska Medical Center, UT Southwestern Simmons Comp. Cancer Center, Fred Hutchinson Comp. Cancer Center, Holden Comp. Cancer Center at Univ. of Iowa, Univ of California-Irvine Cancer Center, Kimmel Comp. Cancer Center at Johns Hopkins, ECHO Institute

Employee of: The University of Texas MD Anderson Cancer Center- and -

I will discuss the following off label use and/or investigational use in my presentation: aspirin for cancer prevention

Effective Cancer Prevention

Evidence-Based Personal Actions

Evidence-Based Population

Actions

Particularly by “reaching” the less fortunate &

underserved sectors of our population

Eliminate tobacco exposure

Eat a healthy diet & limit alcohol

Engage in physical activity

Public policyEducation –

public & professional

Delivery of community-based clinical services

Reduce UV exposure

Follow a cancer-screening program

Use preventive meds & vaccines

Know your family hx / risk

assessment

One-Third to One-Half of Cancer Deaths are Preventable in Western PopulationsEffective Cancer Prevention is Applied in Two Domains Across the Lifespan

Figure updated and adapted from AACR Cancer Progress Report, 2012Data based on Colditz, et al. Sci Trans Med., 2012

Maintain a healthy weight throughout life

MD Anderson Aspirin for Cancer Prevention:What‘s the Evidence?

• Strongest proof of cancer-preventive effect of ASA comes from colorectal adenomas & cancer– Both incidence & mortality

• Compelling evidence for preventive effect on other cancer sites, esp GI cancers– Both incidence & mortality

• Total cancer incidence & mortality? All-cause mortality?

MD Anderson

CAPP2RCT of aspirin

in Lynch Syndrome

WHS RCT of aspirin for

CV and cancer prevention

5RCTs of aspirin for adenoma

recurrence

> 50CV – PreventionRCTs of aspirin

linked with canceroutcomes

> 100Case – control and

cohort studies

Aspirin and CRC: Weight of the Evidence

Slide courtesy of Andrew Chan, MD, MPH; Dana-Farber / Harvard Cancer Center & Massachusetts General Hospital

MD Anderson

Aspirin & Risk of Colorectal AdenomasRCTs with Increased-Risk CohortsAgent / Intervention

Cohort Risk Reduction Reference

Aspirin (81mg/d

or 325mg/d) x 3

years

1211 patients with

prior adenoma

Adenoma: 81mg - 19% (0.69-0.96)

325mg - 4% (NS)

Baron, et al., 2003

Aspirin (325

mg/d) x 3 years

635 patients with

prior re-sected

early stage CRC

Adenoma: 35% (0.46-0.91)

AA: No change

Sandler, et al., 2003

Aspirin (160-

300 mg/d) x 4

years

291 patients with

prior adenomas

Adenoma recurrence 27% (0.52-1.04)

Secondary analysis of large adenomas - 83%, p=0.01

4-yr Follow-up Analysis:

-Proportion of pts with at least 1 recurrent

adenoma: 41% in aspirin vs. 40% in placebo (NS)

-Polyp burden: 3.1±5.8mm vs. 3.4±6.2mm (NS)

-Proportion of pts with at least 1 advanced

recurrent adenoma: 10% vs. 7% (NS)

Benamouzig, et al.,

2003 and 2012

6

MD Anderson

Aspirin & Risk of Colorectal AdenomasRCTs with Increased-Risk Cohorts

Agent / Intervention Cohort Risk Reduction Reference

Aspirin (300 mg/d) and folate (0.5mg/d) in 2X2 factorial design x 3 years

939 patients with prior adenoma, 27-74yo

Adenoma: 21% (0.63-0.99)Adv. Adenoma: 37% (0.43-0.91)

Logan, et al., 2008

Aspirin (100mg/d) x 2 years

311 patients with past colorectal adenomas and CRCs

Adenoma: 40%* Ishikawa, et al. (J-CAPP), 2014

Aspirin (600 mg/d) or resistant starch (30g/d) x 1-12 years in 2X2 factorial design

206 FAP patients,10-21yo

Polyp Count: 23% (NS) Burn, et al., 2011

Aspirin (600 mg/d) or resistant starch (30g/d) x up to 4 years

937 carriers of Lynch Syndrome

Time to First CRC: 37% (NS)For those completing 2 yrs. of intervention: 59% (0.19-0.86) after 10 yrs. f/u

Burn, et al., 2011

7

MD Anderson

Regular Use of Aspirin/NSAIDs & CRC Incidence

Nan et al, JAMA 2015

MD Anderson

Aspirin Significantly Reduces Lifetime CRC Risk

Rothwell et al., The Lancet 2010, v376.

Objective: Determine long-term effect of lower doses of ASA on CRC incidence & mortality

Methods: Analysis of pooled individual pt data from 5 CVD prevention trials (N=14,033)

Conclusions:• Several years of ASA treatment of at least 75

mg/d reduced long-term incidence & mortality due to CRC;

• Benefit increased with scheduled duration of treatment; &

• No increase in benefit at doses > 75 mg/d

MD Anderson

ASA & Cancer IncidenceOutcome Trials k ASA

(#cases /

#subjects)

No ASA

(#cases / #subjects)

Pooled RR (95% CI)

Cancer Incidence

CVD 1° prevention 6 2,155 / 37,301 2,139 / 35,625 0.98 (0.93-1.04)

CVD 1° & 2°prevention, adenoma prev

12 2,288 / 43,858 2,269 / 41,707 0.98 (0.93-1.04)Sens. analysis: Follow-up ≥ 4 yrs & daily dosing = 0.86 (0.74-0.99)

Rothwell meta-analysis, 2012(CVD 1° & 2° prev)

32 407 cases 514 cases 0.79 (0.70-0.90) after 3yrs

Site-Specific Incidence: Rothwell, 2012

• GI tract: 0.79 (0.61-1.02)• Female reproductive tract: 0.54 (0.36-0.82)• Respiratory tract: 0.78 (0.59-1.03)

All after 3 yrs

Whitlock, et al., Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms. A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 132. AHRQ Publication No. 13-05193-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; September 2015.

MD Anderson

Lundholm K, et al. Cancer Res 54:5602-06, 1994

Can Patients with Advanced Cancer be Palliated By Anti-Inflammatories?

MD Anderson

ASA & Cancer MortalityOutcome Trials k ASA


No ASA(#cases / #subjects)

Pooled RR (95% CI)

Cancer Mortality

CVD 1° prevention 10 760 / 52,724 753 / 51,063 0.96 (0.87-1.06)


19 842 / 59,683 841 / 56,801 0.93 (0.85-1.03)Sens. analysis: Follow-up ≥4 yrs &

daily dosing = 0.83 (0.70-0.98)


8 327 / 14,035 347 / 11,535 0.79 (0.68-0.92)

7 N = 23,535 (657 cancer deaths) 0.66 (0.50-0.87) after 5yrs f/u


34 N = 69,224 (1226 cancer deaths) 0.85 (0.76-0.96)0.63 (0.49-0.82) after 5yrs f/u

Site-Specific Mortality: Rothwell, 2011• Pancreas: 0.25 (0.07-0.92)• CRC: 0.41 (0.17-1.00)• All GI: 0.46 (0.27-0.77)• All solid cancers: 0.64 (0.49-0.85)• All adenocarcinomas: 0.53 (0.35-0.81)

All after ≥5 yrs f/u

Whitlock, et al., Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms. A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 132. AHRQ Publication No. 13-05193-EF-1.

Rockville, MD: Agency for Healthcare Research and Quality; September 2015.

MD Anderson

Is Aspirin Use Associated with Reduced All-Cause Mortality?

13

Ratnasinghe L…Hawk E. Anticancer Res 24:3177-84, 2004

Meta-analyses of ASA RCTs can be challenging due to myriad differences in:

• Patient populations (e.g., primary CV risk, secondary CV risk, adenoma risk, age, gender, etc.)

• Interventions (e.g., aspirin type, dose, frequency, duration, indication)

• Endpoints (e.g., duration of follow-up, cancer sites, cancer types, etc.)

MD Anderson

ASA & All-Cause MortalityOutcome Trials k ASA


No ASA(#cases / #subjects)

Pooled RR (95% CI)

All-causeMortality

CVD 1° prevention 10 2,199 / 52,724 2,204 / 51,063 0.94 (0.88-0.99)


25 3,322 / 64,921 3,246 / 61,692 0.93 (0.89-0.98)Sens.analysis: Follow-up ≥4 yrs &

daily dosing = 0.92 (0.85-0.99)

Rothwell meta-analysis, 2012(CVD 1° prev)

12 1165 deaths 1261 deaths 0.92 (0.85-1.00)

ATT Collaboration meta-analysis

6 (1° prev) N = 95,000(3554 serious vascular events, 3435 deaths)

0.95 (0.88-1.02)

16 (2° prev) N = 17,000(3306 serious vascular events)

0.90 (0.82-0.99) thru vascular mortality


MD Anderson

Aspirin - Safety Concerns

15


Disease 1

Most Commonly Reported Adverse Effects

• Abdominal pain

• Dyspepsia

• Nausea

• Vomiting

Most Common Serious Adverse Events

• GI Bleeding

• OR=1.59 (95% CI: 1.32-1.91)

• 0.29 events / 1,000 p-y’s of ASA exposure

• Intracranial Bleeding

• OR=1.27 (95% CI: 0.98-1.66)

• 0.1 events / 1,000 p-y’s of ASA exposure

Risk of Bleeding Increases with Age & Dose

• Age

• IRR=1.05 (95% CI: 1.05-1.05)

• Each year of age associated with a 5% higher

incidence rate for hospitalizations for major

bleeding (GI & cerebral)

• Dose (results from 1 RCT (UK-TIA))

• 1,200 mg users: 11 events / 1,000 p-y’s

• 300 mg users: 7 events / 1,000 p-y’s

• Placebo: 3 events / 1,000 p-y’s

MD Anderson 2016 USPSTF: Aspirin UseNew Recommended Intervention for CVD & CRC

http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/aspirin-to-prevent-cardiovascular-disease-and-cancer

“The USPSTF recommends low-dose aspirin use for the primary

prevention of cardiovascular disease and colorectal cancer…”

CVD risk model includes age, gender, race, total cholesterol, HDL, systolic bp, smoking status, presence of diabetes, treatment for HTN --2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk; Goff, et al., Circulation

MD Anderson

Drew et al, Nat Rev Cancer 2016

Many Interrelated Mechanisms Likely Underlie ASA’s Cancer Preventive Effects

MD Anderson

P for interaction: 4.6 x 10-9

Non-Users Regular Users

TT genotype (96%) 1.00 0.66 (0.61-0.70)

TA/AA genotype (4%) 1.00 1.89 (1.27-2.81)

Regular Use of Aspirin/NSAIDs & CRCStratified by rs2965667


MGST1 may be involved in the Wnt/CTNNB1 (beta-catenin) signaling pathway, which plays a critical role in colorectal carcinogenesis.

Microsomal glutathione S-transferase 1 (MGST1)

rs2965667 is ~950 kb downstream of MGST1

Chromosome 12

MD Anderson

Non-Users Regular Users

AA genotype (91%) 1.00 0.66 (0.62-0.71)

AC/CC genotype (9%) 1.00 0.97 (0.78-1.20)

Regular Use of Aspirin/NSAIDs & CRCStratified by rs16973225

P for interaction: 8.2 x 10-9


IL16, a multifunctional cytokine, plays a critical role in pro-inflammatory processes, such as inflammatory bowel disease as well as many cancers including CRC.

Interleukin 16 (IL16)

Chromosome 15

rs16973225 is 625 kb upstream of IL16

MD Anderson

The Syndemic Model

Aspirin May Address a Syndemic of NCDsCancer & CVD

22

Figure adapted from Singer, et al., Lancet 2017; 389:941-950Koene RJ, et al: Circulation 133:1104-14, 2016

Enhanced disease susceptibility, progression

& negative health outcomes?

Disease 1

Disease 2

Adverse Interactions

Cancer

CVD

Shared risk factors• Obesity• Physical inactivity• Unhealthy diets• Tobacco• Hyperglycemia• Hypertension?

Inflammation?Oxidative Stress?

Hormones?Other mechanisms?

ASA

MD Anderson

Aspirin as Part of a Polypill23

Disease 1

• Polypills routinely used in HIV, TB, malaria

• CVD polypill approved for use in 2° prevention in Latin America & Europe• 100mg ASA, 20mg simvastatin / atorvastatin, 2.5mg/5mg/10mg ramipril

• 6 RCTs in progress, more in development

• 13 polypill formulations identified, 6 incl. ASA• Potential Benefits:

• Simplified treatment regimen• Streamlined supply chain & logistics• Lower costs for production, storage, dispensing• Improved adherence to address poor compliance,

inappropriate use & treatment interruptions• Highly scalable• Incremental cost-effectiveness for 2° prevention:

• $306-388 / QALY with 10-15% reduction in lifetime risk of CVD

Huffman, et al., The Lancet, 2017; 389:1055-1065Webster et al., The Lancet, 2017: 389:1066-1074

• Barriers to Use• Limit autonomy of clinical decision-making• Management of side-effects, risks of stopping• Uncertainties re: cost• Regulatory uncertainties with combos, e.g., patent

protections

MD Anderson 24

Trial Population Intervention Primary Outcome(s) Status P.I. CT/ISRCTNIdentifier

ACCEPT-D Diabetes, no CVD(N=5170)

5yrs 100mg ASA vs. open control; simvastatin for all

Nonfatal MI or stroke, CV death, or other CV hospitalization

Recruitment complete

Antonio Nicolucci,Consorzio Mario Negri Sud (Italy)

ISRCTN48110081(Apr 2015)

ASCEND Diabetes, no CVD(N=15,500)

7.5 yrs 100mg ASA vs. placebo (omega-3 fatty acids vs. placebo)

MI, stroke or TIA, or CV death


Jane M Armitage, Oxford

NCT00135226(Sept 2017)

ARRIVE 10%-20% estimated 10-y risk of CHD(N=12,000)

100mg enteric-coated ASA vs. placebo

MI, stroke or TIA,unstable angina, CV death


NCT00501059(Results postedJan 8 2018)

TIPS-3 No CVD, elevated risk(N=5,000)

5 yrs 75mg ASA CVD events & cancer Recruitment on-going

Salim Yusuf, Population Health Research InstitutePrem Pais,St. John's Research Institute

NCT01646437(June 2019)

ASPREE Elderly, no diabetes or CVD (N=19,000)

5yrs 100mg ASA vs. placebo

Death, dementia or significant disability


John McNeil,Monash UniversityAnne Murray,Berman Center for Outcomes and Clinical Research

NCT01038583(Jan 2018)

On-going ASA Trials for Primary Prevention of CVD(also providing more information on cancer outcomes)

Ann Intern Med. 2016;164(12):846-847. doi:10.7326/M16-0576

MD Anderson 25

Trial Population Intervention Primary Outcome(s) Status P.I. CT/ISRCTNIdentifier

ASA & DFMO Previous adenomas (N=84) Once daily ASA & eflornithine, given PO

Adenoma recurrenceat 1 yr.

On-going, but not recruiting

Frank Sinicrope,Mayo Clinic

NCT00983580(Oct 2016)

ASPIRED Previous adenomas 81-325 mg ASAonce daily x 8-12 weeks

Urinary prostaglandin metabolites (PGE-M)

Enrolling participants by invite only

Andrew Chan,Mass Gen/Harvard

NCT02394769(Sept 2018)

AspECT Barrett's metaplasia (N=2513)

300 mg ASA & 20-80 mg esomeprazole , f/u of 8 -10 yrs

Conversion to adenocarcinoma or HGD


Janusz Jankowski, Queen Mary University of London

NCT00357682(May 2017)

seAFOodPolyp PreventionTrial

55-73 y.o. NHS Bowel Cancer Screening Programme patients with adenomas (N=904, planned)

300 mg once daily ASA &1 g EPA BID x 12 months

# patients with adenomas at 1 yr.


Mark Hull,Leeds Institute

ISRCTN05926847(Expected to publish Oct 2018)

CAPP3 18 y.o. with confirmed germline pathological variant (N=3000, planned)

non-inferiority trial, 100-600 mg enteric-coated ASA, once daily x 2 yrs

L.S. frequency during study & 10-yrs post-trial

Recruiting John Burn,Newcastle University

ISRCTN16261285 (Aug 2021)

On-going ASA Trials in High-Risk Cancer Populations

Source: www.clinicaltrials.gov; accessed 3-15-2017

http://www.clinicaltrials.gov/

aspirin as a cancer preventive agent existing evidence & … · 2018-03-27 · nasa -january...

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