CLEAR Study collaborators meeting December 2013

The NSW CLEAR StudyPotential Collaborator Meetings, December 4th & 5th, 2013

Investigators:Freddy Sitas, CCNSW

Dianne O’Connell, CCNSWEmily Banks, ANU

Michael Barton, UNSWKaren Canfell, UNSW

Contents

• CLEAR Study Overview - Slides 2 to 17• Smoking/Tobacco Use - Slides 18 to 27• Hormones - Slides 28 to 41• Sun Exposure/Sleep - Slides 42 to 55• BMI Exercise & Alcohol - Slides 56 to 70• Infections - Slides 71 to 86

CLEAR Study Overview

The NSW CLEAR StudyCollaborator Meeting Day 1

Thursday December 5th, 2013

• University of Oxford: – Johannesburg Cancer Case Control Study.

Professor Valerie Beral• University of Oxford / Peking Union Medical

College:– Million Deaths study. Professors Richard Peto,

Bo-Qi Liu (spouse control)• Share some questions with 45 and Up study

The NSW CLEAR Study

Overview and Methodology

Provenance

The NSW CLEAR Study


1. To investigate the molecular and environmental risk factors for cancer in NSW

2. Understand the relative importance of leading / emerging risk factors for cancer in a local setting

3. (Future) Construct a ‘cancer cohort’ study to investigate the consequences of a cancer diagnosis

4. Develop a research platform between epidemiologists, basic scientists and clinicians

CLEAR Study Aims

The NSW CLEAR Study


Participation – Consent – Questionnaire – +/- blood sample

Recruitment−Targeted−Non-targeted

Eligibility criteria−Incident cases−NSW resident−> 18 years

CLEAR Study Operations

The NSW CLEAR Study


Male Case

Female Case

Female Partner

Male Partner

Case and Control Design

The NSW CLEAR Study


• Representative of the background population (if the cases are so)

• Comes from the same catchment area as the case

• Would use the same hospital if they became a case

1Breslow and Day, Rothman, Schlesselman, Miettinen

A Good Control Group

The NSW CLEAR Study


SESIAHS ClinCR41%

SSWAHS ClinCR24%

Cancer Council NSW9%

Riverina Cancer Care Centre

6%

HCF Health Fund Registry

4%

Liverpool Hospital3%

Royal Prince Alfred Hospital

2%

Port Macquarie Hospital

2%

St Vincents Hospital2%

Other8%

Recruitment Sites of Participants

The NSW CLEAR Study


Actual Numbers (see Data book, page 5)

Note: Cancer types with less than N=20 are grouped under the Other category

The NSW CLEAR Study

Overview and MethodologyIllustrative Numbers of Cancer Patients (18-79 years)

• Now:• Link to NSW Central Cancer Registry

– Diagnosis, topography morphology and staging

• Future:– Deaths, Event and COD, [RBDM, ABS]– Admitted Patient Data Collection– Pathology records (negotiating)– Dental records– Medicare (negotiating) [MBS, PBS]

The NSW CLEAR Study

Biobank Collection Protocol

ACD - RTSST - ~4⁰C

ACD PlasmaACD Buffy coatSerum

-80⁰CProcess≤48hrs

The NSW CLEAR Study

Protocol Compliance

0 1 2 3 4 5 6 7 >70

500

1000

1500

2000

2500

3000

3500

4000

4500

Days

Sam

ples

rece

ived

(n) 82% QUALITY REPORTING

• Delivery temperature• Date/Time of collection• Date/Time of

processing• Haemolysis score• Short fill

The NSW CLEAR Study

Biospecimen Quality Control

CCNSW Stability Study• pre-analytic variation (t and time)• 4 vacutainer types• several molecular groups eg;

antibodies, cytokines, ncRNAs

Further enquiries: [email protected]

The NSW CLEAR Study

Application ProcessOnline Application

Data Access Coordinator (practical feasibility check)

Y/N

Expert Advisory Committee (EAC) (peer review of all aspects of application)

CLEAR Principal Investigator

Feedback to Applicant

The NSW CLEAR Study

Cost Structure

• Application Fee: $500

• Licence Fee: $20,000

• Linked data - additional fee: $3,000

• Preparation for linkage: $3,000

• Data cleaning: $100 per hour

The NSW CLEAR Study

Cost Structure

Application Fee: $500.00

Plasma and Serum: $20 per 500µl aliquot

DNA: $47.50 per 25 µl aliquot

Licence Fee applies if variables beyond minimum data set are requested

Timing of release of aliquots may be dependent on quantities requested and on other applications for the same product.

Smoking and Tobacco


Thursday December 5th, 2013

The NSW CLEAR Study

Smoking / Tobacco Questions

The NSW CLEAR Study

Frequency of Cancer Types

The NSW CLEAR Study

Frequency of Exposures

The NSW CLEAR Study

Our current work on Smoking/Tob.

• No contemporary studies of risk of smoking

• All estimates indirect

−Underestimate?

Australia

Year of study M F

1959-1965 12 3

1982-1988 25 13

2000-2010 27 26

Relative risk of developing lung cancer

(US Smoker vs. non-smoker)

The NSW CLEAR Study


The importance of local studies

The NSW CLEAR Study


Research Questions

1. Contemporary risks of smoking on cancer in Australia

2. Add to evidence where causation is inconclusive•Bowel (IARC 100th Mono)•Prostate •Breast

Cancer type Study Variable OR (95% CI)Women Men

Lung cancer CLEAR* Never 1.0 1.0

Past 5.1 (3.1, 8.3) 5.8 (2.9, 11.7)

Current† 20.9 (12.0, 36.3) 31.7 (14.9, 67.7)

Cancer Prevention Study**

Never 1.0 1.0

Past 8.1 (7.2, 9.1) 7.1 (6.1, 8.2)

Current†† 23.4 (19.6, 25.6) 25.6 (21.7, 30.3)

Million Women Study***

Never 1.0

Past

Current 21.4 (19.7, 23.2)

* adjusted for age, socioeconomic status and migrant status** adjusted for cohort, age, race and education level***adjusted for recruitment site, age, body mass index, socioeconomic status, current alcohol intake, physical activity, oral contraceptive use, menopausal status and hormone therapy use.† current smokers are classified as those who still smoke or those who had quit smoking within the previous five years from date of recruitment into study† † current smokers are classified as those who were still smoking at time of recruitment into study

The NSW CLEAR Study


The NSW CLEAR Study


• adjusted for age, socioeconomic status and migrant status• **** adjusted for age, education, smoking status and cooking fuel† current smokers are classified as those who still smoke or those who had quit smoking within the previous five years from date of recruitment into study

Cancer type

Study Variable OR (95% CI)

Women Men

Tobacco relatedcancers

CLEAR* Never 1.0 1.0

Past 1.4 (1.0, 2.1) 1.4 (1.0, 1.9)

Current† 2.2 (1.5, 3.4) 4.9 (3.5, 7.0)

JCCC**** Never 1.0 1.0

Past 1.4 (1.1, 1.8) 2.8 (2.2, 3.5)

Current† 1.9 (1.6, 2.2) 4.6 (3.7, 5.7)

The NSW CLEAR Study


A Typical Analysis (e.g. Stein et al 2008)

Hormones

The NSW CLEAR StudyCollaborator Meeting Day 1Wednesday December 4th,

2013

The NSW CLEAR Study

Hormones Questions

Hormone Exposure in Women

The NSW CLEAR Study

Hormones Questions

Hormone Exposure in Women (Cont’d)

The NSW CLEAR Study

Hormones Questions

• Family history of breast and ovarian cancers

• Hysterectomy , oophorectomy, sterilisation and pregnancy terminations

• Breast screening mammograms and Pap smear test histories

Other related information captured in CLEAR

The NSW CLEAR Study

Hormones Questions

Hormone Exposure in Men

The NSW CLEAR Study


The NSW CLEAR Study


The NSW CLEAR Study


The NSW CLEAR Study

Our current work on Hormones

Hormones and Breast cancer risk Case-control analyses using data

from the NSW CLEAR study

PhD candidate – Usha SalagameSupervisors – A/Prof Karen Canfell A/Prof Freddy Sitas Prof Emily Banks

The NSW CLEAR Study


Research Objectives

Estimating the risk associated with specific exposures and comparing them with results from large collaborative studies to validate the study design and use of spouse controls

• Age at menarche• Abortion• Age at first birth• Use of oral

contraceptives • Breast feeding• Menopausal status • Parity• Family history

The NSW CLEAR Study


Case-control analysis- MHT use and breast cancer risk

Analysis by • current, past and ever use of

MHT• by duration of use• type of MHT preparation

Research Objectives Cont’d

The NSW CLEAR Study


Why study MHT use and its association to breast cancer?

• Increased risk of breast cancer due to menopausal hormone therapy -established elsewhere in the world1,2.

• An estimation of the risks specifically in NSW among Australian women through CLEAR study -contemporary and local.

• Prior work suggests that much of the drop in breast cancer incidence rates is due to the concurrent decline in HRT prescriptions in Australia3.

1.Writing group for the Women's Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy menopausal women: principal results from the Women's Health Initiative randomised controlled trial. JAMA 2002; 288: 321-33.

2.Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003; 362:419-27.

3.Karen Canfell, Emily Banks, Aye M Moa and Valerie Beral. Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia.MJA 2008; 188:641-44.

The NSW CLEAR Study


Example of analysis: The Million Women Study 2003

Sun Exposure and Sleep


Thursday December 5ht, 2013

The NSW CLEAR StudySun Exposure and Sensitivity Questions

Outdoor UV Exposure

The NSW CLEAR StudyUV Exposure and Sleep Questions

Indoor UV Exposure

Sleep

The NSW CLEAR Study

Sun exposure and cancer risk

Sun Exposure and Internal Cancer Risk

Vitamin D hypothesis-vitamin D deficiency may be a

risk factor for cancer.

The NSW CLEAR Study

Current evidence

Vitamin D and cancer risk - Health Professionals Study (USA) 2006

The NSW CLEAR Study

Current evidence

Sun exposure and cancer risk:NIH-AARP Diet and Health Study (2012)

The NSW CLEAR Study

Current evidence- NSW

Sun exposure and prostate cancer in NSW:Prostate Cancer Care and Outcomes -Sun Study (2012)

Table 1. Odds ratios for prostate cancer in quartiles of increasing weekly hours of sun exposure

1Adjusted for year of birth and sun sensitivity.

Solar UV exposure (Quartiles)

Odds ratio1 (95% CI)

Weekly Weekend Q1 1.00 1.00

Q2 1.3 (0.9,1.9) 1.4 (0.9,2.0) Q3 1.5 (1.0,2.2) 1.6 (1.1,2.3) Q4 2.1 (1.4,3.2) 5.6 (2.9,10.5)

p-value4 0.007 <0.0001

The NSW CLEAR Study

Systematic review

Sun exposure, vitamin D and cancer risk (De Vries 2013)

• Almost all epidemiological studies suggest that sun exposure is linked with risk of colorectal, breast, prostate, NHL cancers

• No associations between vitamin D and cancers of the prostate and NHL.

• Prostate and NHL“other sunlight potentiated and vitamin D independent pathways i.e. immune modulation and circadian rhythm and folic degradation may play a role”.

The NSW CLEAR Study

Sleep and cancer risk

"shift-work that involves circadian disruption" as "probably carcinogenic to humans" (Group 2A)

- The International Agency for Research on Cancer

Circadian Rhythm and Cancer Risk

The NSW CLEAR Study

Evidence on sleep and cancer risk

Meta-analysis of the association between long sleep and risk of cancer: Prospective Cohort Studies (Lu et al 2013)

The NSW CLEAR Study

Our current work on Sun Exp/Sleep

• Time spent outdoors

Sun exposure and cancer link in CLEAR

The NSW CLEAR Study


• Places lived• Solarium use• Duration of sleep• Shift work

The NSW CLEAR Study


BMI / Physical ActivityAlcohol



The NSW CLEAR Study

BMI/Physical Activity Questions

Similar Q in 45+

The NSW CLEAR Study

BMI/Physical Activity Questions

CLEAR Study – BMI questions

The NSW CLEAR Study

Alcohol Questions

The NSW CLEAR Study


The NSW CLEAR Study


The NSW CLEAR Study


The NSW CLEAR Study


The NSW CLEAR Study


• Which cancers are associated with BMI in Australia

• Are there differences – between M&F– Migrant groups– BMI at different ages– Pre and post-menopausal?

The NSW CLEAR Study

BMI/Phys Act

Research Questions

Possible analyses using CLEAR (Reeves et al, MWS 2008)

The NSW CLEAR Study

BMI/Phys Act

The NSW CLEAR Study

Alcohol

Alcohol Smoking Comment

- - Baseline – Methodological problems of ascertaining former vs. never drinkers. Use co-morbidities as proxy?

+ - Studies limited by statistical power. InterSCOPE shows some associations

+ Adj or not sp.

Association well established for numerous cancer types

+ + Strong, consistent association – multiplicative

The NSW CLEAR StudyCurrent work on Alcohol: InterSCOPE, n=4000

The NSW CLEAR Study

Alcohol

• Which cancers are associated with alcohol– Upper digestive, bowel, breast, …

• Interactions? With BMI, Smoking• Alcohol dehydrogenase ($)

Infectious Diseases



The NSW CLEAR Study

Infectious Diseases Questions

Lifestyle related questions

The NSW CLEAR Study


Tattoos and Peircings IV Drug Use

The NSW CLEAR Study


Blood Transfusion Organ Transplant

The NSW CLEAR Study


The NSW CLEAR Study


The NSW CLEAR Study


The NSW CLEAR Study

Our current work on Infect. Dis.

Research Opportunities

• Number of cancers caused by known infections in Australia is small ~3%

• Still cause significant mortality and morbidity• Infections can be removed• Infectious disease discovery not over yet

−Bladder, H&N, Prostate?, haematological, [skin] …o Spinoffs: diagnostics, blood supply,

vaccine, chemotherapy• Add other studies that can increase sample

sizes

The NSW CLEAR Study


Research Questions

• Questionnaire correlates– Are specific lifestyle factors correlated with

specific cancers? • Sex behaviour• Tattoos • Piercings• IV drugs• Prostatitis• Blood transfusion• Organ transplant

The NSW CLEAR Study


Research Questions

• Pathogen-related screening tools developed for – cervical cancer (HPV screening)– liver cancer (hepatitis B, C)

• No screening tools for – H&N, male genital, stomach, …

• Suspected infectious cause for several cancers yet to be unravelled

The NSW CLEAR Study


List of Pathogens – DKFZ ~100

• HPV1-107• L1, E2, E6, E7• SV40• Polyoma BK, JV, MC

• H.pylori 21 proteins

• Hepatitis B, C• Herpes I,II, CMV, EBV

• Retroviruses

• Luminex platform• Several under construction

• High throughput• ~AU$15 per sample, 50 results

• 0.2ml serum

The NSW CLEAR Study


Types of Research Questions

• Serotype distribution of HPV in background (controls) and in cases of H&N, cervix, other genital sites (n?)

• Improving predictive value of serological markers

• Existing pathogen, new disease• New pathogen?

The NSW CLEAR Study


Illustration of Results – New Pathogen e.g. Sitas 1999

1. How common?2. How dangerous?3. Which cancers?4. Which cancers

NOT?

The NSW CLEAR Study

Our current work on Infect. Dis.Many pathogens, one cancer: InterSCOPE: HPV serological markers and OSCC

Health & Medicine

CLEAR Study collaborators meeting December 2013