Global monitoring of the WHO ‘25 by 25’ target - proposal from the Section of Cancer Information Freddie Bray WHO target - IARC proposal • Global target to reduce premature mortality from all NCDs by 25% by 2025 (4 key NCDs, ages 30-69) • Proposal: – Evaluate national cancer mortality trends against the ‘25 by 25’ target • Quantify whether the reduction is attainable based on recent trends via prediction models • Deliver a report card on cancer control progress at the national and global level Data sources and availability • Mortality extracted from the WHO mortality database by country, cancer site, year, sex, age • Data available for ≥15 years: – 78 countries (35 Europe, 25 Americas, 15 Asia, 2 Oceania, 1 Africa) • Data available for <15 years: – 8 countries (4 Asia, 2 Europe, 2 Africa) • Quality (coverage, completeness, timeliness) National mortality series: availability Methods • Standard prediction models fitted to recent trends (e.g. 1991-2010) to predict mortality 2011-2025 • National data available for ≥15 years: – Age-period-cohort models based on a 15- or 20-year prediction base: NORDPRED (Moller et al, 2003) • National data available for <15 years: – Time-linear models based on a 10-year prediction base (e.g. Dyba & Hakulinen, 1997) • Future ‘all sites’ burden derived from site-specific analyses (top ten cancers + residual sites by sex) Key output & dissemination For ‘all sites’ + leading 10 cancers, ages 30–69 & all ages, by country and sex: • Number of recorded deaths and age-standardised rates (up to 2010) and predicted (up to 2025) • Cumulative risk of death (up to age 70) • % change in cancer deaths (2008 v. 2025) Dissemination • Global Status Report Online user-friendly toolkit Deaths 2008 Deaths 2025 % change % due to pop % due to risk Males 33462 42904 28 51 -23 Females 29085 35939 24 31 -7 62457 78843 26 41 -15 Total Questions for the Scientific Council • What could be done in monitoring the target in LMIC? • Should we incorporate other indicators (incidence, survival)? • Is the analytic strategy adequate? • Extensions – Revision of target for remaining major NCD groups? – Incorporate scenarios for specific cancer interventions? Future perspectives of quantitative risk assessment for the IARC Monographs Kurt Straif, IMO IARC Scientific Council, January 2013 IARC Monographs on the Evaluation of Carcinogenic Risks to Humans “A cancer ‘hazard’ is an agent that is capable of causing cancer under some circumstances, while a cancer ‘risk’ is an estimate of the carcinogenic effects expected from exposure to a cancer hazard. The Monographs are an exercise in evaluating cancer hazards, despite the historical presence of the word ‘risks’ in the title.” (Preamble, 2006) Problems encountered with hazard identification • "International cancer experts have moved tanning beds and other sources of ultraviolet radiation into the top cancer risk category, deeming them as deadly as arsenic and mustard gas.“ (Associated Press, 2009) • “Evaluations in the IARC Monographs provide a qualitative assessment of carcinogenicity. The HPV types that have been classified as carcinogenic to humans can differ by an order of magnitude in risk for cervical cancer. The Working Group cautions that the design of HPV screening tests must also consider other factors that are discussed in the General Remarks.“ (Vol. 90) Consideration of risk assessment in IARC Monographs • IARC workshop: Quantitative Estimation and Prediction of Risk (IARC Sci Pub 131, 1999). - no recommendations regarding risk assessment for the IARC Monographs • Advisory Group on Future Priorities for the IARC Monographs, 2003 - many different approaches to risk assessment, - inclusion of critical reviews of published risk assessments? - approach based on epidemiological data? - Working Groups themselves would not embark on risk assessment. Consideration of risk assessment in IARC Monographs Advisory Groups on amendment of the Preamble to the IARC Monographs, 2005. • inclusion of a new section in future Monographs that would summarize data on carcinogenic risks (focus on results that involve minimal or no unverifiable assumptions, summary relative risks from meta-analyses), • systematic incorporation of quantitative analysis of carcinogenic risk that do not involve extrapolation outside the range of the available data, • use of a separate group of experts to develop a supplement to a specific Monograph focusing on quantitative risk assessment. • a programme in QRA will require specialized expertise and a significant commitment of resources. Consideration of risk assessment in Monographs The amended Preamble (IARC, 2006) includes the following guidance on quantitative data: • Objective and Scope: “A Monograph may undertake to estimate dose–response relationships within the range of the available epidemiological data, or it may compare the dose–response information from experimental and epidemiological studies. In some cases, a subsequent publication may be prepared by a separate Working Group with expertise in quantitative dose–response assessment.” • Cancer in humans: “Dose–response and other quantitative data may be summarized when available.“ • Cancer in experimental animals: “…dose–response and other quantitative data are also summarized.” Advisory Group meeting planned for November 2013 on “Perspectives of quantitative risk assessment for the IARC Monographs“ Specific questions to be addressed by the SC 1. Pros and Cons of a move towards risk assessment (including issues such as other key players and potential users); 2. Potential approaches for the IARC Monographs: - integration into regular Monographs versus separate meetings on selected agents; - restriction to observed exposure–response relationships on cancer in humans versus low dose-extrapolation, between species extrapolation and/or use of mechanistic data to inform such extrapolations; 3. Strategic approach for funding: if move towards risk assessment is recommended by the AG should this be integrated into the next 5-year grant proposal to US NCI due in summer 2014 and/or which other funding sources would be suggested? Current Scientific Initiatives Mechanisms of Carcinogenesis Section (MCA) Zdenko Herceg, PhD Carcinogenesis in aristolochic acid nephropathy (MMB Group) Aim: Elucidate molecular basis and develop biomarkers for Upper Urinary Tract (UUT) carcinogenesis associated with aristolochic acid nephropathy (AAN) AAN is a public health problem of global proportions caused by dietary exposures to aristolochic acid Aristolochic acid is a highly potent carcinogen (Group I) present in plant species used on a worldwide scale in herbal remedies (India, Asia, Africa, N.& Central America, Europe) As the source of the exposure is known and its effects can be detected at the molecular level, this is a potentially preventable cancer UUT tumor sites AAN = global public health problem prospectively preventable malignancy, with largely unknown and underestimated incidence 128 47+ 4 4 1 2 6 16 116 33 ? 158 ? Debelle F.D. et al, Kidney Int, 2008 Heinrich M. et al, J Ethnopharm, 2009 Moriya M. et al, Int J Cancer 2011 Jelakovic B. et al, Kidney Int, 2012 Chen C.H. et al, PNAS USA, 2012 Country/Region Established cases (published) Population at risk Belgium 128 1,800 The Balkans 47+ 100,000 Taiwan 126+ 8,000,000 China 116+ 100,000,000 India 33 ? Approach to study molecular mechanisms and identify biomarkers Clinical course Molecular mechanisms/epidemiology • Exposure to AA • Mol. mechanisms (identify early « driver » events) • Nephrotoxicity, renal failure • Prophylactic renal surgery • UUT carcinoma <30 yrs • Tumor resection +2-10 yrs • 2o tumour formation • Contralateral kidney UUC • Bladder • Identify biomarkers of AA exposures and carcinogenesis (mutations, miRNAs) • Assess biomarkers in new and unmapped populations at risk Identification of “driver” mutations in AAN-linked UUT cancers Mutation type distribution in tumours (whole-exome sequencing, n=3) Genome-wide A>T distribution A>T 40 30 20 10 0 60 30 0 - AA-induced tumors exhibit stochastic accumulation of genome-wide A>T transversions - 65% of missense deleterious SNV alterations are A>T - A>T is a candidate « driver » event in AAN tumorigenesis (to be tested in animal/cell models) 300 150 0 J. Zavadil, unpublished Questions • Can we exploit animal/cellular models of AAinduced cancer to study early (“driver”) and genetic/epigenetic events • How should we best utilize results of these studies to build relevant and efficient preventive measures in populations at risk Epigenetic biomarkers associated with cancer risk (EGE Group) Question: Can epigenome changes in peripheral blood be used as biomarkers of exposure or intermediate biomarkers for cancer risk Most studies investigated epigenetic changes in cancer tissues Advances in epigenomics have opened opportunities for identifying epigenetic biomarkers in genome-wide and high throughput settings Aims: Analyse the epigenome (methylome) of WBC of cancer cases and controls using large samples from the EPIC prospective cohort and epigenome-wide technology Identify epigenome changes associated with cancer risk and diet/lifestyle (alcohol, obesity/physical activity) and endogenous factors (1-carbon metabolites, hormones) Focus on breast cancer (collaboration with NME Section); other cancer types (lung cancer, collaboration with GEN Section) are considered Study design EPIC Cohort Selection of breast cancer cases (n=500) Selection of matched controls (n=500) DNA methylome profiling (Illumina 450K Arrays) Bioinformatics analysis Analysis of onecarbon metabolites Validation of top hits in 1500 cases and 1500 controls (pyrosequencing) Biostatistics/bioinformatics analysis Epigenetic predictors of cancer risk Epigenetic signatures of exposures Database on risk factors/exposures/ hormones Expected outcome •Discover whether significant epigenome variations in WBC among cancer cases and controls exist prior to diagnosis •Discover whether epigenetic variations are caused by endogenous (hormones, 1-carbon metabolites) and/or environ. factors •Prospective design will rule out the possibility that changes are not influenced by the disease process (“reverse causality”) Questions •Issues relevant to epigenomic profiling of prospectively collected blood samples in studying exposures/cancer risk •Criteria in selecting exposures associated with breast cancer (low- vs high-resource settings) Section of Molecular Pathology Head: Dr Hiroko Ohgaki Objectives - To elucidate the molecular bases and genetic pathways to human tumours, and to identify clues as to their etiology - To correlate histologically recognized phenotypes with genotypes - To establish a molecular classification of tumours Achievements - Identification of genetic pathways to gliomas - Definition of primary and secondary glioblastomas - Population-based genetic analyses in gliomas in Zurich, Switzerland - Contributions to the WHO Classification of Tumours of Nervous System Plan of exome sequencing analysis in glioblastomas diagnosed in a population Objectives: - To assess genetic profiles of glioblastomas at a population level - To identify molecular markers that predict sensitivity to radio-chemotherapy in particular in elderly patients Research plan: Cancer registries, neurosurgeons, neuropathologists, University Hospitals Zurich (population, approx. 1 300 000) Basel (population: Basel Stadt, 185 000; Basel Land, 269 000) Ticino (population, 328 000) Diagnosed in 2014 - 2016 (estimated no. of cases, approx. 320) To collect frozen tumour tissues and blood samples from all patients for exome sequencing Challenges In contrast to retrospective population-based studies, patients will be initially identified in surgical centres, but not by cancer registries. Thus, identifying all cases at a population level may be challenging, and we may lose a significant fraction of elderly patients if they are not treated in surgical centres. Questions to Scientific Council: Does the Scientific Council recommend that IARC carries out populationbased exome sequencing study on brain tumours? What are the questions that cannot be answered using samples collected in clinical trials? WHO Classification of Tumours Series (WHO Blue Books) Objectives: To establish a histopathological and molecular classification of human tumours that is accepted and used worldwide. Without clearly defined clinical and histopathological diagnostic criteria, and more recently genetic and expression profiles, epidemiological studies and clinical trials are difficult to conduct. WHO Classification of Tumours (WHO Blue Books) 4th edition Central Nervous System July 2007 Print run 20,000 Haematopoietic and Lymphoid Tissues Sept 2008 45,000 Digestive System Oct 2010 20,000 Breast Soft Tissue and Bone June 2012 Initial 10,000 Jan 2013 Initial 10,000 616 contributors (pathologists, clinicians, scientists) from 39 countries participated >64,000 copies were distributed in >105 countries by WHO Press Accepted as the international standard of histological and genetic criteria of diagnosis of human tumours Challenges In order to deal with rapid progress in genetics in human neoplasms, it is necessary to revise the WHO Classification more frequently than previously. Increasing demand of online version. Meeting on the Strategic Directions on Future of the WHO Classification of Tumours (January 11, 2013) - New procedures to speed up completion of the 4th edition - To move to the online option in the near future - PubCan as online version of WHO Classification of Tumours PubCan (Public database of human cancers) Developed by Dr Paul Kleihues, former IARC Director Officially transferred to IARC in 2011 Contains all disease entities in the latest WHO Classification tables and all terminologies in the ICD-O3 (International Classification of Diseases for Oncology) Two volumes of WHO Blue Books were transferred to PubCan Tumours of the Digestive System 4th edition Tumours of Haematopoietic and Lymphoid Tissues 4th edition Questions for the SC Does the Scientific Council support our intention to move to the online option in the near future? What should be the timeline? What additional considerations should the Agency consider in moving forward? Cervical cancer prevention in Bhutan and Rwanda and synergies between oncogenic viruses with environmental factors Infections Section and Cancer Infections and Cancer Biology Group. Head: Dr Massimo Tommasino Infections and Cancer Epidemiology Group. Silvia Franceschi Monitoring HPV vaccination and HPV screening programs to promote sustained implementation in low-income countries (PI: Dr Gary Clifford, ICE) • Bhutan and Rwanda have been the first low-resource countries (LRCs) to implement a successful nation-wide HPV vaccination program; • They will be important to determine if the full anticipated decrease in disease can be realized in LRCs; • Monitoring HPV vaccine impact on cervical cancer onset will take more than 20 years; • In the near-term, the most feasible and informative outcome to measure is the variation in type-specific HPV infection in sentinel populations of young sexually active women and adolescents. Monitoring HPV vaccination and HPV screening programs to promote sustained implementation in low-income countries Bhutan Rwanda Population ~700,000 ~15 M Cervical cancer incidence ≥ 20.4/100,000 ≥ 34.5/100,000 First HPV vaccination year 2010 2011 Age target (yrs) 12-18 6th grade (~10-15) Vaccine delivery Mainly schools Mainly schools Campaign 92% 93% Routine (mainly health centers) 60-80% Not yet, Catch up on-going Current cervical screening Pap test, ~25% None Cervical screening plans Rapid HPV testing Rapid HPV testing/VIA HPV vaccine coverage Objectives of HPV monitoring 1. Age- and type-specific prevalence of HPV in exfoliated cervical cells in women aged 18-69 years (n=2,500), and cervical cancer and CIN2/3 (2012-13); 2. Double HPV testing in IARC (ultra-sensitive) and Amsterdam (clinically set sensitivity); 3. Early impact of HPV vaccination by repeat cervical cell surveys (2016; 2021) of young women <29 years (n=1,500); 4. Type-specific prevalence in urine in girls aged 18-19-year (n=1,000) (2013; 2015; 2017). 5. Shifting from cytology (Bhutan) to or introduction (Rwanda) of cervical screening using Rapid HPV testing in women aged 30+ (from 2013). This investment would improve cervical cancer prevention in older women and could ultimately serve as the basis for long-term vaccination monitoring. IARC HPV Surveys, sexually active women, 15-59 yrs (1995-2013) HPV Prevalence (%) N Guinea Mongolia Vanuatu Nigeria Bhutan Poland China, Shenzhen Argentina India China, Shenyang China, Shanxi Chile Colombia Georgia Korea Mexico Vietnam, Ho Chi Minh Italy, Turin Thailand, Lampang Nepal Iran Netherlands Algeria Thailand, Songkla Spain Pakistan Vietnam, Hanoi 833 969 987 932 2066 834 1027 978 1891 685 662 955 1834 1309 863 1340 922 1013 1035 932 825 3304 759 706 911 899 994 0 5 10 15 20 25 30 35 40 45 50 hpv 16 or 18 other high-risk type low-risk type only 55 When vaccines are not available, intervention on environmental co-factors is especially promising Inhibition of apoptosis Infection Induction of proliferation Facilitators of viral life cycle Oncoproteins Evasion of the immune system Persistent infection immunosuppressants Inflammation DNA damaging agents Chromosomal instability Well known association: Aflatoxin B1 and HBV in sub-Saharan Africa, work from C Wild et al Cancer Aflatoxin B1 stimulates Epstein-Barr Virus replication in in vitro experimental models: a role for EBV, in addition to malaria, in Burkitt Lymphoma in subSaharan Africa? EBV + in presence or absence of Aflatoxin B1 0.12 viral copy number/infected cell Primary B cells 0.08 0.04 0.00 Control Aflatoxin 1 UV, beta HPV types and squamous-cell skin cancer • UV irradiation is a key risk factor for squamous-cell carcinoma (SCC) in HPV38 E6/E7 transgenic mice (183 and 187 lines) 1.0 • UV and impairment of the immune system (HIV+; organrecipients) also strongly increases the risk of SCC in humans 1.0 0.6 0.4 Tg-1 183 Tg-2 187 0.2 120 0.4 450 0.6 0.8 SCC incidence UVB doses (mJ/cm2) 183 187 FVB/N 0.8 Chronic UV irradiation of WT or HPV38 E6/E7 transgenic mice 0.2 1 2 3 15 16 17 18 (Weeks) 19 20 29 30 WT 0.0 0 0.0 00 55 20 20 25 25 Weeks of UV irradiation 30 30 Discussion topics • Monitoring HPV vaccination from 2018 until the predictable decline of cervical cancer in Cancer Registry can be seen (~2040) • Further studies aiming to identify novel unknown synergies between oncogenic viruses with environmental factors 1. Adding genotyping to HPV-based cervical screening; 2. Improving information on HPV vaccination status, eg, computerization of initial vaccination records (~130,000 in Rwanda and 50,000 in Bhutan); 3. Other (immunogenicity; vaccine failures, etc.) 1. New hypothesis? 2. Strategies and procedures to evaluate synergies/interactions? Environment and Radiation Section Dr Joachim Schüz Pesticides and cancer (AGRICOH) AGRICOH – consortium of agricultural cohort studies • Participating studies are 27 cohort studies from 11 countries • Objective of AGRICOH: promote collaboration and pooling of data to study the association between a wide range of agricultural exposures and health outcomes. • Farmers and agricultural workers form large proportion of work force worldwide • Lower morbidity for some diseases but increased risk of several cancer types, respiratory diseases, or neurotoxic outcomes Leon et al. 2011, Int J Environ Res Public Health AGRICOH • A consortium of agricultural cohort studies can address research gaps in health outcomes associated with agricultural exposures by pooling data from studies collaborating in research projects • Pooling data can increase statistical power to study rare diseases (e.g. ovarian, testicular, thyroid cancers) or uncommon exposures (infrequently applied chemicals) • Opportunity to replicate findings from individual studies • IARC-ENV: - Study coordinator - Member of Steering Group - Data Management Center Cohort studies included in AGRICOH Norway (3) Canada (3) UK (1) USA (7) Denmark (1) France (3) Korea (1) Costa Rica (2) South Africa (2) Australia (2) New Zealand (2) Ongoing projects lead by IARC/ENV • Exposure to pesticides and risk of lymphoma, myeloma and leukaemia in the AGRICOH consortium: a pooled analysis – Cohorts from France (187,471 adult farmers), Norway (248,000) and USA (52,394) – Funded by ONEMA (France) • Cancer incidence and mortality in agricultural cohort studies in the AGRICOH consortium – Cohorts from Australia (n=2), South Korea (1), France (1), Norway (3), USA (2) – Co-Funded by NCI Questions to the SC • STRATEGIC: Less than half of cohorts can provide cancer data. IARC coordinates and contributes heavily to infrastructure. Should this continue or should we advocate a coordination more subdivided by outcome? • EXPANSION: Majority of cohorts are from highincome countries. To include more cohorts from low-medium income countries, general population cohorts including farmers might need to be considered. Balance being open for LMIC while staying restrictive for HIC? Research on Chernobyl Health available infrastructures Cohorts of: • exposed to Chernobyl fallout in childhood and adolescence in Belarus and Ukraine with detailed thyroid dose measurements (BelAm, UkrAm cohorts ~30,000) • Chernobyl clean up workers (liquidators) from Baltic countries, Belarus, Russia and Ukraine (~600,000) • Evacuees (including exposed in utero) (~100,000) and offspring of exposed parents (~43,000) Registries: • Cancer registries (Baltic countries, Belarus, Ukraine) • Chernobyl registries (Belarus, Ukraine), National Medical and Dosimetric Registry (Russia) ARCH – what is proposed? • ARCH assembled a group of experts who developed a strategic research agenda (SRA) and recommended: – – setting up an international mechanism to coordinate and fund studies to enable assessment of the overall long-term health effects - Chernobyl Health Effects Research Foundation creation, maintenance and follow-up of Chernobyl Life Span cohort New IARC/ENV initiative on international cooperation • Building partnerships with Belarus, Russian federation, Ukraine, Japan, US and EU to take the Strategic Research Agenda forward: – bring together key scientific players and funding partners – seek sustainable funding for Chernobyl research priority areas – identify the nature and structure of an international coordinating mechanism Questions to the SC • How much should IARC support the training and education of researchers in Belarus, Russian federation and Ukraine e.g. for monitoring and analysing cancer trends in the contaminated regions? • The question whether there was an increase in infant leukaemia in Europe after Chernobyl is still open; how much effort should be made to collect additional data? Section of Genetics James McKay Genetic Cancer Susceptibility Group Genetics Section • Two opportunities that take advantage of the large GEN bio-repositories and NGS: 1. Mutation profiling of tumours • Focus on rare histologies/subtypes • Targeted sequencing of known cancer genes (identified from TCGA) 2. Genomic biomarkers • Early detection and outcome 1. Mutation profiling in tumour subgroups • Early stage lung cancer cases from CRC Moscow - All with blood and tumour tissue, some adjacent normal tissue - Comprehensive baseline and follow-up details - 450 collected, expand to 900 by 2014 • Initial focus on bronchioloalveolar carcinoma (BC) - Relatively rare subtype, particular clinical characteristics 41 cases identified 23 NEVER SMOKERS (56%) 22 WOMEN (54%) 30 ALIVE AFTER ONE YEAR (73%) • Exome sequencing finalised on 12 pairs of normal and tumour material and underway for remaining 29 Effect of smoking on mutations results from initial 12 tumours Genes observed mutated TP53, KRAS (poster) Questions to be investigated Compare BC-LC with adenocarcinoma LC and squamous LC (data from The Cancer Genome Consortium (TCGA)) Overlap with Adeno & Squamous What somatic variants are unique to BC? Relation to Outcome Lung Adeno. (n=334 TCGA) BC n=52 (IARC 41 & 11 TCGA) Lung Squam. (n=243 TCGA) Both questions are of clinical relevance for treatment and subsequent outcomes Mutation profiling in tumour subgroups within GEN • Other potential priority cancer sites: – Head and neck cancer with a focus on HPV status (IARC-INCA Brazil collaborative project) – EBV status in Hodgkin’s lymphoma Genes mutated within head and neck tumours • Within 100 (TCGA) head and neck tumours, 95% mutations reported within 10 genes. • It becomes possible to design targeted sequencing assays to cover most mutations, and at low cost. Stransky N et al (2011). Science Rapid and cheap comprehensive sequencing of many tumours is only now becoming feasible Exome/Genome Sequencing Many genes/Few samples Targeted Resequencing Few genes/Many samples Targeted Resequencing Ion Torrent Experiment Cost (35 amplicons, 150X coverage) 72.8 €/sample X 6 cost through GCS optimization 12.2 €/sample Plan to sequence 450 lung cancer tumours for top (TCGA) mutated genes 2. Genomic biomarkers for early detection Circulating tumour DNA (ctDNA) in the blood • Tumour ctDNA comprises ~ 0.2% of total plasma DNAs, excess of wild-type DNA makes ctDNA identification challenging. • NGS to screen many genes at a very high sensitivity (sequencing at > 5000X coverage to be able to detect 0.2% ctDNA). • Ion Torrent sequencing pilot data (MMB group): expected EGFR mutations detected within patient plasma material (totalling 1 to 3% of sequence reads). Circulating tumor DNA (ctDNA) as a non-invasive biomarker • To what extent are tumour mutations (or mutation combinations) also identifiable in ctDNAs from blood? • 450 early stage LC define mutation profile by sequencing 10 commonly mutated genes (TCGA: TP53, CDNK2A….) • Can we detect DNA mutations in the plasma from same patients? • If so, can we detect mutations in samples collected 1-3 years prior to diagnosis (EPIC study)? Questions for the Scientific Council • What types of sequencing studies should we try to initiate, taking into account our access to large bio-repositories but our limited sequencing capabilities? • Should we take advantage of other biomarker opportunities that arise with NGS, including studies that aim to detect circulating tumour DNA in plasma or serum samples?