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Gianluca tognon - cancer epidemiology


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Gianluca tognon - cancer epidemiology

  1. 1. Cancer epidemiology over the life course Gianluca Tognon
  2. 2. Background  The incidence of cancer has increased from 12.7 million in 2008 to 14.1 million in 2012, and this trend is projected to continue, with the number of new cases expected to rise  This will bring the number of cancer cases close to 25 million over the next two decades (+ 70%)  More than 60% of the world’s cancer cases occur in Africa, Asia, and Central and South America, and these regions account for about 70% of the cancer deaths
  3. 3.  Among men, the five most common sites of cancer diagnosed in 2012 were the lung (16.7% of the total), prostate (15.0%), colorectum (10.0%), stomach (8.5%), and liver (7.5%)  Among women, the five most common incident sites of cancer were the breast (25.2% of the total), colorectum (9.2%), lung (8.7%), cervix (7.9%), and stomach (4.8%)  The worldwide estimate for the number of cancers diagnosed in childhood (ages 0–14 years) in 2012 is 165 000 (95 000 in boys and 70 000 in girls)
  4. 4. Childhood cancer  Overall annual incidence rates vary between 50 and 200 per million in children and between 90 to 300 per million in adolescents  Reliable data on cancer in children and adolescents are available for only a small fraction of the world’s population  Over the past 50 years, 5-year survival has improved in high-income countries from less than 30% to more than 80%  The growing population of survivors requires specialized follow-up and care
  5. 5. Cancer etiology
  6. 6. The global tobacco epidemic  Tobacco use remains an enormous health problem that kills 6 millions people annually worldwide, mainly for CVD, COPD and lung cancer  Use is currently decreasing in most high-income countries but increasing or persisting at high levels in many low- and middle-income countries  More than 80% of all smokers reside in low- and middle-income countries  Effective tobacco control strategies such as large periodic increases in excise taxes and the elimination of advertising provide opportunities for cancer prevention worldwide
  7. 7. Smokeless tobacco  Example of smokeless tobacco products include: loose leaf for chewing, solid compressed tobacco products in the form of chunks or sticks, viscous pastes, dry or moist ground tobacco (snus) for oral or nasal use, tobacco- smoke water for gargling, ecc.  Oral smokeless tobacco use delivers nicotine more slowly than cigarette smoking does  Over the course of the day, smokeless tobacco users may ingest twice as much nicotine as smokers  Smokeless tobacco products (as with many cigarette brands) usually have an increased pH to promote availability of nicotine for absorption
  8. 8. Chemicals in smoking products Tobacco smoke contains > 7,000 chemicals including numerous known carcinogens: PAH, N-nitrosamines, aromatic amines, volatile aldehydes and phenolic amines Smokeless tobacco contains more than 3,000 chemicals and at least 28 carcinogens, many the same contained in tobacco smoke products
  9. 9. Alcohol consumption  Epidemiological and biological research on the association between alcohol and cancer has established that alcohol consumption causes cancers of the mouth, pharynx, larynx, oesophagus, liver, colorectum and female breast  Typically a dose-response association has been established  For 2010, alcohol-attributable cancers were estimated to be responsible for 337,400 deaths worldwide, predominantly among men (liver cancer showed the largest proportion of deaths)
  10. 10. Alcohol content of selected beverages Starköl vol. 5.6% Lättöl vol. 2,3% Red wine vol. 12% Port wine vol. 20% White wine vol. 10% Whisky vol. 40% Alcohol in 100 g 4,5 1,8 9,9 16,0 7,9 32 1 standard drink = 10 to 14 g of alcohol
  11. 11. Alcohol metabolism ADH = Alcol dehydrogenase ALDH = Aldehyde dehydrogenase Liver enzymes
  12. 12. Infections  Infections with viruses, bacteria, and macroparasites have been identified as strong risk factors for specific cancers  2 million (16%) of the total of 12.7 million new cancer cases in 2008 are attributable to infections  This fraction varies 10-fold by region: it is lowest in North America, Australia and New Zealand (≤ 4%) and highest in sub-Saharan Africa (33%)  Helicobacter pylori, HBV/HCV and human papillomaviruses are responsible for 1.9 million cancer cases globally, including gastric, liver and cervical cancer respectively  Infection with HIV substantially increases the risk of virus- associated cancers, through immunosuppresion
  13. 13. Reproductive and hormonal factors  Reproductive and menstrual factors are relevant to the etiology of breast, endometrial and ovarian cancers although the exact biological mechanisms are still not known  Parity is inversely related to the risk of breast, ovarian and endometrial cancers (for breast, first child before the age of 30)  Breastfeeding for a longer period is inversely related to breast cancer  Breast and endometrial cancers are predicted by early age at menarche and later age at natural menopause  Women who had surgical ovary removal are at reduced risk of breast cancer (taking the surgery before the age of 40 halves the risk compared to a natural menopause at 55)  Obesity is inversely related to premenopausal breast cancer (probably due to anovulation), but is positively associated to postmenopausal BC
  14. 14. Contraceptives and hormone use Use of oral contraceptives substantially reduces the risk of endometrial and ovarian cancers but appears to increase the risk of breast and of cervical cancers Use of menopausal hormones has been associated with increased risk of ovarian and endometrial cancer
  15. 15.
  16. 16. Male cancers  Breast: the incidence is 1% the rate in women. Increased risk after gynaecomastia and with Klinefelter syndrome, obesity and low physical activity, prior bone fractures and cigarette smoking. The association with endogenous hormones has not been assessed  Testicular: height, subfertility and (possibly) exposure to endocrine disruptors. Other risk factors include: cryptorchidism, hypospadias, inguinal hernia, low birth weight, short gestational age and being a twin  Prostate cancer: these cancers respond well to anti-androgens therapies and both surgical and medical castration reduce the risk of metastasis. Any endogenous hormone has been proved to be a risk factor. However, finasteride use reduces prostate cancer risk by blocking the conversion of testosterone to dihydrotestosterone
  17. 17. Lifestyle factors  Excess body fat increases the risk of cancers of the oesophagus (reflux), colon, pancreas, endometrium and kidney as well as postmenopausal breast cancer  Dietary factors associated with weight reduction (low intakes of sodas, refined sugars, high-calorie foods, etc.) are protective  High consumption of red meat (especially processed) is associated with risk of colorectal cancer  A diet high in fruit and vegetables and whole grains does not appear to be strongly inversely associated with the risk of cancer  High intakes of dairy products protect from colorectal cancer but increases the risk of fatal prostate cancer  Low levels of vitamin D increases the risk of colorectal cancer and mortality, but more research is needed  Additional studies are needed to assess the role of physical activity, further than those related to weight control
  18. 18. Carcinogens in food PAHs and heterocyclic amines from high cooking temperature N-nitroso compounds which are result from nitrate or nitrite added during processing and formed endogenously from haem iron Food contaminants Mycotoxins (aflatoxins)
  19. 19. Occupation  32 occupational agents as well as 11 exposure circumstances are identified as carcinogenic to humans  An additional 27 agents and 6 exposure circumstances primarily relevant to occupational exposure are probably carcinogenic to humans (list on the WCR 2014)  Workplace exposure to several well-recognized carcinogens (asbestos, PAHs, heavy metals, diesel engine emissions and silica) is still widespread  Recent estimates have been in the range of 4-8% of all cancers attributable to occupational cancer risk factors in developed countries  Little information is available on occupational cancer risk in low-income countries
  20. 20. Problems…  Multiple attempts (often controversial) have been performed to estimate the proportion of cancer cases attributable to occupation  Estimating attributable fractions is feasible when the exposure factor is well defined and there is a body of evidence to support estimates of the magnitude of risk associated with the risk factor  None of these conditions generally exist for the generic class of occupational exposures  Moreover, confounding by SES and smoking status can be strong  ”Healthy worker effect”  Common problems include incomplete lists of occupational carcinogens, meagre information on quantitative relative risks associated with exposure to known carcinogens and scant information on the prevalence of exposure
  21. 21. ”Dirty” blue-collar jobs  As a result of many social, economic and technological forces, in the past 50 years there have been a decline in the numbers of workers involved in the ”dirty” blue-collar work in developed countries  Unfortunately, the reverse is true in developing countries, where occupational environment continues to be poorly regulated  An increase in the prevalence of occupational cancers in developing countries is therefore expected
  22. 22. Prevention Workers’ education Safer occupational practices Surveillance
  23. 23. Ionizing, UV and electromagnetic radiations
  24. 24. Risks due to exposure  Exposure to all types of ionizing radiation, from both natural and man-made sources, increases the risk of various types of malignancy  The risk is higher if the exposure occurs early in life  There is current consensus on the absence of a threshold for the induction of cancers by radiation and presumption of a linear dose-response relationship  Exposure to UV radiation, both from the sun and from tanning devices, is established to cause all types of skin cancers, including melanoma  Associations between heavy use of mobile phones and certain brain cancers have been observed, but causal interpretation is controversial
  25. 25. UV exposure  Over the last 50 years, the incidence of all skin cancer types has steeply increased in Caucasian populations worldwide, with highest incidence rates where fair-skinned populations are exposed to intense UV radiation in countries such as Australia  The solar radiation is composed of 95% UVA and 5% UVB, since the latter are more blocked by the ozone layer  Tanning lamps and beds emit mainly UVA, with less than 5% UVB  Powerful tanning equipment may be a source 10-15 times as intense as midday sunlight on the Mediterranean sea  Tanning of the skin is predominantly triggered by DNA damage induced by UV radiation  UVB is far more efficient than UVA in inducing a deep, persistent tan and is 1000 times as potent as UVA in inducing sunburn
  26. 26. Extremely low-frequency electromagnetic fields  Ubiquitous exposure occurs due to power transmission and use of electrical appliances, as well as to fields in the radiofrequency range due to communication and broadcasting  A small fraction of households located very close to high-voltage power lines or other sources can have appreciably higher background exposures  For most people, the highest exposure to radiofrequency electromagnetic fields occurs when using mobile phones, since the source of emission is held close to the head  The number of sources continue to increase
  27. 27. Pollution of air, water and soil  Air pollution can be divided into indoor and outdoor  Sources of indoor air pollution include tobacco smoking and burning or solid fuels (coal and biomass)  Sources of outdoor air pollution include emissions from vehicles, power generation, household combustion of solid fuels and a range of industries  Exposure to indoor pollution is associated with lung cancer, particularly in low-income countries where solid fuels are common  Exposure to outdoor pollution is associated with cardiovascular disease and lung cancer
  28. 28. Asbestos  One of the best characterized causes of human cancer in the workplace  The installation, degradation, removal and repair of asbestos-containing products in the context of household maintenance represents another mode of residential exposure  Exposure can also occur through contacts with dust-contaminated clothes  It causes mesothelioma and lung cancer, the latter particularly among smokers
  29. 29. Particulate matter (PM)  It is a mix of hundreds of individual chemicals and its composition varies around the world, reflecting different sources of pollution and meteorological conditions  It also contains carcinogens (PAHs, benzene, inorganic compounds)  The smaller the particle, the more dangerous it is. The measurement of PM2.5 levels is generally considered more informative than PM10  Increased PM levels are associated with CVD and lung cancer. These levels are decreasing in high-income countries, while are still very high in many low-income countries
  30. 30. Pesticides  A large and diverse number of chemicals designed to kill pests such as weeds, insects, rodents, algae and moulds for agricultural, residential and public health purposes  They are designed for the release in the environment and exposure can occur occupationally or through the ingestion of contaminated foods  Despite widespread potential exposure, cancer risks associated with long-term exposure to specific pesticides are generally not well characterized  Several organochlorine and organophosphate insecticides have been linked with an increased risk of prostate cancer  Inorganic arsenic compounds are classified as Group 1 by IARC  The fungicide captafol and the fumigant ethylene dibromide are classified as Group 2A (probably cancerogenic)  Several are listed as Group 3 (not classifiable as carcinogenic)
  31. 31. Water disinfection  In drinking water, inorganic arsenic is a recognized carcinogen  Arsenic is often a natural water contaminants, which causes cancer of the skin, bladder and lung  Other contaminants include disinfection by-products (chloroform and other trihalomethanes), organic solvents, nitrates, nitrites and some pesticides  Consumption of chlorinated drinking water is associated with an increase in bladder cancer  Alternative/complementary methods include UV irradiation, microfiltration, oxygen
  32. 32. Soil contaminants  A variety of toxic agents, including heavy metals, solvents, and persistent organic pollutants (POPs) contaminate the soil  In some regions, such pollution occurs by substances produced as waste or as other consequences of a particular mining or industrial process  Soil contaminants present a carcinogenic risk as a result of being vaporized and consequently inhaled, or being leached from the soil to contaminate water supplies  Accordingly, risk of cancer is generally evaluated in relation to water or air pollution
  33. 33. Pharmaceutical drugs Pharmaceutical drugs may have the potential to induce or prevent cancer development Antineoplastic agents used in cancer therapy can induce second cancers, mostly because of the genotoxicity of these agents A few drugs have been approved for cancer preventive therapy (for instance in breast receptor- positive women), and several others are being evaluated as preventive agents, including aromatase inhibitors, aspirin, statins and metformin
  34. 34. Tamoxifen  Indicated as adjuvant therapy for treatment of postmenopausal estrogen-receptor-positive or progesterone-receptor-positive breast cancer in men and women  Approved as a breast cancer preventive agent among women at high risk of breast cancer  Observational epidemiological studies and RCT have consistently shown that use of tamoxifen increases the risk of endometrial cancer  There is also some indication that it may be associated with an increased risk of some types of gastrointestinal cancer (not conclusive evidence)
  35. 35. Mycotoxins  Mycotoxins are secondary metabolites produced by molds in appropriate microclimate conditions of temperature and humidity (hot/humid)  They constitutes a heterogeneous group both chemically and biologically  Their growth is influenced by the level of moisture, the temperature and the pH and can be made:  directly on the plant  during transfer to storage sites  during storage
  36. 36. Main toxic effects Genotoxicity, Carcinogenicity, Mutagenicity Nephrotoxicity Teratogenicity Immunotoxicity Endocrine disruption
  37. 37. Common strains and mycotoxins Aflatoxins (Aspergillus sp.) Fumonisins (Fusarium sp.) Griseofulvin (Penicillium sp.) Ochratoxin A (Aspergillus and Penicillium sp.) Sterigmatocystin (Aspergillus sp.)
  38. 38. Products that can be contaminated Raw materials (grains, seeds, fruits and vegetables, dried fruits, coffee, cocoa, spices) Food items (products made from cereals, oils, sweets made of chocolate, beer, products containing spices, fruit juices, etc.). Even meat and dairy products may be contaminated!
  39. 39. Cancer biology
  40. 40. TP53  The tumour suppressor gene TP53 has been studied for 20 years and encodes a protein called p53  p53 plays an important role in the maintenance of cell integrity by repressing proliferative signalling, enhance the effects of growth suppressors, sensitize cells to apoptosis, suppress replicative immortality through senescence and many others  IARC maintains a database that documents all TP53 gene variations reported in the literature  > 30 000 somatic mutations are known, mostly single- amino-acid substitutions in the DNA-binding domain which disrupt p53 function
  41. 41. Epigenetics
  42. 42. Epigenetic therapy Epigenetic changes are revesible and, therefore, a potential target for therapy DNA methylation can be reversed by DNA demethylating agents (two have been approved by the FDA for haematological disorders) Histone deacethylation can be reversed by histone deacetylase inhibitors (two drugs approved for cutaneous lymphoma) DNA methylation can be revesed by DNA demethylating agents
  43. 43. Cancer prevention The reversibility of epigenetic changes could be used also for prevention, although long- term effects needs to be considered However, it is now possible to identify individuals at extremely high risk of some cancers by assessing accumulation levels of aberrant DNA methylation These individuals would certainly benefits from effective chemoprevention Multiple studies are strongly required
  44. 44. Cancer prevention
  45. 45. Lifestyle changes Stop smoking Improve diet Control weight Participate in cancer screening
  46. 46. Vaccination  A notable fraction of human cancers (16%) are caused by infections  Hepatitis B virus, human papillomavirus (HPV) and the helicobacter pylori are the three most important infections associated with cancer (liver, anogenital tract and stomach)  HPV is considered a necessary cause of cervical cancer and vaccines exists: bivalent (against HPV16 and 18) as well as quadrivalent (also against HPV6 and 11) both give almost 100% to cancer  The quadrivalent vaccine costs more but also offers protection to anogenital warts as well as to the majority of vulvar and vaginal HPV infections  They are recommended for girls before initiation of sexual activity (i.e. 12 yr-olds) with additional «catch-up» programs for young women (13-18 yr-olds) in some countries
  47. 47. Hepatitis B virus  Hepatitis B virus (HBV) causes chronic hepatitis, cirrhosis and a large fraction of liver cancer cases  HBV is a very common infection in some areas of the world  Among people chronically infected, about 25% die from liver disease, including cancer  HBV is responsible for 50-90% of liver cancer cases in high-risk areas  Most countries include HBV vaccination in their childhood immunization programs
  48. 48. Cancer by organ site
  49. 49. Lung cancer  The most common cancer in men and the third most common in women  Risk factors: tobacco smoking (including second-hand), radon exposure, occupational exposure to PAHs, certain metals, asbestos and silica, outdoor air pollution  The distinction between small and non-small cell lung carcinoma has been replaced by the distinction between adenocarcinoma and squamous cell carcinoma because of major differences in genetics and response to therapy  Lung cancer is one of the most aggressive human cancers with a 5-year overall survival of 10-15%  Screening by CT-scan is under development
  50. 50. Colorectal cancer  One of the most common cancers in both men and women, representing almost 10% of the global cancer incidence  Third most common cancer in men and second in women  Fourth most common cause of death from cancer worldwide  > 65% of cases occurs in highly-developed countries (half of new cases in Europe and Americas)  Diet, obesity and lack of physical activity are known risk factors, but the underlying causative biological processes are not defined  Inflammatory bowel disease, when long-standing, predisposes to colorectal cancer
  51. 51. Pancreatic cancer  A majority of pancreatic cancers occurs in highly-developed countries  It is the 7th cause of cancer death worldwide, with a 5-year survival rate of 5%  The most common type (90%) is the infiltrating ductal adenocarcinoma  The leading known risk factor is cigarette smoking  Body fatness is another established risk factor
  52. 52. Future prospects  Although ductal adenocarcinomas of the pancreas have seemed to present an impenetrable barrier to progress, several recent advances provide hope  Personalized therapy is slowly becoming a reality with poly(ADP- ribose) polymerase (PARP) inhibitors or mitomycin C for cancers with BRCA2 or PALB2 mutations  Recent studies suggest that it takes many years for a genetically altered cell in the pancreas to invade and eventually metastasize  This suggests a large window of opportunity for the early detection of curable neoplasia  The discovery of some genes responsible for the familiar aggregation of pancreatic cancer is another good news  Finally, a small % of the genetic changes identified are targetable with existing therapeutical agents
  53. 53. Final considerations  Cancer is still a huge problem for the humankind  Increasingly, cancer is a particular burden for low- and middle-income countries  Better cancer control can be achieved by implementing screening as well as by continuing investing in research  Detailed knowledge of how individuals and communities are affected and the implementation of policies whose efficacy have already been proved in other countries can increase the success in preventing and treating this disease
  54. 54. Thank you! Gianluca Tognon