Post on 07-May-2015
Cancer epidemiology over the life course
Gianluca Tognonwww.gianlucatognon.com
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
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)
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
Cancer etiology
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
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
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
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)
Alcohol content of selected beverages
Starkölvol.
5.6%
Lättölvol.
2,3%
Red wine
vol. 12%Port winevol. 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
Alcohol metabolism
ADH = Alcol dehydrogenaseALDH = Aldehyde dehydrogenase Liver enzymes
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
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
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
http://www.cancer.gov/bcrisktool/
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
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
Carcinogens in foodPAHs 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)
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
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
”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
PreventionWorkers’ education
Safer occupational practices
Surveillance
Ionizing, UV and electromagnetic radiations
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
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
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
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
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
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
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)
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
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
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
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)
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
Main toxic effects
Genotoxicity, Carcinogenicity,
Mutagenicity
Nephrotoxicity
Teratogenicity
Immunotoxicity
Endocrine disruption
Common strains and mycotoxins
Aflatoxins (Aspergillus sp.)
Fumonisins (Fusarium sp.)
Griseofulvin (Penicillium sp.)
Ochratoxin A (Aspergillus and Penicillium sp.)
Sterigmatocystin (Aspergillus sp.)
Products that can be contaminatedRaw 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!
Cancer biology
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
Epigenetics
Epigenetic therapyEpigenetic 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
Cancer preventionThe 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
Cancer preventi
on
Lifestyle changes
Stop smoking
Improve diet
Control weight
Participate in cancer screening
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
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
Cancer by organ
site
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
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
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
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
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
Thank you!
Gianluca Tognonwww.gianlucatognon.com