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