Cancer Prevention and Screening Mauricio Burotto MD National Cancer Institute National Institutes of Health

Rudolph Ludwig Karl Virchow 1821- 1902

Virchow’s Accomplishment Defined cancer as a disease involving uncontrolled cell growth The initial description of leukemia Defined cancer using a light microscope on specimens obtained on autopsy

Adenocarcinoma

Cancer is uncontrolled cell growth, uncontrolled mitoses

Virchow’s Accomplishments The definition of cancer used in 2015 is largely that of Virchow with minor modifications More than 160 years later, we still use his definitions using a light microscope. There is clear evidence that some early detected cancers do not pose a threat and do not need to be treated

Hallmarks of Cancer

Different approches Integrative or complex perspective For basic and translational cancer research Operational perspective For medical (public health, provider) intervention

Operational perspective

Operational perspective

Definitions Primary prevention Prevention Secondary prevention Screening Tertiary prevention Treatment

Concept Message The number of new cancer cases is expected to rise by more than 50% in US and more than double worldwide by 2030, it is estimated that more than half of all cancers can be prevented by applying what we already know.

Prevention in Cancer Avoid exposures Interventions Tobacco Behavioral Alcohol Interventions Behavioral Decrease obesity Pharmacological Vaccines

Prevention in Cancer Avoid exposures Interventions Tobacco*** Alcohol Interventions Behavioral Decrease obesity** Pharmacological Vaccine

Copyright 1964, U.S. Department of Health, Education, and Welfare

Copyright 1964, U.S. Department of Health, Education, and Welfare Basis of more than 7,000 articles relating to smoking and disease already available at that time in the biomedical literature, the Advisory Committee concluded that smoking is: A cause of lung and laryngeal cancer in men A probable cause of lung cancer in women The most important cause of chronic bronchitis Copyright 1964, U.S. Department of Health, Education, and Welfare

Tobacco Tobacco accounts for approximately one third of all cancer deaths, more than any other risk factor Obesity is now the risk factor with the highest attributable cancer mortality (14% to 20%) after tobacco

Overweight and obesity By the evidence Definitively associated with an increased risk of six cancers Breast, CRC, Esophagus (ADC), Pancreas, Endometrial and RCC Associated with increased death rates in The same as before plus ovarian and prostate cancers

Diet modification and vitamins for cancer prevention

Diet and Cancer Prevention

Evidence in cancer prevention Observational studies More Publication Bias to positives findings Randomized studies Less Expensive Longer follow-up

American Cancer Society Recommendations Presented By Jeffrey Meyerhardt at 2014 ASCO Annual Meeting

Toxicity: What does it take to recognize small increases in risk Toxicity: What does it take to recognize small increases in risk? -carotene -ATBC 29,133 smokers -CARET 18,314 at-risk NEJM 330:1029, 1994

Prevention acting on infectious risk factor

Prevention acting on infectious risk factor

Approved agents for cancer chemoprevention

Approved agents for cancer chemoprevention

Ideal target for chemoprevention Requires: Abnormal level of expression in early, preinvasive human neoplasia relative to normal epithelium Clear biological contribution to the initiation, maintenance, or progression of a preinvasive neoplasm to cancer

Ideal target for prevention Pharmacologic accessibility : Its modulation cause reductions in neoplastic incidence Cancer mortality Pathological evidence of improvement Specificity for neoplasia, rather than the normal tissue from which cancers arise

Oral Oncology 2014

Effect of PPARγ Agonists on NSCLC: Treatment Animal Models (Lung) -tumor volume ↓ 66.7% -growth delay 104 days Keshamouni et al. Oncogene 2004 36

Principles of Screening The basics

Cancer Screening Screening is doing a test to determine if cancer might be present in an asymptomatic individual. Diagnostic tests are used when there are symptoms to cause a clinical suspicion of disease.

Principles of Screening Finding disease is not a measure of success in screening* Increased survival is not a legitimate measure of success outside of a randomized clinical trial Reduction of cancer specific mortality in a randomized trial is the only true proof of effective screening

Cancer Screening A series of tests with some uncertainties: some known proven harms some possible benefits some proven benefits

Lead-time bias

Length Bias Cancer diagnosed in between scheduled screens is more aggressive than those diagnosed at scheduled screenings. Those diagnosed at initial screening are least aggressive of all.

Screening Recommendations By Cancer Site Comments

Cancer Screening Well designed clinical studies have consistently demonstrated the mortality reduction through: Mammography for Breast Cancer Stool Blood Testing, Sigmoidoscopy and Colonoscopy for Colorectal Cancer Pap and Visual Screening for Cervical Cancer Low Dose Spiral CT for those at high risk of Lung Cancer

Cervical Cancer

A Comment about Cervical Screening American Cancer Society recommends annual cytological screening (Pap testing) beginning at age 21 and women who have three consecutive normal should be screened every three years. HPV testing is becoming common in US practices Visual Examination of the Cervix with Vinegar is effective especially in third world countries.

Colon Cancer

Colorectal Cancer Mortality 1975-2010 Age Adjusted Mortality Rate per 100,000 NCI SEER 2012

Colon Cancer Mortality Decline due to: Improvements in treatment Screening with stool blood examination, sigmoidoscopy, colonoscopy Awareness of symptoms and early presentation

Lung Cancer (NSCLC)

The National Lung Screening Trial Nearly 54,000, age 55 and above. 30 pack year or greater history of smoking. If quit, did so less than 15 years prior to trial entry. Reasonable health. Prospectively randomized to PA Chest Xray or Low Dose spiral CT yearly x 3. Done at 30 sites with lung cancer expertise. Analysis 10 years from start of screening showed 20% relative risk reduction.

The National Lung Screening Trial (one view of the 20 percent reduction in mortality) Comparing the two groups (ten years from the start of screening) 80 to 90 lung cancer deaths were prevented in the screened group (87 less deaths). About 350 still died of lung cancer. 16 died due to interventions caused by screening (six did not have cancer).

Science January 2015

“Here we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells” “The majority is due “bad luck”, that is, random mutations arising during DNA replication of normal stem cells” Science January 2015

What about cervix and gastric ???

Message Avoiding exposures tobacco and “healthy life” are the most effective measure of cancer control We are still learning which are the best screening methods Which is better for US or Europe is not necessarily the best for our countries Be critical about scientific and medical literature

Clinical Research Center NCI-NIH Clinical Research Center