Cancer Prevention. Underlying Assumptions. Other Known Risk Factors. Other Known Risk Factors 6/25/2009

Transcription

1 Underlying Assumptions Cancer Prevention Judith A. Luce, M.D. The Model of Carcinogenesis Multistep, multiple mutations Takes years: peak annual 70+ yrs Accelerated by genetic factors, e.g.: DNA repair defects (MSH, BRCA) Cell cycle control defects (p53, Rb) Contributions from post-translational modification and other epigenetic events Increase rates/sites of DNA damage Increased genetic risk if fail to detox rapidly May be direct or indirect Hormones (breast, prostate) Increase rates/sites Tobacco causes of DNA 30% of damage all cancer Increased genetic Deaths risk in if the fail U. to S. detox rapidly May be direct or indirect Hormones (breast, prostate) 1

2 Increase rates/sites of DNA damage Increased genetic risk if fail to detox rapidly Cervical May cancer be direct is the or second indirect most HCC is the number 2 Common cause of cancer death Cancer killer in the In women worldwide Developing world Hormones (breast, prostate) Increase rates/sites of DNA damage Increased genetic risk if fail to detox rapidly May be direct or indirect Hormones (breast, prostate) They are #1 cancers in The developed world H pylori causes 5-10% of world s CA So Where to Intervene? But for Most of Us Primary prevention: could reduce burden of cancer by the largest amount! Carcinogen exposure Vaccination Disease prevention (HIV, HPV, Hep, H pylori) Secondary prevention Screening for early cancers Tertiary prevention Screening and/or chemoprevention in persons already treated for cancer at high risk of another Cancer prevention= chemo prevention Administration of food or drug or activity that is aimed at reducing the risk of developing a cancer or cancers (Michael Sporn) Cancer prevention should concentrate on the most common cancers Most people don t pay attention to this health problem until middle age and beyond 2

3 One way to find targets for prevention interventions: what are the most common cancers in the U.S. Another analysis: who is at highest risk, and what is that level of risk? Do the Math Although cancer is common, the annual risk of any individual is small, even in the oldest cohorts of risk A 40 yo man has 1 in 12 chance of cancer over the next 20 years on an average, that s 4 chances in a thousand per year Therefore, the odds are that the NNT will be high and cost-effectiveness an issue And cancer prevention interventions do not replace screening, but add to it Controversial Assumptions in Cancer Prevention Interventions to prevent cancer are mostly risk-free, especially if they are non-drug Risks and benefits need to be carefully defined in the context of a clinical trial, preferably with placebo control Trade-offs are different for patients at high vs average risk Interventions may benefit adults who adopt them in mid- or later life 3

4 Finding Preventive Agents Based on epidemiologic studies Case-control studies of diet, lifestyle, habits Subject to recall bias, lack of long term data, multiple analyses of multiple variables, tend to isolate the substance from the source Based on cohort studies Nested case-control studies with better longitudinal data: nurses, physicians, teachers Still subject to problem of multiple variables Prevention Based on Epi/cohort studies: Lung Cancer Diet and lung cancer due to smoking: the case for beta-carotene/retinoids Epi data consistently showed that highest quartile of consumption or highest blood levels at lowest risk Laboratory data was after the fact but suggested maturation of epithelial cells Animal data never compelling Multiple clinical trials showed either no effect or actual increase in risk for current smokers Prevention Based on Epi/cohort Studies: Colorectal Cancer Consistent evidence from both kinds of study that users of full dose NSAIDS had lower risk of colorectal CA Does not apply to 81 mg dose Appears to apply to all NSAIDS Lab data: clear biological activity in suppressing PPAR-gammamediated proliferation, Cox-2 mediated No good animal models COX-2 inhibitors developed--dose to get cellular effect was higher vs therapeutic dose for clinical use Successful suppression of new adenomatous polyps by COX-2 inhibitors in small trials Further trials on hold due to COX-2 toxicity! Prevention Based on Epi/cohort Studies: Prostate Cancer Selenium levels correlate with risk of CaP in case-control studies Incidental prevention effects found in other trials: Selenized yeast 200mcg daily in skin ca prevention trial reduced risk of CaP by about half In ABTC lung prevention trial, tocopherol associated with reduction in CaP risk 32% Idea of SELECT was to combine these in 2x2 randomized trial Better tolerated than Finasteride, good overall compliance 4

5 SELECT Results SELECT: other ca endpoints JAMA, 1/7/09, 301:39-51 Prevention Based on Biology NSAIDs and colorectal cancer Really discovered after epi data was clear Success modulated by toxicity SERMs and breast cancer Obvious trial based on results of treatment of breast cancer, with 50% reduction in new ca BCPT-1 showed 50% reduction, suppresses ER positive not ER negative Raloxifene compared in BCPT-2 based on toxicity concerns: equal activity in invasive dz, less toxicity Wide use of either has not been common! Prevention Based on Biology: The Prostate Cancer Prevention Trial Alpha reductase inhibitors lower tissue levels of DHT Known to shrink BPH and normal glands and reduce PSA Placebo: 24.4% new CaP, 5.1% high grade Finasteride: 18.4% new CaP, 6.4% high grade Why? Finasteride lowers PSA and shrinks gland more sensitive biopsies, easier detection Possible explanation is that F suppresses sensitive CaP, but not resistant CaP (similar to Tam and breast cancer) F may slightly raise risk cardiovascular dz (HR 1.25, p=0.04, CI ) 18.3% on F quit study at 1 y vs 9.9% on P No widespread adoption 5

6 And In the Works. Future Prevention Trials REDUCE Reduction by DUtasteride of Prostate Cancer Events Dutasteride is alpha 1 and 2 blocker more effective? REDEEM Reduction by Dutasteride of clinical progression Events in Expectant Management Early low risk prostate cancer TARP Therapeutic Assessment of Rising PSA s Asymptomatic PSA only recurrence Will be based on tumor biology Growth factors/growth factor receptors Antiproliferative agents Maturation/differentiation agents, esp aimed at epigenetics (HDAC inhibitors, de-methylation agents) Specific gene inhibitors in genetic risk pts (e.g. PPAR antagonists in BRCA and HNPCC) Will be done in more pre-cancerous conditions Trick is finding them, e.g. lung cancer Model will be survivors at risk for second primary Preventing Oral Cancer: Biology-Based Trial Design Funded Prevention Studies M.D. Anderson Hospital Highest risk: intraepithelial neoplasia (CIS) and LOH for 3p14 or 9p21 Pts with prior oral ca or leukoplakia Use of TK inhibitor for EGFR works for invasive ca, gene known to be activated Hormones: levonorgestrel and ca endometrium, with flutamide in Ca ovary Anti-hormones: AIs and breast cancer Cox-2s: FAP families; Barrett s esoph Fat-soluble statins: breast cancer ER- Smokers: enzastaurin, iloprostin, pioglitazone, phenethyl isothiocyanate S-adenosylmethionine for HCC 6

7 Funded CAM Interventions Exercise and Cancer Mindful meditation and cervical dysplasia Arnebia indigo jade pearl and anal SIL Green tea and LGSIL, lung ca, Barrett s, Breast: flax seed, grape powder, soy, acolbifene, HCG Colorectal: resveratrol, circumin Prostate: fish oil, green tea, lycopene Fairly high quality cohort studies: Breast cancer, pre- and post-menopause Prostate cancer Ovarian cancer, one study, China Colorectal cancer, Kaiser study Theories? Weight reduction: lower hormone levels, lower IGF levels,? Other hormones Better overall habits, esp dietary Unsolved: lifetime habits versus late adopters Summing Up Prudent Advice for Real People Public health measures can greatly reduce the cancer burden: tobacco, vaccines Prevention efforts are complicated by costeffectiveness and toxicity issues Prevention trials based mostly on epidemiologic studies have largely failed Prevention trials based on tumor biology have been more successful, but have not been widely adopted in practice Start young Eat well Exercise regularly Keep weight down Never smoke Be aware of familial risk Get screened 7