Cancer. First-second most common cause of death in Western world One in 2-3 Western people will die of cancer

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1 Cancer First-second most common cause of death in Western world One in 2-3 Western people will die of cancer

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3 clonal lezione del dr Cirò

4 Metaplasia an adaptive substitution of one type of adult tissue to another type of adult tissue under stress a more vulnerable type of tissue will be replaced by another more capable of withstanding stress

5 Dysplasia An abnormality in cell size, appearance, with or without a disorganized growth pattern

6 Neoplasia A disease of cells characterized by alteration of normal growth regulatory mechanisms

7 Classification-approach Terminology which is used to describe a mass is based on the clinical, gross and microscopic features-which in combination are a reflection of the predicted/expected biologic behavior Benign? Malignant

8 Neoplastic progression Benign or malignant neoplasms can acquire increasingly aggressive features Most malignant neoplasms arise de novo Neoplasms are thought to be preceded by preneoplastic conditions

9 Invasion and Metastasis Characteristics that are unique to malignant neoplasms (cancer) The major cause of morbidity and mortality

10 Importance of early detection in cancer Increase of large scale screenings (breast cancer, prostate cancer, colon cancer etc)

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12 Core Issues in Screening It is difficult to make healthy people better off than they already are. It is sometimes easy to make healthy people worse off. Strong evidence of benefit is important when putting large numbers of healthy people in harm s way.

13 Consequences of Screening: The Good 1. Reduced risk of death from the target cancer (compared to no screening) Nearly always need a randomized controlled trial to determine this 2. Reassurance (assuming healthy people need reassurance)

14 Consequences of Screening: The Bad 1. False reassurance when you have cancer 2. False alarms (false positive tests) Harms of an unnecessary work-up 3. Harms of the test: bleeding, sepsis after biopsy, etc. 4. Detection of a lethal cancer without changing the outcome Spend more of your life as a cancer patient 5. Detection of non-lethal cancers (overdiagnosis) Unnecessary treatment Treatment-related deaths of other causes (e.g., heart disease, secondary cancers)

15 Overdiagnosis Screened and cured Cancer Death unrelated to cancer Never screened

16 36 Years Ago

17 Transformation of Philosophy in the Era of Omics The old days: You are healthy until proven otherwise. The modern era: You are sick until proven otherwise. Adapted from E. Diamondis & M. Li, Clin Chem Lab Med 2016;54(3):

18 100 Consequences of Screening for Cancer Risk Proportion of Population Affected 0 Risk Factor for Risk Factor Risk Factor Preneoplasia Asymptomatic Cancer Symptoms Appear Risk of Having/Getting Cancer 18

19 The increased vigilance against pre-diseases might also change the way we perceive life itself, slowly transforming life into what can be characterized as pre-death. Bjorn Hofmann and John-Arne Skolbekken Surge in Publications on Early Detection, BMJ, 2017

20 Research Strategies to Investigate Overdiagnosis Use clinical opportunities to study natural history of indolent lesions Prostate cancer: active surveillance Barrett s esophagus: serial endoscopy/biopsy Better animal models of progression of very early lesions 20

21 Screening Mammography one real life example

22 What if you were completing 5 years of tamoxifen after a partial mastectomy and breast irradiation, coping with premature menopause, and undergoing annual mammograms of the other breast, you learn that there was a one in three chance of not having had breast cancer?

23 Compare overdiagnosis risk with benefit of screening

24 The Treatment and Cost of Breast Cancer Overdiagnosis mastectomy or lumpectomy + radiation anti-hormone therapy for 5-10 years HER2/neu+: trastuzumab IV q 3 wks x 1 yr Triple neg: chemotherapy Overtreatment antidotes Premature menopause: supportive care Osteopenia: biphosphonate, etc. Cost Financial, physical, emotional,

25 Randomized Trials of Screening Mammography 30 to 50 Years Ago Trial Health Insurance Plan of New York, 1963 Malmo Study Two-County Trial Gothenburg Breast Screening Trial Stockholm Trial Edinburgh Trial Canadian Natl. Breast Screening Trial 1 Canadian Natl. Breast Screening Trial 2 Country U.S. Sweden Sweden Sweden Sweden Scotland Canada Canada Mortality Benefit Problem(s) Screening arm included MD Exam Benefit Cochrane only in Analysis y/o s One Breast biased cancer trial mortality excluded was 600,000 an unreliable women outcome in biased analyses in favor of screening, Three mainly trials because with of adequate differential randomization did misclassification not show a significant of cause of reduction death in breast Trials with cancer adequate mortality randomization at 13 years did (RR=0.90, not find an CI effect ) of screening on cancer 4 mortality: trials with suboptimal randomization showed Either a breast significant cancer, reduction after 10 in years BrCa mortality (RR=1.02, with 95% an CI RR= ), (CI ) or None The All-cause RR for all mortality 7 trials combined after 13 years was 0.81 (CI(RR=0.99, ) 95% CI 0.95 to 1.03) None Actually worse in screened subjects

26 Comparison of Old vs USPSTF Guidelines ACS, NCCN, USPSTF, 2009 Heidi Nelson, MD, MPH OHSU 44 Mammograms 30+ msv 13 Mammograms Current Average Lifespan of Oregon s Females * Age +Pop Health Metrics 2011

27 How Screening Mammograms Cause Breast Cancer (and not from the radiation of mammograms) To the extent that screening mammograms result in the diagnosis of cancer that either does not need to be diagnosed or detected when it is, it can be said that they cause breast cancer. These women undergo the same diagnostic interventions and treatment (including surgery, radiation, and hormonal therapy and in some chemotherapy) and the associated adverse physical, emotional, and financial effects of women who develop breast cancer without being screened.

28 One in every 8 women will develop breast cancer in her lifetime If 31% of all breast cancer is overdiagnosed, the actual risk is one in every 11 women

29 How much of the reported improvement in overall breast cancer survival is an artifact of overdiagnosis?

30 Cancer Grade Alternate term tumor grade (G0-G3) Based on microscopic features (cytology or histology) low grade moderate high

31 Cancer Stage Reflects degree of spread, for an individual cancer patient Assigned at the time of diagnosis, may be updated as patient progresses T Tumor characteristics N Nodal involvement M Metastasis

32 Epidemiologia dei tumori

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38 Il cancro è una malattia genetica La componente ambientale gioca però un ruolo fondamentale: Sociologia dei tumori

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42 Ereditarietá dei tumori Una componente ereditaria é piú o meno facilmente identificable sia per la predisposizione, che per la insorgenza di diversi tipi di tumori; Tumori ereditari: retinoblastoma, adenomatosi familiare del colon, piccola frazione dei tumori mammari/ovarici Tumori familiari: manifestazione familiare di tumori esistenti anche in forma sporadica Sindromi da difetti nel sistema di riparazione del DNA

43 Cancer Sporadic/Shared Factors ~90% 5-10% Hereditary Susceptibility

44 Types of Genetic Testing Germline Studies Evaluation of a blood or saliva specimen to identify inherited genetic mutations Genomic Tumor Studies Aid in determining treatment Oncotype TM (breast) May enable personalized therapy that is targeted to a specific gene pathway EGFR mutations (lung) Can sometimes identify hereditary cancer predispositions

45 Genome Medicine/Precision Medicine The use of knowledge from genetic testing of tumor (somatic) or germline to direct a patient s cancer care Next Generation Sequencing (NGS) the ability to analyze multiple genes or DNA fragments simultaneously-- faster and at less cost (gene panels)

46 Implications of Identifying a Mutation ov ca dx 45 br ca dx 47 childbirth br ca dx50 BSO 35 br ca dx br ca dx BRCA2 Cancer Risks (lifetime) 60% Breast Cancer Risk (Avg) 30-40% Second Breast Cancer 16-27% Ovary Cancer Risk 5% Pancreas Cancer 39% Prostate Cancer 5% Melanoma

47 Cancer Gene Panel High-Risk Genes Well studied Lifetime risk of cancer >50% May be related to more than 1 type of cancer Guidelines for screening and prevention established Moderate-Risk Genes Well studied Lifetime risk of developing breast cancer 24-49% Guidelines for screening available Guidelines for prevention not established Newer Genes Not as well studied Data based on small numbers of patients Cancer risks not yet determined May increase risks for breast and other cancers Guidelines for care not established

48 Possible Genetic Test Results Pathogenic Variant Detected or Positive Result No Pathogenic Variant Detected or Negative Result Increased Cancer Risks Apply Management Guidelines if available Test other family members if actionable Assess result based on family history Screen based on family history No genetic testing for unaffected family members Variant of Uncertain Significance (VUS) Subtle DNA change Unknown if benign variant (normal) or disease causing Follow based on family history More info may become available

49 Another reason to consider updated/additional genetic testing is a change in personal or cancer family history (new diagnoses) 49

50 Summary Testing technology changes and updated testing may be a consideration Personal and family cancer histories change and additional testing may be considered NGS multigene panels provide additional information, but not all pathogenic variants (mutations) identified will result in a change in clinical management (new genes) Testing more genes means there is a greater chance to identify a VUS Testing not be completely covered by insurance due to lack of evidence regarding medical interventions for some genes evaluated