Cancer • First-second most common cause of death

in Western world • One in 2-3 Western people will die of

cancer

lezione del dr Cirò

lezione del dr Cirò

clonal

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

Dysplasia

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

Neoplasia

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

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 ?

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

Invasion and Metastasis

• Characteristics that are unique to malignant neoplasms (cancer)

• The major cause of morbidity and mortality

Importance of early detection in cancer

Increase of large scale screenings (breast cancer, prostate cancer, colon

cancer…etc)

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.

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)

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 (over-diagnosis)

• Unnecessary treatment • Treatment-related deaths of other causes (e.g., heart

disease, secondary cancers)

Prerequisite Stage Shift for a Successful Cancer Screening Program

Early Stage

Cancer

Late Stage

Cancer

Incidence Reciprocal Stage Shift

Advent of screening

Incidence per 100,00

0

Annual Incidence of Colorectal Carcinoma by Extent of Disease at Diagnosis, SEER9

0

20

40

60

80

Age 50+

Localized Regional

Distant

Localized Regional

Distant 0

2

4

1970 1975 1980 1985 1990 1995 2000 2005 2010

Age <50 Unscreened

Overdiagnosis

Cancer

Screened and “cured”

Never screened

Death unrelated to cancer

36 Years Ago

Neuroblastoma Incidence and Mortality Trends in Japan after Discontinuation of the National Screening Program

T. Shinagawa et al. Int J Cancer 140:618-625 (2016)

Annual Incidence of In Situ and Localized Breast Cancer, Age 40+ - Western Washington State

0

50

100

150

200

250

300

1970 1980 1990 2000 2010

Incidence per

100,000 Doubling

UW ACS

Professor Clinical

Oncology 1983-1990

Relay for Life

Gordon Klatt, MD

1983: Screening Mammography Initiated in Washington

Randomized Trials of Screening Mammography 30 to 50 Years Ago

Trial Country Mortality Benefit Problem(s)

Health Insurance Plan of New York, 1963 U.S. Screening arm included MD Exam

Benefit only in 50-59 y/o’s

Malmo Study Sweden

Two-County Trial Sweden

Gothenburg Breast Screening Trial Sweden

Stockholm Trial Sweden

Edinburgh Trial Scotland

Canadian Natl. Breast Screening Trial 1

Canada None Actually worse in screened subjects

Canadian Natl. Breast Screening Trial 2

Canada None

Cochrane Analysis

•One biased trial excluded 600,000 women in analyses •Three trials with adequate randomization did not show a significant reduction in breast cancer mortality at 13 years (RR=0.90, CI 0.79-1.02) •4 trials with suboptimal randomization showed a significant reduction in BrCa mortality with an RR=0.75 (CI 0.67-0.83) •The RR for all 7 trials combined was 0.81 (CI 0.74-0.87)

Cochrane Analysis •Breast cancer mortality was an unreliable outcome biased in favor of screening, mainly because of differential misclassification of cause of death •Trials with adequate randomization did not find an effect of screening on cancer mortality:

• Either breast cancer, after 10 years (RR=1.02, 95% CI 0.95-1.10), or

• All-cause mortality after 13 years (RR=0.99, 95% CI 0.95 to 1.03)

Randomized Trials of Screening Mammography 30 to 50 Years Ago

Trial Country Mortality Benefit Problem(s)

Health Insurance Plan of New York, 1963 U.S. Screening arm included MD Exam

Benefit only in 50-59 y/o’s

Malmo Study Sweden

Two-County Trial Sweden

Gothenburg Breast Screening Trial Sweden

Stockholm Trial Sweden

Edinburgh Trial Scotland

Canadian Natl. Breast Screening Trial 1

Canada None Actually worse in screened subjects

Canadian Natl. Breast Screening Trial 2

Canada None

Cochrane Analysis

•One biased trial excluded 600,000 women in analyses •Three trials with adequate randomization did not show a significant reduction in breast cancer mortality at 13 years (RR=0.90, CI 0.79-1.02) •4 trials with suboptimal randomization showed a significant reduction in BrCa mortality with an RR=0.75 (CI 0.67-0.83) •The RR for all 7 trials combined was 0.81 (CI 0.74-0.87)

Cochrane Analysis •Breast cancer mortality was an unreliable outcome biased in favor of screening, mainly because of differential misclassification of cause of death •Trials with adequate randomization did not find an effect of screening on cancer mortality:

• Either breast cancer, after 10 years (RR=1.02, 95% CI 0.95-1.10), or

• All-cause mortality after 13 years (RR=0.99, 95% CI 0.95 to 1.03)

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

?

“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

How much of the reported improvement in overall breast cancer survival is

an artifact of overdiagnosis ?

27

Research Strategies to Investigate Overdiagnosis (2)

• 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

Cancer Grade • Alternate term “tumor grade” (G0-G3) • Based on microscopic features

(cytology or histology)

low grade moderate high

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

Epidemiologia dei tumori

Il cancro è una malattia genetica

La componente “ambientale” gioca però un ruolo fondamentale:

Sociologia dei tumori

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

5-10%

Hereditary Susceptibility

Sporadic/Shared Factors

~90%

Cancer

Features of Hereditary Cancer Syndromes

• Multiple family members with the same or related types of cancer across several generations (Autosomal Dominant inheritance)

• Young age at diagnosis (under 45)

• Individuals with multiple separate cancer diagnosis

• Uncommon cancers (male breast, ovary)

• Suggestive Tumor studies (TNBC <60, MMR deficient colon tumors)

• Ethnicity

Implications of Identifying a Mutation

48

br ca dx 48

79 78

BSO 35

60 29

childbirth

63 57

50

76 48

br ca dx 45

75

45

50

br ca dx 47

45

ov ca dx 45

br ca dx50

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

Clinical Management: Mutation-Positive Patient

Mutation Positive

Testing for other adult relatives

Increased surveillance

Preventive surgery

Medication to lower risk

Treatment options

Cancer Gene Panel High-Risk Genes

Moderate-Risk Genes

Newer Genes

• Well studied

• Lifetime risk of cancer >50%

• May be related to more than 1 type of cancer

• Guidelines for screening and prevention established

• Well studied • Lifetime risk of

developing breast cancer 24-49%

• Guidelines for

screening available • Guidelines for

prevention not established

• 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