Post on 14-Feb-2019
Cancer • First-second most common cause of death
in Western world • One in 2-3 Western people will die of
cancer
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
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
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
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
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