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Marcatori Tumorali
Breast self exam.
Clinical Breast exam.
Fecal occul blood test
CA Cancer J Clin 2010;60:99-119
CA Cancer J Clin 2010;60:99-119
CLASSI DI MARCATORI TUMORALI
•
Proteine oncofetali
– Antigene carcinoembrionario (CEA)
– Alfa-fetoproteina (AFP)
– Gonadotropina corionica umana (hCG)
– Antigene del carcinoma a cellule squamose (SCC)
•
Glicoproteine (Carbohydrate Antigen, CA)
– CA-125
– CA 19-9
– CA-15-3
•
Enzimi
–
–
–
•
Prostate-specific antigen (PSA)
Enolasi neurone-specifica (NSE)
Fosfatasi alcalina
Ormoni e recettori ormonali
– ACTH e altri ormoni
– Recettori mammari per estrogeni e progesterone
•
Proteine di superficie cellulare
– Beta2-microglobulina
•
Marcatori cellulari
– Oncogeni (N-ras)
– Geni soppressori (p53)
– BRCA1 e BRCA2
– c-erB-2 (HER-2)/neu
Gion & Daidone Eur J Cancer 2004;40:2613-22
MARKERS TUMORALI
IDEAL TUMOR MARKER
• Be specific to the tumor
• Level should change in response to tumor size
• An abnormal level should be obtained in the
presence of micrometastases
• The level should not have large fluctuations that
are independent of changes in tumor size
• Levels in healthy individuals are at much lower
concentrations than those found in cancer
patients
• Predict recurrences before they are clinically
detectable
• Test should be cost effective
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Tumor Markers some key facts:
1.
2.
3.
4.
5.
6.
Lack of specificity
Cancer heterogeneity
False negatives
Benign diseases positive CA 125 or CEA
Smokers have raised CEA
Many men (20-40% !?) die with, not from,
prostate ca.
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MARKERS TUMORALI
•
OBIETTIVO CLINICO
•
Diagnosi differenziale con malattia benigna: markers tumorali che hanno
potenzialità diagnostica nel distinguere appunto il tumore dalle patologie
benigne dello stesso organo;
•
Bilancio di base: markers tumorali utili nell'inquadramento iniziale del
paziente a diagnosi fatta, prima di ogni intervento terapeutico; in particolare
si riferisce se i markers tumorali danno indicazioni sull'estensione della
malattia, sul tipo istologico o sulla prognosi;
•
Risposta al trattamento primario: markers tumorali che danno indicazioni
circa la radicalità del trattamento del tumore primitivo;
•
Riconoscimento precoce della progressione: markers tumorali che sono
considerati efficaci per l'identificazione precoce di una eventuale ricaduta
della malattia.
•
Monitoraggio della terapia per la malattia avanzata: markers tumorali
che possono essere usati per monitorare l'efficacaia delle terapie per la
malattia metastatica.
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Antigene polipeptidico tissutale
Mucinous-like cancer antigen
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La proteina di Bence Jones: il primo marcatore
tumorale nella storia della medicina
CEA: antigene carcinoembrionario
identificazione: Gold P., Freedman S.O., 1965
categoria: antigene tumore associato
natura chimica: glicoproteina
peso molecolare: 200 kD
tempo di dimezzamento: circa 6-8 gg
cause non oncologiche di incremento:
- patologia benigna del tratto gastroenterico,
del fegato, del polmone,
- insufficienza renale cronica
Carlo Franzini - Università degli
Studi di Milano - 2004
12
13
Carlo Franzini - Università degli
Studi di Milano - 2004
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Carlo Franzini - Università degli
Studi di Milano - 2004
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Carlo Franzini - Università degli
Studi di Milano - 2004
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AFP: alfafetoproteina
identificazione: Abelev G.T., 1963
categoria: antigene tumore associato
natura chimica: glicoproteina (alfa-1-globulina)
peso molecolare: circa 67 kD
tempo di dimezzamento: 5-6 gg
cause non oncologiche di incremento:
- epatopatia cronica,
- gravidanza
CYFRA21.1
identificazione: Stieber P. et al; Pujol, J.L. et al, 1993
categoria: frammento solubile della citocheratina 19
natura chimica: proteina
peso molecolare: 40 kD
tempo di dimezzamento: non noto
principali cause non oncologiche di incremento:
- epatopatia,
- malattie broncopolmonari croniche
CA15.3
identificazione: Kufe D., 1984
categoria: mucina
natura chimica: glicoproteina mucino simile
peso molecolare: 300-450 kD
tempo di dimezzamento: non determinato
principali cause non oncologiche di incremento:
- epatopatia
NSE: enolasi neurone specifica
identificazione (come marker tumorale): Tapia E.J.,
1981
categoria: enzimi
natura chimica: glicoproteina
peso molecolare: circa 90 kD
tempo di dimezzamento: non determinato
cause non oncologiche di incremento:
- emolisi del campione
2007 UPDATE OF ASCO
RECOMMENDATIONS FOR
THE USE OF TUMOR MARKERS IN
BREAST CANCER
Clinical Practice Guideline
JCO, Vol 25, No 33 (November 20), 2007:5287-5312
Not Recommended
Recommended
CA 15-3, CA 27.29
(Circulating)
Screening, diagnosis,
staging, prognosis, or
surveillance. Using alone
for monitoring.
For monitoring patients with metastatic
disease during active therapy, in
conjunction with diagnostic imaging,
history, and physical exam.
CEA (Circulating)
Screening, diagnosis,
staging, prognosis, or
surveillance. Using alone
for monitoring.
For monitoring patients with metastatic
disease during active therapy,
conjunction with diagnostic imaging,
history, and physical exam.
ER (tissue), PgR
(tissue)
For women with DCIS who are
candidates for hormonal
therapy.
For diagnosis, treatment planning – on
every primary invasive breast cancer and
on metastatic lesions if would influence
treatment planning.
DNA Flow Cytometrybased proliferation
(tissue)
Screening, diagnosis,
staging, prognosis,
surveillance, or monitoring.
Ki67, Cyclin D, Cyclin Screening, diagnosis,
E, p27, p21, thymidine staging, prognosis,
kinase, topoisomerase surveillance, or monitoring.
II, or other markers
of proliferation
(tissue)
HER2 (tissue)
Human epidermal growth
factor receptor-2 (HER2)
Screening, diagnosis,
staging, prognosis,
surveillance, or monitoring.
Should not be used to
withhold or select one
specific type of endocrine
treatment. Not to Guide use
of adjuvant taxane treatment.
Circulating
Extracellular Domain
of HER2
Screening, diagnosis,
staging, prognosis,
surveillance, or monitoring.
For treatment planning, identification
of patients who may benefit from
trastuzumab and/or from anthracyclinebased adjuvant therapy.
ASCO 2006 Update of Recommendations for the Use of Tumor
Markers in Gastrointestinal Cancer
Recommendations and Conclusion
For colorectal cancer, it is recommended that:
CEA be ordered preoperatively, if it would assist in staging and surgical
planning.
Postoperative CEA levels should be performed every 3 months for stage II
and III disease for at least 3 years if the patient is a potential candidate for
surgery or chemotherapy of metastatic disease.
CEA is the marker of choice for monitoring the response of metastatic
disease to systemic therapy.
Data are insufficient to recommend the routine use of p53, ras, thymidine
synthase, dihydropyrimidine dehydrogenase,
thymidine phosphorylase, microsatellite instability, 18q loss of
heterozygosity, or deleted in colon cancer (DCC) protein in the
management of patients with colorectal cancer.
J Clin Oncol 24:5313-5327 2006
CA19-9 (pancreatic cancer)
Screening
CA19-9 is not recommended for use as a screening test for pancreatic cancer.
Operability
The use of CA19-9 testing alone is not recommended for use in determining operability or
the results of operability in pancreatic cancer.
Evidence of recurrence
CA19-9 determinations by themselves cannot provide definitive evidence of disease
recurrence without seeking confirmation with imaging studies for clinical findings and/or
biopsy.
Monitoring response to therapy
Present data are insufficient to recommend the routine use of serum CA19-9 levels alone
for monitoring response to treatment. However, CA19-9 can be measured at the start of
treatment for locally advanced metastatic disease and every one to three months during
active treatment. If there is an elevation in serial CA19-9 determinations, this may be an
indication of progressive disease and confirmation with other studies should be sought.
Zones of the Prostate
Urinary
Bladder
Transition
Zone (BPH)
Anterior
Fibromuscular
Stroma
Urethra
Ejaculatory
Duct
Rectum
Central
Zone
Peripheral Zone
(Prostate
Cancer)
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Diagnosing Prostate Cancer
DETECTING PROSTATE CANCER
 PSA
 Digital Rectal Exam
 Biopsy
STAGING PROSATE CANCER
 The TNM staging system
 Histologic Grading: The Gleason Score
 Post-Surgical Evaluation
 Imaging Bone Metastases
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PSA and Prostate Cancer Incidence
and Mortality
(U.S. 1975-2000)
250
15
PSA Screening
200
14
175
13
150
12
125
100
Mortality
Incidence
225
11
75
Source: Surveillance, Epidemiology, and End Results Program, 1975-2000, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2003.
2000
1995
1990
1985
1980
10
1975
50
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What is PSA?
 Prostate-Specific Antigen
 An antigen is something an antibody binds to.
 Member of the Kallikrein protease family.
 Vast majority of PSA in our body is produced
by secretory prostate epithelial cells.
 Also made in very low amounts in the breast,
thyroid, and placenta, among others.
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Normal Function of PSA
Secreted in high concentrations into
the seminal fluid (mg/mL), where it
cleaves gel-forming proteins
semenogelin and fibronectin to increase
sperm motility
Normally found in low concentration in
sera (ng/mL).
Serum PSA increases as epithelial cell
number (tumor volume) increases.
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PSA Function and Activity
Pro-PSA (Inactive)
Inhibitory Region
PSA (Active)
Pro-Seminogelin (Inactive)
Seminogelin (Active)
Liquefaction of Seminal Fluid
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Forms of PSA in Blood
 70-90% of serum PSA is bound to the
protease inhibitor a1-Anti-Chymotrypsin
(ACT).
 10-30% of serum PSA is free and unbound.
 Minor amounts (<1.0%) are bound to a2MicroGlobulin (MG – undetectable using
current clinical methods).
 PSA index: ratio of free/total PSA. Aids in
the discrimination between BPH and PCa,
values < 7% are associated with PCa, values
>25% are usually not associated with PCa
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PSA Levels and Turnover
Semen: 0.5-2.0 milligram/mL (1/1000
gram).
Normal Blood: varies with age, race, and
prostate volume. Around 1.0
nanogram/mL.
The serum half-life of PSA is 2-3 days.
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Use of PSA as a Marker for
Prostate Cell Growth
PSA elevations may indicate the
presence of prostate disease.
Normal prostatic growth: 0.04ng/mL
increase per year.
BPH: 0.07-0.27ng/mL increase per year.
Prostate Cancer: greater than
0.75ng/mL increase per year.
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The Predictive Power of SPSA
Approximate chance of having prostate
cancer on biopsy:
Below
4 ng/mL
Between
4-10 ng/mL
Greater than
10 ng/mL
1 in 50
1 in 4
1 in 2
to
2 in 3
Comparison: A man older than 50 years with PSA abnormality is 2x
more likely to harbor a tumor than a woman older than 50 years of
age with an abnormal mammogram.
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Factors That Influence PSA Levels
 Prostate Disease
– BPH (Benign Prostatic Hyperplasia)
– Prostatitis (Inflammation)
– Prostate Cancer
 Prostate Manipulation
– Prostate Massage (DRE)
– Prostate Biopsy
– Sexual Activity
 PSA gene expression is regulated by
Androgens.
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DRE and PSA Combined
In a screening study where 264 cancers
were found:
18% would have been missed if PSA alone
had been used.
45% would have been missed is DRE alone
was used.
Other studies have confirmed that both
PSA and DRE are complimentary
approaches.
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Prostate Biopsy
Gold standard to confirm the
presence of prostate cancer.
Used after rising PSA and/or
suspicious DRE.
Purpose: take prostate tissue and
examine under a microscope
(Histology).
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Schröder et al. Screening and prostate-cancer mortality in a
randomized European study. N Engl J Med. 2009 Mar
26;360(13):1320-8.
We identified 182,000 men between the ages of 50 and 74 years, they
were randomly assigned to a group that was offered PSA screening at an
average of once every 4 years or to a control group that did not receive
such screening.
Results. 1410 men would need to be screened and 48 additional cases of
prostate cancer would need to be treated to prevent one death from
prostate cancer.
Conclusions PSA-based screening reduced the rate of death from
prostate cancer by 20% but was associated with a high risk of
overdiagnosis.
Andriole et al. Mortality results from a randomized prostatecancer screening trial. N Engl J Med. 2009 Mar
26;360(13):1310-9.
We randomly assigned 76,693 men at 10 U.S. study centers to receive
either annual screening (38,343 subjects) or usual care as the control
(38,350 subjects). Men in the screening group were offered annual PSA
testing for 6 years and digital rectal examination for 4 years.
Results After 7 years of follow-up, the incidence of prostate cancer per
10,000 person-years was 116 (2820 cancers) in the screening group and
95 (2322 cancers) in the control group. The incidence of death per 10,000
person-years was 2.0 (50 deaths) in the screening group and 1.7 (44
deaths) in the control group
Conclusions After 7 to 10 years of follow-up, the rate of death from
prostate cancer was very low and did not differ significantly between the
two study groups.
CA Cancer J Clin 2010;60:70–98.
Figure 1. Trends in prostate cancer incidence and mortality rates, US, 1975-2006.
American Cancer Society Guideline for Early Prostate Cancer
Detection 2010
• The ACS recommends that asymptomatic men who have at least a 10-year
life expectancy should have an opportunity to make an informed decision
with their health care provider about whether to be screened for prostate
cancer, after receiving information about the uncertainties, risks, and
potential benefits associated with prostate cancer screening.
• Prostate cancer screening should not occur without an informed decisionmaking process.
• Men at average risk should receive this information beginning at age 50
years.
• Men at higher risk, including African American men and men who have a
first-degree relative (father or brother) diagnosed with prostate cancer
before age 65 years, should receive this information beginning at age 45
years.
• Men at appreciably higher risk (multiple family members diagnosed with
prostate cancer
before age 65 years) should receive this information beginning at age 40
years.
CA Cancer J Clin 2010;60:70–98.
American Cancer Society Guideline for Early Prostate Cancer
Detection 2010
• For men who are unable to decide, the screening decision can be
left to the discretion of the health care provider
• Asymptomatic men who have less than a 10-year life expectancy
based on age and health status should not be offered prostate cancer
screening.
• At age 75 years, only about half of men have a life expectancy of 10
years or more. Men in this age group with significant comorbidities,
as well as younger men with life-limiting comorbid conditions, are
not likely to benefit from screening.
CA Cancer J Clin 2010;60:70–98.