LECTURE

Trilis Yulianty M.Kes

1 Desember 2010

FAKTA!!

„ Trend jumlah penderita kanker terus

meningkat, thn 2020 mencapai 16 juta,
2/3nya di negara industri baru / negara
berkembang (The International Agency for
Research on Cancer 2009)
„ Di Indonesia : prevalensi 4,3/1000
penduduk penyebab kematian no.7
penduduk, no 7
(Riskesdas 2007)
The problem..
problem

„ Sebagian besar didiagnosis pada stadium

lanjut
j
„ Belum tersedia terapi yang efektif untuk
kanker stadium lanjut
Æ perlu sarana deteksi dini untuk
memperbaiki prognosis

Pencitraan

CT SCAN MRI

Anti Cancer Res, 2004

 Pencitraan

„ Teknik Imaging :
py
--oscopy

64 slice – MSCT
Nodul 2mm
Anti Cancer Res, 2004

Limitation
• Kelemahan teknik p
pencitraan :
• Mahal
• Kurang sesuai untuk skrining populasi skala
besar
g terdeteksi
• Perlu ukuran tumor tertentu agar
• Pemeriksaan Tumor Marker
e j d pilihan
menjadi p lain untuk
u u sskrining
g karena
e
bersifat non
non--invasif & mudah dilakukan

Anti Cancer Res, 2004

T mor Marker Rate
Tumor

What are ？

adalah substansi yang diproduksi /

dikeluarkan oleh sel tumor (kanker) atau oleh
bagian tubuh lainnya sebagai respon terhadap
adanya pertumbuhan tumor (kanker)
• Mencerminkan ukuran & sifat kanker (agresivitas,
diferensiasi, respon terapi, potensi metastasis,
mutasi genetik, dll)
• Dapat dideteksi di dalam sel / cairan tubuh
(peripheral blood, in lymph nodes, in bone
marrow or in other body fluid (urine,
marrow, (urine stool
stool, ascites)
 Application of
„ Screeningg for cancer
„ Diagnosing cancer
„ Evaluation Cancer Prognosis
„ Predicting of Therapeutic response
„ Tumor staging
„ Detection tumor recurrence/ remission
„ Localizing tumor and directing radio-therapeutic
agents
„ Monitoring the effectiveness of cancer therapy

SEJARAH

1846 - Bence-Jones Protein

1940 - Acid Phosphatase
1960 - Alpha-fetoprotein (AFP)
1965 - Carcinoembryonic
C b A
Antigen (CEA)
1975 - Monoclonal Antibodies
1980 - CA 125,
125 PSA,
PSA Carbohydrate Antigens
1970-1980 Oncogenes & Tumor Suppressor Genes
present Æ Microarrays,
2001 - p y , Mass Spectrometry,
p y,
Neural Network, Multiparametric Analysis,
Bioinformatics
 TIPE

1. Enzim (PSA)
2. Hormon (hCG)
3. Antigen onkofetal (AFP, CEA)
4. Karbohidrat antigen (CA 125
125, CA 15-3
15 3,
5. Blood Group antigen (CA 19-9)

Anti Cancer Res, 2004

IDEAL

11. Organ
O specific
ifi andd tumor
t specific
ifi
2. Positive only when malignancy is
presentt
3. Positive early in the development of
malignancy
li
4. Easy to measure in blood

Robins, Basic Pathology 7th edition

Laposata, Lab Medicine
Æ Tumor marker yang saat ini ada tidak spesifik organ

CA 15-3

CA 27.29

ER & PR HER2/neu
c erbB 2
c-erbB-2
BRCA1
CA15 3 cancer antigen 15-3
CA15-3
„ Reference value
– 98.7% general population < 30 U/ml
„ Indication: breast cancer
– At the time of suspected breast cancer
• Unable to detect localized or metastatic breast cancer
– Prognostic value
• CA15-3 > 50 U/ml = high suspicion of metastasis with poor
prognosis

CA15-3
– Follow-up: 6 weeks after surgery
– Clinical follow-up
• 3yrs a year then every 6 months
• > 50% of reference value predict reccurence or metastasis
• The association of CA15-3 and CEA assays = increase
sensitivity by 10%
• Monthly assay during chemotherapy in metastasis stages
• High correlation with the clinical response to treatment
„ Non-specific increases
– Liver cirrhosis, acute hepatitis, severe chronic hepatitis
(< 50 U/ml)
– Other metastasis: pancreas, ovary, colorectal, lung,
stomach and uterus = rarely > 50 U/ml except
pancreas adenocarcinoma
d i
Ca 27.29
27 29
„ CA 27.29
27 29 iis highly
hi hl associated
i t d with
ith breast
b t cancer, although
lth h
levels are elevated in several other malignancies:
– Co
Colon,
o , ga
gastric,
c, hepatic,
epa c, lung,g, pa
pancreatic,
c ea c, o
ovarian,
a a ,a and
d
prostate cancers
„ CA 27.29 also can be found in patients with benign
di d off the
disorders th bbreast,
t liver,
li andd kidney,
kid andd in
i patients
ti t
with ovarian cysts
„ CA 27.29 levels higher than 100 units per mL are rare in
benign conditions

Ca 27.29
„ The CA 27.29 level is elevated in approximately
one third of women with early
early-stage
stage breast
cancer (stage I or II) and in two thirds of women
with late-stage disease ((stage III or IV))
„ CA 27.29 lacks predictive value in the earliest
stages of breast cancer no role in screening for or
diagnosing the malignancy
„ in patients at high risk for recurrence of breast
cancer (stage II or III) found that CA 27.29 was
highly specific and sensitive in detecting
p ecli ical metastasis.
preclinical etastasis
Estrogen & progestin
p
receptor
Clinical utility
„ Predictive indicators of response
p to endocrine
therapies such as
– tamoxifen, toremifene, droloxifene (anti estrogen)
– Medroxyprogesterone acetate, megestrol acetate
(progestin mimics)
„ ER & PR eemployed
l ed as prognostic
g tic ffactors
ct withith
other factors to distinguish breast cancers patient
at high risk for recurrence (poor prognosis) from
those at low risk (good prognosis)

„ HER-2/neu
E 2/ e o oncogene
coge e ((using g monoclonal
o oc o a
antibody)：overexpression related to poor
prognosis in breast cancer, related to
t at
tratuzumabab therapy
the ap

„ Oncogene c-erbB-2 gene：overexpressed in

30% of breast cancers, correlation between c-
erbB-2 gene positivity, positive axillary node
status, reduced time to relapse and reduced
overall survival

„ BRCA1 gene on chromosome 17q：familial

breast-ovarian
breast ovarian cancer syndrome,
syndrome and breast
cancer in early-onset breast cancer families →
high risk screening
 CA 125

hE4

CA 125
„ Screening
– The problem: lack of sensitivity for early stage
disease (hanya 50% stage I yg ↑)
– EGTM guidelines: CA 125 Not recommended 
for general population screening
– NIH has recommended CA 125 + TVS +
rectovaginal pelvic exam Æ screening for
h d
hereditary ovarian cancer syndrome
d
„ Diagnosis
„ Prognosis & monitoring
CA 125
„ Annual ultrasound examination and CA 125 screening
h
have been
b advocated
d t d for
f women with ith h
hereditary
dit
ovarian cancer syndromes
„ Normal：<35
Normal： 35 U/ml, t ½：4
½：4~55 days
„ For follow up, an increase may predict recurrent disease,
may precede clinical recurrence by months
„ >80% of epithelial ovarian cancer, cell types： serous >
endometriod, clear cell > mucinous
„ Correlate with tumor bulk

PSA
Free PSA
PSA
– Tissue specific
p antigen,
g produced byy
p
prostatic alveolar and ductal epithelial cells , a
serine protease, t 1/2：2~3 days
– Ref value : <= 4.0 ng/mL
– Screening at 45 years old appropriate in men
at increased risk (african- american) ( ACS
guideline) Æ annualy
– Screening at 40 years old in individual with
familiy history of prostate cancer Æ annualy

PSA

– Reflect response to treatment and correspond

to tumor volume and androgen level
– PSA is expected to be undetectable >30 days
after the radical prostatectomy, persistent
elevated
l t d level
l l iindicate
di t residual
id l disease
di
Free PSA
„ Free PSA：PSA that is not bound to the plasma
antiproteases
ti t α1-antichymotrypsin
1 ti h t i andd α2-macroglobulin
2 l b li
„ An ↑in ratio of free/total PSA is associated with increased
probability of prostate cancer
„ 97% specific for this disease, 96% sensitivity in detecting
disease
„ For population screening and diagnosis：an increase
of 0.75 ng/ml per year in any given patient has high
sensitivity and specificity for prostate cancer vs BPH,
especially when combined with DRE and TRUS

Afp
Hcg
 Alpha-Fetoprotein in HCC
„ Glycoprotein, found in fetal liver, yolk sac,
GI tract,
tract biochemically related to albumin
in adults
„ h lf lif ：4 6 days
half-life：4~6 d
„ Normal serum levels：
12~15th gestational 30~40 ng/ml
week
At birth 30 ng/ml
>1 years old (adult) <20 ng

Alpha-Fetoprotein in HCC
„ Increased in 70% HCC, elevated in hepatoblastoma,
20~70% germ cell tumors (yolk sac tumors, embryonal
cell carcinoma)
c ci ) off te
testis d ovary, except
ti and e cept
dysgerminoma

„ F Hbs
For Hb Ag
A ((+)) chronic
h i h hepatitis/cirrhosis
titi / i h i screening
i

„ The absolute AFP level correlates with tumor bulk

„ Benign：conditions that cause hepatic parenchymal

inflammation, hepatic necrosis and hepatic regeneration,
ex. hepatitis,
h titi pregnancy, primary
i bili
biliary cirrhosis,
i h i
extrahepatic biliary obstruction
Human chorionic gonodotropin
p
(βHCG)
– Glycoprotein
Gl t i synthesized
th i d b by
syncythiotrophoblastic cells of normal placenta,
– Serum and urine HCG ↑in early gestation and
peak in the first trimester (60~90 days)
– T ½: 1.25
1 25 days,
days ~30 hours
– Elevated in：gestational trophoblastic disease
(a progressive rise in after 90 days of gestation
→ highly suggestive), choriocarcinoma

βHCG
– evaluate radicalityy of the surgery:
g y ex. In
testicular cancer, the presence of β-HCG after
orchiectomy → residual cancer and needs
further treatment
– Monitor relapse (reliable indicator of Cancer
R l
Relapse) )
 cea

CEA
„ Found also in 30~50% of breast cancer, small cell
lung cancer, mucinous cystadenocarcinoma of ovary,
adenocarcinoma of cervix

„ Elevation (<10 ng/ml) in smokers, COPD,

inflammatory or peptic bowel disease, liver
inflammation or cirrhosis, renal failure, fibrocystic
breast disease
 Carcinoembryonic antigen (CEA)

– fetal g
glycoprotein
y p found on cell surfaces,,
produced by fetal GI tract, liver, and pancreas
– Normal serum and tissue fluid value：<3.0
ng/ml
/ l
– Circulating half-life：weeks
– Detect
D t t earlyl relapse
l off colorectal
l t l cancer and
d
prognostic indicator
• Normal p pretherapy
py C
CEA：lower metastasis
incidence
• High initial CEA：higher metastasis incidence
– In
I 2/3 off patients
ti t an elevated
l t d CEA may be
b the
th
st
1 indication of relapse

Ca 19-9
CA 19-9：
19 9：

– mucin, normal：<37
q
– infrequently y elevated in p
patients with other
mucin-secreting cancer (colorectal, gastric
cancer)
– Diagnosis, monitor, detect relapse, 70%
specificity and 90% sensitivity
– Mild ↑in pancreatitis and early stage of
pancreatic cancer, not for diagnosing early-
stage panc
pancreatic
eatic cane
caner

CA 19-9：
– Low specificity and poor sensitivity in detecting small
small-
volume disease
– Also found in carcinoma of pancreas, colon ,
gallbladder, stomach, kidney, breast, and lung
– Endometriosis is the most common alternative
PID 1st
diagnosis elevated levels also found in PID,
diagnosis,
trimester
– does not increase during pregnancy
– Monitor of a subpopulation of patients that did not
express CA 125, ex. Mucinous (76%) > serous (27%)
 Nse

Cyfra 21-1

Pro GRP

NSE
„ Glycolytic enzime enolase
„ The Ag and αγ enolase enzyme known as NSE ( neuron
specific enolase)
„ Ref value: < 16.3 ng/mL
„ Produced in central and peripheral neuron and malinant
tumor of neuroectodermal origin:
– Small cells lung carcinoma
– Neuroblastoma
– Intestinal carcinoid
C fra 21-1
Cyfra 21 1

„ Ref value : < 3.3 ng/mL

„ Tumor marker which uses two monoclonal
antibody directed againts cytokeratin 19
fragment
„ Cyfra is abundant in carcinoma of lung
„ M sensitive
Most i i ffor non smallll cells
ll llung
carcinoma (NSCLC)

Tumor marker use in Lung

cancer
Lung carcinoma Baseline marker

Adenocarcinoma CYFRA 21 -1 and CEA

Squomouse cell carcinoma CYFRA 21 -1
Large cell carcinoma CYFRA 21 -1 and CEA
S ll cells
Small ll carcinoma
i NSE and
d Cyfra
C f 21-1
21 1
Unknown NSE, Cysfra 21-1 and CEA
Pro GRP

„ emerging tumor marker for lung

carcinoma
„ Stable precusor of hprmone gastrine
releasing peptide (GRP)
„ Predominantly found in gastro intestinal
and respiratory tract also nervous system
„ Pro GRP is releases by small cells lung
carcinoma
i (SCLC)
 Take Home Message
„ Screening：most tumor markers fail, because
– 1. Low prevalence of malignancy in asymptomatic
persons
– 2. Not elevated in patients with small-volume (early)
cancer
„ Diagnosis：most markers have low specificity, only for
high risk groups (αFP, β
β-HCG
HCG , PSA, thyrocalcitonin)
„ Prognosis：markers correlate with tumor burden
„ Monitor treatment response：most markers’ level
alone cannot be used to define Complete Remission (CR)
(except: β-HCG in trophoblastic malignancy)
„ Early detection of recurrence
Thank you for your attention!