BIO DATA

• Nama : Dr. dr. Sri Hartini SpPK (K), MARS

• Riwayat Pendidikan :
– Spesialis Pat.Klin : FKUI, 1985
– Magister Administrasi RS : Fak. Pasca Sarjana UI, 1999
– Konsultan Onkologi : Kolegium Patologi Klinik, 2008
– Doktor Program Biomedik FK UGM, 2015
• Riwayat Pekerjaan :
– Peneliti Keselamatan Radiasi & Kedokteran Nuklir BATAN
1985-1993
– SMF Pat. Klin RS Kanker Dharmais (RSKD) 1993-2001
– Ka. Instalasi Patologi KLinik RSKD 2001-2002
– Direktur Penunjang Medik RSKD 2002 – 2006
– Direktur Umum & Operasional RSKD 2006-2008
– Dosen Program Biomedik Kekhususan Onkologi FKUI di RSKD
2008 - sekarang
• Qrganisasi :
– IDI ; PP PDS. PatKLIn ; Perhimpunan Onkologi Indonesia
BIOMARKERS OF SOLID TUMOR :
FROM SEROLOGY TO
MICROARRAY

Sri Hartini
Dharmais Cancer Hospital
 OUTLINES
• Onkogen & TSG
Onko- • Changes in malignat cells
genesis • Definitian of Cancer
Biomarkers
Type of • Secreted / Serum markers
Cancer • Cellular
Biomarkers • Molecular

Detection & • Key technologies

Clinical • Clinical use
Application
 Micro-RNA
Non-coding RNA
Regulators of regulators

Growth promoting Tumor suppressor

oncogenes genes
Care taker genes
DNA repair genes
Activation Inactivation
Amplific Mutations
Mutations Epigenetics
Oncogenesis :
Transformation
Uncontrolled growth,
Maturation arrest
Abnormal diff
 somal
transloc
• Morphol
ations)
og ;
• Genetics
Surface
(oncoge
markers
markers
nes,
(CD’s)
TSG,
Molecular
• Intracell
miRNA
ular
markers
in tissue)
• (proteins,
Circulat
enzymes)
ing
• Circulati
DNA,
Produ
Cellular markers
• ng
mRNA,
Tumor
cts of
miRNA
Cells ;
cance
Cancer
r cells
Stem serum markers
Produ
• Cell
• Growth
cts
substances /
behaviou
associ
r (cell
Secreted
cycle
ated
analysis)
with
cance MARKERS OF MALIGNANCIES
r CHANGES IN MALIGNANT CELLS
 DEFINITION of
BIOMARKERS
A biological molecule found in blood, other body fluids,
or tissues that is a sign of a normal or abnormal process,
or of a condition or disease. A biomarker may be used to
see how well the body responds to a treatment for a
disease or condition. Also called molecular marker and
signature molecule.
(The NCI Dictionary of Cancer www.cancer.gov/publications/dictionaries/
cancer
terms cdrid=45618 )

A cancer biomarker refers to a substance or process

that is indicative of the presence of cancer in the body.
A biomarker may be a molecule secreted by atumor or a
specific response of the body to the presence of cancer.
 TUMOR DEVELOPMENT AND METHODS OF DETECTION

Diagnostic threshold
“early”
“late”
Long “invisible” preliminary
stage: months to many years.

Molecular methods
DNA/RNA technology

10 - 100 g 1 kg
1 mcg 1 mg 1g 1012 cells
109 cells 1010 - 1011 cells
103 cells 106 cells
Immunological
methods
Biophysical
methods
 SERUM TUMOR MARKERS
(conventional tumor markers)

SECRETED SUBSTANCES

• Products of transformed cells or benign cells,
• Products released from normal cells in response to cancer

Never use for screening !
(except for high risk conditions)
• Additional tool for diagnosis, staging, prognosis
• Useful for monitoring course of disease
• Determine effectiveness of treatment
INDICATION OF TUMOR MARKER MEASUREMENT
Marker Screening Diagnosis Follow up Prognosis
CEA Risk group C-cell Ca Colon, breast, lung, C-cell Colon
AFP Risk group Germ cell, HCC Germ cell, HCC Germ cell
CA19.9 -- Pancreas Pancreas, billiary duct --
CA125 -- -- Ovary --
He-4 -- Ovary Ovary Ovary
NSE -- SCLC SCLC, neurobl --
SCC -- -- Cervical, ENT, esophagus --
Cyfra21.1 -- -- NSCLC --
HCG Risk group Germ cell, trophobl Germ cell, trophobl tumor Germ cell
tumor trophobl
PSA Males>50 Prostate Prostate --
TG + TG-Ab -- Thyroid Ca (follicular) Thyroid Ca (follicular) --

Ca15-3 -- -- Breast --

Her2/neu -- -- Breast Breast

M2PK -- CRC CRC CRC

CA 125
• Skrining (- ) ; ROCA ( Risk of Ovarian Cancer Algorithm = Ca 125
level, umur & statistical Risk untuk a change point (rapid rise in
CA 125 above baseline). Intermediate ROCA risk in unaffected
women: repeat CA 125 level measurement in 3 months, elevated
risk warrants a transvaginal ultrasound. In women of higher risk,
as in personal or family history of BRCA-related cancers, an
intermediate ROCA risk warrants transvaginal ultrasound, and an
elevated ROCA risk warrants a consult with a gynecological
oncologist.; women with BRCA1 and BRCA2 mutations have been
advised to pursue screening with CA 125 and transvaginal
ultrasound starting between age 30 and 35 years
• Diagnostic : sensitivity of CA 125 in distinguishing between
benign and malignant masses ranges between 61% and 90%,
while specificity ranges between 35% and 91% -
• When the levels of Ca 125 & He4 are combined into the Risk of
Ovarian Malignancy Algorithm (ROMA), the combined sensitivity
and specificity of detecting an ovarian cancer using CA 125 and
HE4 have been reported as 76% and 95%, respectively. Trials are
currently under way to investigate the use of CA 125 and HE4 as
targets of antibody therapy. -
http://slideplayer.com/slide/4562511/
IDENTIFICATION OF EPITHELIAL TUMOR CELLS IN
BLOOD

Reuben 2010
CTC’s IN ADVANCED EPITHELIAL
MALIGNANCIES

Allard WJ et al 2004
PROGRESSION-FREE SURVIVAL OF PATIENTS WITH
METASTATIC BREAST CANCER (BASED ON CTC LEVELS)

Beveridge 2007
 Identifying Cancer Stem Cells in
Tumors
Tumor Type Cell Surface Markers
Acute myeloid leukemia CD34+CD38-
Breast CD44+CD24-ESA+
Brain CD133+
Colon CD133+
Head and neck CD44+
Prostate CD44+
Metastatic melanoma CD20+
Colorectal EpCAMhighCD44+CD166+
Pancreatic CD24+CD44+ESA+
Lung adenocarcinoma Scal+CD45-Pecam-CD34+
Bone sarcoma Strol+CD105+CD44+

Tang C, et al. FASEB J. 2007;11:[Epub ahead of print].

 • GF/
GFR :
K­Ras,
VEGF, GENETIK
EGFR,
Her 2­
MUTASI
Nu
• neu
cle
• TSG :
• Hip
oso
BRC
er/
DNA & miRNA
m
A 1 CTCIRCULATING
Hip
•  mi
o
RN
met
A
ilasi
K
• Ase
EPIGENETI
tilas
i/
Dea
MOLEKULER MARKER
setil
asi
 EPIGENETIK
• Pengertian :
– Perubahan fenotip atau ekspresi gen yang bukan
disebabkan oleh perubahan urutan nukleotida yang
menyusun DNA
– Dipengaruhi faktor al : lingkungan kimia, obat2an,
makanan dan usia
– Mekanisme :
• Metilasi
• Asetilasi
• Fosforilasi
 NUCLEOSOM
• Free circulating DNA
• Partikel inti :
– Histon H2A ; H2B ;
– H3 ; H4
– 146 ps basa DNA
• Berkorelasi dengan :
– Respon terapi
– Rekurensi
Nucleosome distribution according to Chemoth/
response

A clear trend for decrease in both

measurements is shown in responding BMC Cancer20055:65, Cervical
patients. Ca
DOI: 10.1186/1471-2407-5-65
A microRNA (
miRNA) is a
small non-
coding
RNA molecule
(containing
about
22nucleotides)
 

British Journal of Cancer Advance Online Publication (2015)
113, 569­573 doi:10.1038/bjc.2015.253
MICRO-RNA RELATED TO PROGNOSIS OF CANCER

CANCER miRNA

Lung Let-7, miR-155, miR-221, miR-137

Hepatocellular miR-125b
carcinoma
Breast miR-21, miR-10b, miR-155, miR-9

Colorectal cancer miR-21, miR-106a

Head and neck miR-7d, miR-205

Modified from: Tanaka et al. Int J Mol Sc 2010; 11: 3209-25

ROLE IDENTIFIED FOR miRNA’s IN BREAST CANCER
METASTASIS AND THEIR POTENTIAL TARGETS
miRNA Role in metastasis Target identified
miR-10b Promoter RHOC
miR-373 Promoter CD44
miR-502c Promoter CD44
miR-21 Promoter HER2
miR-200bc Suppressor ZEB-1
miR-146 Suppressor NF-kB

miR-335 Suppressor SOX4, TNC

miR-126 Suppressor -
miR-206 Suppressor -
miR-224 Suppressor CDC42, CKCR4
miR-31 Suppressor -

Corcoran et al. Clin Chem 2011; 57: 18-32

MOLECULAR BIOMARKERS FOR THE DETECTION OF
CRC
CLINICAL SUBJECTS TYPE POTENTIAL MARKERS
USE
In use Stool Protein Fecal hemoglobin

Serum Protein CEA

Carbohydrate CA19.9

Clinical Stool DNA K-ras

validation DNA APC
DNA L-DNA
DNA P53
Serum Protein TIMP-1
Protein M2-PK
Preclinical Serum Protein MMP-9
development Protein Laminin
DNA Septin-9
Plasma DNA 5 gene panel (CDA, BANK1
BCNP,MS4A1,MGC20553)
Modified from Tanaka et al. Int J Mol Sc 2011;11:3209-25
 Targeting the EGFR pathway:
K-Ras mutations
EGFR overexpression:
TGF-α • CRC (27–77%)
• Pancreatic cancer (30–50%)
• Lung cancer (40–80%)
• NSCLC (14–91%)

K-Ras* K-Ras mutation:

EGFR* Sos
• CRC (30–50%)
Grb2 • Pancreatic cancer (90%)
B-Raf* • Papillary thyroid cancer (60%)
• NSCLC (30%)

EGFR mutation:
• NSCLC (10%) MEK
• Glioblastoma (20%) B-Raf mutation:
• CRC (10%)
• Melanoma (70%)
MAPK • Papillary thyroid cancer (50%)

*Mutated in human cancers

NSCLC = non-small cell lung cancer
TGF = transforming growth factor Adapted from Roberts Der. Oncogene 2007
 Kaplan Meier
PFS Curve in
NSCLC
undergoing
Erlotinib th/ by
Plasma EGFR
mutation status
Plasma EGFR Mutationsin NSCLC
Journal of Thoracic Oncology Volume 4,
Number 12, December2009
 CIRCULATING B-RAF IN
MELANOMA

Quantitative assessment of BRAF V600

mutant circulating cft DNA as a tool for therapeutic monitoring in metastatic
melanoma patients treated with BRAF/MEK inhibitors.
Schreuer et al. J Transl Med (2016) 14:
95
ERBB2 (human) is a protein that in humans is encoded by the ERBB2 gene,
which is also frequently called HER2 (from human epidermal growth factor
receptor 2) or HER2/neu. In the Jan 2007 the Journal of Clinical Oncology guidelines
were published the serum HER-2/neu test is an additional tool for managing breast
cancer patients and should always be used in conjunction with other diagnostic tools

http://www.healthcare.siemens.com/clinical-specialities/oncology
/laboratory-diagnostics-in-oncology/breast-cancer
RISK FOR BREAST AND OVARIAN CANCER IN
BRCA1 AND BRCA2 CARRIERS
 CLINICAL  APPLICATION

Biomarkers profile as  parameter of

Suceptibility Therapeutic
Predisposition Early detection selection

    Preneoplasia Prognosis
Gene therapy ?
 Key technologies
NY-ESO-1 108 MW 180 148
E7 MW
 SUMMARY

CONVENTIONAL/SERUM MARKERS
AND CELLULAR MARKERS

NEW EMERGING DIAGNOSTIC/PROGNOSTIC
MARKERS: 
Proteins/Enzymes, Circulating Tumor Cells,
Molecular markers:  Circulating DNA/mRNA,
miRNA

MOLECULAR MARKERS:
Screening and early detection, predictive markers
(e.g.predict metastasis) 
Chance of cure markers:  Molecularly guided
treatment / targeted therapy
 TAKE HOME
MESSAGES
Development of Medical Science &
Technology in Solid tumor
biomarkers
Challenges in readiness of facilities
& Profesional HR

The era of increased cancer incidens

trend in Indonesia

Thank You