BIOMARKERS

(TUMOR MARKERS, CARDIAC

MARKERS)
CLINICAL CHEMISTRY II

presented by: Jannica Dominique Claros, RMT

FACULTY- LPU-ST. CABRINI SCHOOL OF HEALTH
SCIENCES
 Topic Outline and Objectives:
• ideal characteristics of a biochemical markers
• role of markers in diagnosis and management of
patients
• Know the emerging technologies for marker
determination
• role of biomarkers for therapeutic selection
• pathophysiology
• role of point-of-care testing for biochemical
markers
TUMOR MARKERS
How do we diagnose cancer today?
- Physical Examination
- Blood tests
- CT scans
- Biopsy
- Techniques like normal blood smear
Characteristics of an ideal tumor marker
• Specificity for a single type of cancer
• High sensitivity and specificity for cancerous growth
• A tumor marker should be present in or produced by

tumor itself. A tumor marker should not be present in

healthy tissues.
• A tumor marker should be present in plasma at a

detectable level, eventhough tumor size is very small.

• Correlation of marker level with tumor size
• Homogeneous (i.e., minimal post-translational
modifications)
• Short half-life in circulation
• Simply and cheap test.
 Roles for tumor markers
• Determine risk (PSA)
• Screen for early cancer (calcitonin, occult blood)
• Diagnose a type of cancer (hCG, catecholamines)
• Estimate prognosis (CA125)
Prognosis: estimating the progress of the disease
• Predict response to therapy (CA15-3, CA125, PSA,
hCG)
• Monitor for disease recurrence or progression
(most widely used function)
• Therapeutic selection (her2/neu, kras)
 TUMOR MARKER PER MOLECULE
CLASSIFICATION

• Enzymes or isoenzymes (ALP)

• Hormones (calcitonin)
• Oncofetal antigens (AFP, CEA)
• Carbohydrate epitopes recognised by

• monoclonal antibodies (CA 15-3, CA

19-9, CA125)
• Receptors (Estrogen, progesterone)
 Tumor markers in routine use
Marker Cancer
CA15-3, BR 27.29 Breast
CEA, CA 19-9 Colorectal
CA 72.4, CA 19-9, CEA Gastric
NSE, CYFA 21.1 Lung
PSA, PAP Prostate
CA 125 Ovarian
Calcitonin, thyroglobulin Thyroid
hCG Trophoblastic
CA 19-9, CEA Pancreatic
AFP, CA 19-1 Hepatocellular
BAP, Osteocalcin, NTx Bone
Catecholamines, metabolites Pheochromocytoma
Fecal occult blood Colon cancer
 Alpha Fetoprotein
• Hepatocellular carcinoma, Germ Cell Tumors
• α-fetoprotein is a marker for liver/ testicular cancer.
• It is also increased in pregnancy and chronic liver
diseases.
• AFP is useful for screening (AFP levels greater than
1000 µg/L are indicative for cancer except pregnancy)
• AFP level not directly related to tumor size
• Elevated in pregnancy, liver disease (hepatitis, cirrhosis,
GI tumors)
• Serum AFP levels is less than 10 µg/L in healthy adults.
Elevated AFP levels are associated with shorter survival
time
• Normal: less than 7 ng/ml
 CEA
• 150-300 kDa glycoprotein
• It is a cell-surface protein and a well defined tumor
marker.
• CEA is a marker for colorectal, gastrointestinal, lung and

breast carcinoma.
• CEA levels are elevated in smokers and some patients

having benign conditions such as cirrhosis, rectal polyps,

ulcerative colitis and benign breast disease.
• CEA testing should not be used for screening. Some

tumors don’t produce CEA. It is useful for staging and

monitoring therapy (recurrence).
• Normal: 0-2.5 ng/ml
• Smokers: 0-0.5 ng/ml
CA 15-3/CA 27.29
• High molecular weight glycoprotein (Polymorphic
Epithelial Mucin)
• Breast cancer marker
– Correlate with stage and tumor size
– Prognosis & predict response to chemotherapy
– Detect residual disease following initial therapy
– Detect recurrence, correlates with disease progression or
regression
– NOT sensitive enough for early detection
• Elevated in benign diseases of liver & breast
• Elevated in other cancers: pancreatic, lung, ovarian,
colorectal, & liver
Normal: less than 30 U/ml
 CA 125
• >200-2000 kDa glycoprotein
• Increased in benign diseases: pregnancy,
endometriosis, ovarian cysts, Pelvic Inflammatory
Disease, cirrhosis, hepatitis, pericarditis
• Increased in other cancers: lung, breast, GI, endometrial,
& pancreatic
• It is useful in detecting residual disease in cancer

patients following initial therapy.

• Screening of high risk population (BRCA1-2 Carriers)
• Normal: less than 35 U/ml
 CA 19-9
• CA 19-9 is a marker for both colorectal and pancreatic
carcinoma.
• However elevated levels were seen in patients with
hepatobiliary, gastric, hepatocellular and breast cancer
and in benign conditions such as pancreatitis and benign
gastrointestinal diseases.
• 21-42% elevated in gastric carcinoma
• 20-40% elevated in colonic carcinoma

• 71-93% elevated in pancreatic carcinoma

• Useful for differentiated benign from malignant disease

• Normal: less than 37 U/ml

SPECIFIC MARKERS:
β2-microglobulin
-β2-microglobulin is a marker for multiple
myeloma, Hodgkin lymphoma. It also
increased in chronic inflammation and viral
hepatitis.

Thyroglobulin
-It is a useful marker for detection of
differentiated thyroid cancer.
Alkaline Phosphatase (ALP)
• Increased alkaline phosphatase
activities are seen in primary or
secondary liver cancer.
• Its level may be helpful in evaluating
metastatic cancer with bone or liver
involvement.
• Elevates in a variety of malignancies,
including ovarian, lung, gastrointestinal
cancers and Hodgkin’s disease.
 PROSTATE SPECIFIC ANTIGEN
• The clinical use of PAP has been replaced by PSA.
• PSA is much more specific for screening or for detection
early cancer (+rectal exam)
• It is found mainly in prostatic tissue.
• PSA exists in two major forms in blood circulation. The
majority of PSA is complexed with some proteins. A
minor component of PSA is free.
• PSA testing itself is not effective in detecting early
prostate cancer. Other prostatic diseases (urinary
bladder) may lead an increased PSA level in serum.
• The ratio between free and total PSA is an reliable
marker for differentiation of prostatic cancer from benign
prostatic hyperplasia.
• Normal: less than 4 ng/ml
• >60: : less than 3 ng/ml

Calcitonin
• Calcitonin is a hormone which decreases blood calcium
concentration.
• Its elevated level is usually associated with thyroid
cancer.
• Calcitonin levels appear to correlate with tumor volume
and metastasis.
• Calcitonin is also useful for monitoring treatment and
detecting the recurrence of cancer.
• calcitonin levels are also at a high levels in some
patients with cancer of lung, breast, kidney, liver and in
nonmalignant conditions
• Normal: less than 100-150 pg/ml
 Human Chorionic Gonadotropin (hCG)
• It is a glycoprotein appears in pregnancy. Its high levels
is a useful marker for tumors of placenta and some
tumors of testes.
• hCG is also at a high level in patients with primary testes
insufficiency.
• hCG does not cross the blood-brain barrier. Higher levels
may indicate metastasis
• Normal: less than 5 IU/L
 RECEPTOR MARKERS
• Estrogen and progesterone receptors are
used in breast cancer as indicators for
hormonal therapy.
• Patients with positive estrogen and
progesterone receptors tend to respond to
hormonal treatment.
• Those with negative receptors will be
treated by other therapies.
 DIAGNOSTIC METHODS
IMMUNOHISTOCHEMISTRY
FLOURESCENT IN SITU HYBRIDIZATION (FISH)
MEDICATIONS

BIOMARKER DRUG CANCER

Her2.neu Trastuzumab Breast ca.
KRAS Cetuximab, Colorectal
BRAF panitumumab Melanoma
ALK Fusion Vemurafenib Non-small cell lung ca.
EGFR Crizotinib Non-small cell lung ca.
BCL-ABL translocation Gefitinib, erlotinib Chronic myeloid
Imatinib, dasatinib, leukemia
nilotinib
CARDIAC MARKERS
CARDIAC BIOMARKERS: protein molecules
released in the bloodstream after a heart muscle
damage

Biomarkers vs ECG: Rise and fall pattern

CHARACTERISTICS OF A GOOD CARDIAC

MARKER:

• High specificity
• Pharmacodynamics
• earliest diagnostic appearance
• Must have a designated role in treatment and
manage well of patients
 CLASSIFICATION OF CARDIAC BIOMARKERS:

INJURY TYPE: MYOCARDIAL INJURY

MARKERS OF MYOCARIAL NECROSIS:

• - CREATININE KINASE - MB
• - MYOGLOBIN
• - TROPONINS

MARKERS OF MYOCARDIAL ISCHEMIA:

• - ISCHEMIA MODIFIED ALBUMIN
• - HEART-TYPE FATTY ACID BINDING PROTEIN
INJURY TYPE: INFLAMMATION
MARKERS: hsCRP, homocysteine

INJURY TYPE: HEMODYNAMIC STRESS

MARKERS: ANP, BNP, PRO-BNP
COMMON CARDIAC MARKERS:
Myoglobin
- oxygen-binding heme protein that is present
in both cardiac and skeletal muscle
- lacks specificity, early release from damaged
cardiac or skeletal muscle
- rises as early as 1–4 hours after the onset of
symptoms, is found in all AMI patients
- not cardiac specific, so care must be taken
in its interpretation in patients with renal
failure, trauma, or diseases involving skeletal
muscle. - rapid clearance by the kidneys
Troponins(I, T, C)
- preferred biomarkers for assessment of
myocardial necrosis

-the major
function of troponins is to bind calcium and
regulate muscle contraction.
- Following injury to skeletal or heart muscle
cells, the troponin complex and free troponin
subunits are released
- high sensitivity and specificity for myocardial
damage
-Data indicate that troponins rise 4–10 hours
hsCRP
- markers of inflammation
- an acute-phase protein produced by the liver in
response to injury, infection, and inflammation
-general nonspecific marker of inflammation

Ischemia modified albumin (IMA)

- marker of ischemia that is produced when
circulating serum albumin contacts ischemic
heart tissues
- measured by the albumin cobalt binding assay
- rise within minutes of transient ischemia, peak
within 6 hours, remain elevated for as long as 12
hours
CREATININE KINASE
- enzyme that stimulates the transfer of high energy
phosphate groups
- found in skeletal muscle, myocardium, and the brain
- Concentrated in cytoplasm of tissues that require high
amount of energy specially in striated (skeletal) muscles
- amount of circulating CK is related to individual’s muscle
mass.
-AMI: serum CK rise sharply 6-8 hrs after onset of chest
pain
- Vigorous exercise, fall, deep IM injection, trauma,
surgery can also cause elevation in CK levels
LACTATE DEHYDROGENASE
-enzyme that catalyses the reversible formation of
lactate from pyruvate in the final step of glycolysis
- AMI: serum LDH rises in 24-48 hours, peaks at
2-3 days, and returns to normal in 8-14 days after
onset of chest pain
- major limitation: lack of specificity (in tissues
including the heart, liver lungs kidney ,skeletal
muscle, red blood cells and lympocytes).
- heart contains mainly LDH1 and to a lesser
extent LDH2
- LDH and LDH isoenzymes are no longer
recommended for the evaluation of the patient
with ACS
ASPARTATE AMINOTRANSFERASE
- enzyme involved in amino acid synthesis (transfer of amino grp)
- widely distributed in the liver, heart, skeletal muscle, red blood cells, kidney
and pancreas
- rises within 12 hours of AMI, peak in 24-48 hrs, return to baseline in 3-4 days

BNP (B type natriuretic peptide)

- neurohormone released by ventricular myocardium in response to volume
overload
- shown to be a strong predictor of short and long-term mortality in patients
with ACS

N- Terminal-ProBNP(NT-proBNP)
- more stable form of BNP It is formed by the enzymatic cleavage of
PreproBNP,a precursor of BNP
- NT- proBNP levels are elevated in the elderly

CRP, C-REACTIVE PROTEIN:

- acute-phase reactant that is released in the presence of inflammatory
processes
- Synthesized in the liver and normally present in trace amounts in peripheral
circulation
END OF LECTURE. THANK YOU