1. Tumor Markers

2. Tumor
Tumor refers to the uncontrolled growth of cells that can develop into a solid mass and spread to other areas of the body
Although it is often specified as a single disorder, cancer is a broad term used to describe more than 200 different diseases that affect more than 50 tissues
It is important to understand that not all tumors are cancerous.
There are benign tumors where the growth is limited to certain part of the body.
A tumor becomes cancer when it is malignant.

3. Tumor
The formation (tumorigenesis) and spreading (metastasis) of tumors are caused by a complex combination of inherited and acquired genetic mutations
During tumorigenesis, these mutations include:
activation of growth factors (e.g., epidermal growth factor [EGF]) and oncogenes (e.g., K-ras),
in combination with inhibition of apoptosis, tumor suppressor, and cell cycle regulation genes (e.g., BRCA1, p53, cyclins)
As cancer progresses toward metastasis, additional genetic changes are required such as:
loss of cell adhesion proteins (e.g., Beta-catenin and E-cadherin)
and activation of angiogenesis genes (e.g., VEGF)

4. Stages of Tumor
Cancer severity is generally classified by a combination of several factors.
Depending on the type of cancer, these factors include tumor size, histology, regional lymph node involvement, and presence of metastasis.
For most solid tumors (e.g., breast, lung, kidney), cancer is broadly classified (using roman numerals I–IV) into four stages

6. Tumor Markers
A Tumor marker is a biological substance synthesized and released by:
The tumor
or by the host in response to tumor tissue
It may be used to:
Detect the presence of a tumor
Monitor the progress of disease
Monitor the response to treatment

7. Tumor Antigens Tumor specific antigens Tumor associated antigens
Direct product of oncogenesis
Disorganization of the genetic information leading to synthesis of antigens that are unique to the specific tumor cell
Tumor associated antigens
Most antigens are not specific for individual tumors but rather are usually associated with different tumors derived from the same or closely related tissue
E.g. Oncofetal antigens: Antigens present in normal fetal growth and stimulated by malignancies later in life

8. How to identify tumor marker ?
On cell
Immunocytochemistry, Flow cytometry
On tissue
Immunohistochemistry
In body fluids
Blood, urine, CSF, Amniotic fluid
RIA, EIA

9. Tumor markers in Cancer Management
Screening
Diagnosis
Staging & Prognosis
Therapy Monitoring
Detecting recurrence

10. Tumor markers in Cancer Management

11. Screening
Tumor markers play a limited role for tumor screening, because
relatively low sensitivity
lack of specificity
Inappropriate for the detection of small in situ cancer
However, successful cancer screening has been carried out by measuring tumor markers
Eg. PSA → prostate cancer
Carcinoma in situ is, by definition, a localized phenomenon, with no potential for metastasis unless it progresses into cancer.

12. Screening
Susceptibility to cancer can be determined using molecular diagnostics in patients with breast, ovarian, or colon cancer
Screening for susceptibility to breast and ovarian cancers is done by:
identifying germline BRCA1 and BRCA2 mutations.
Similarly, familial colon cancers can be identified by:
the presence of the adenomatous polyposis coli gene (APC)

13. Diagnosis
Tumor marker is not the key diagnostic examination, but can be a complementary sign to clinical finding or medical imaging
AFP → hepatoma

14. Staging & Prognosis
The major clinical value of tumor markers is in tumor staging, monitoring therapeutic response and detecting recurrence
The tumor markers and medical imaging are complementary in the pre-therapeutic and post-therapeutic staging

15. Staging & Prognosis
Serum concentration of tumor markers increases with tumor progression and usually reaches the highest levels when tumors become metastasized.
The serum levels of tumor markers at diagnosis are likely to reflect the aggressiveness of the tumor and help predict the outcome for the patients.
High levels indicate the presence of a malignant or metastatic tumor → poor prognosis.

16. Monitoring and Disease Recurrence
One of the most useful applications of tumor markers is monitoring therapy efficacy and detecting disease recurrence.
After surgical resection, radiation, or drug therapy of cancer (chemotherapy), tumor markers are routinely followed.
In patients with elevated tumor markers at diagnosis, effective therapy results in a dramatic decrease or disappearance of the tumor marker.

17. Monitoring and Disease Recurrence
If the initial treatment is effective, the appearance of circulating tumor markers can then be used as a highly sensitive marker of recurrence
Many markers have a significant lead time of several months before disease would be detected by other methods, allowing treatment of an earlier-stage cancer.

18. Ideal Tumor Marker Characteristics
Sensitive & Specific
Presence of a given marker identifies an exact malignancy
Concentration proportional to tumor size
Concentration changes with growth or reduction of malignancy
Concentration is low after remission
Concentration is a good indicator of prognosis
Short half-life (concentration reflects current conditions)

19. Reality of tumor markers
Unfortunately, most tumor markers only possess some of the ideal characteristics (never all of them)
Most tumor markers are not very sensitive and are poor screening tests for the detection of malignancies
Most tumor markers are best utilized to confirm or monitor already diagnosed cancers
ability to correctly identify people who have the disease

20. Different Types of Tumor Markers
Fetal antigens
Proteins
Hormones
Enzymes
Steroid Receptors

21. Oncofetal antigens
Oncofetal antigens expressed transiently during normal fetal development and are then turned on again in the formation tumors

22. CEA (Carcinoembryonic Antigen )
Oncofetal antigen
Best tumor marker for monitoring of colon cancer
Also elevated in
Smokers, Alcoholic cirrhosis & Ulcerative colitis
Good correlation with treatment and prognosis of colon cancer
↓ CEA after surgical removal of tumor
↑ CEA if malignancy re-occurs or metastasizes
Levels correlate well with chemotherapy and irradiation treatment
Assay: ELISA and RIA

23. Alpha –FetoProtein (AFP)
Oncofetal antigen
↑ in pregnancy and certain malignancies
Useful tumor marker for monitoring
Liver cancer, hepatocellular carcinomas (HCC)
Gonadal malignancies
Serial measurements of AFP used to monitor treatment and post-surgery in patients with HCC.
Assay: ELISA and RIA

24. Prostate Specific Antigen (PSA)
PSA is a tissue specific protein secreted by malignant prostate cells
PSA is present in low concentrations of normal males, but elevated in malignancies and other conditions
Good screening test for the detection of prostate cancer in older males and the monitoring of previously diagnosed tumors
Complete removal of prostate should result in an undetectable total PSA in serum, any measurable tPSA would indicate residual prostatic tissue or metastasis.
Assay: Immunoassays (ELISA)
Total (t) PSA = free (f) PSA + complex (c) PSA

25. CA 125
CA 125 is a protein that is associated with normal ductal tissue
Utilized to evaluate gonadal ovarian cancers
CA125 is not efficient in detecting early (more treatable) ovarian cancers
CA125 is useful in detecting late ovarian cancers and recurrence of cancers
False positives may occur, resulting in unnecessary treatment 75 % of ovarian cancers are not diagnosed until late in the disease.
Assay: ELISA , RIA

26. Paraproteins
Any of the incomplete monoclonal immunoglobulins that occur in plasma cell disorders
Paraproteins are detectable in either serum or urine in 98-99% of patients with Multiple Myeloma.
Their detection is valuable in the diagnosis of this condition
Paraprotein concentrations correlate well with Tumor bulk
Reduction in the amount of paraprotein is a good indicator of the efficacy of treatment.

27. Hormones as tumor markers
hCG is a hormone produced by the normal placenta (pregnancy)
The presence of hCG in the plasma at other times indicates the presence of abnormal trophoblastic tissue tumors of the ovary and testis.
The outermost layer of cells of the mammalian blastocyst that attaches the fertilized ovum to the uterine wall and serves as a nutritive pathway for the embryo.
It is a prognostic indicator for
ovarian cancer, a diagnostic marker
for classification of testicular cancer
Assay: ELISA
Human Chorionic Gonadotropin

28. Enzymes as Tumor Markers
Plasma enzyme activities are often increased in patients with cancer,
usually a secondary effect of the tumor rather than a result of secretion of an enzyme by the tumor.
Examples include the increase in alkaline phosphatase activity seen in patients with bone cancer.
Increase in the plasma activity of the placental type in plasma occurs in many patients with lung, ovarian & others
Measurement of placental alkaline phosphatase is of value in monitoring the response of such patients to treatment.

29. Steroid Receptors
Hormonally dependent organs (breast) give rise to malignancies that may in themselves be hormonally dependent
Eliminating hormonal stimulation by drugs leads to a regression of the respective malignancy
Predicting which tumor respond to hormonal manipulation can be achieved by measuring steroid hormone receptors on tumors

30. Estrogen & Progesterone Receptors
It is a protein localized in the nuclei of mammary and uterine tissue.
Patients whose primary tumors demonstrated ER will respond to hormone therapy.
ER and progesterone receptor assays are used to predict the therapeutic response of breast cancer patients to hormonal treatment