Tumor markers are substances that can be found in the body (usually in the blood or urine) when cancer is present. Along with other tests, tumor markers can be used to help show if cancer is present, to determine the type of cancer, and in some cases to help show if treatment is working. Some of the more common tumor markers are discussed here.

1. Vivek Misra
B.Tech. (Genetic Engg), M.S. (Neuroscience)
Research Associate
TS Srinivasan Institute Neurokrish
Of Neuroscience Consulting Pvt. Ltd
Tumor Biomarkers
For
Screening, Progression and Prognosis
vivek@uberbrain.net
www.UberBrain.net

2. What Are Tumour Markers ?
Tumour markers are indicators of cellular,
biochemical, molecular, or genetic alterations by
which neoplasia can be recognized.
These surrogate measures of the biology of the
cancer provide insight into the clinical behaviour of the
tumour.

3. How Does They Help ?
Diagnostic and distinguish benign from malignant
disease
• Correlate with the amount of tumour present (so-
called tumour burden)
• Allow subtype classification to more accurately stage
patients
• Be prognostic, either by the presence or absence of
the marker or by its concentration
• Guide choice of therapy and predict response to
therapy

4. Characteristics Of Ideal
Tumour Marker
The marker is expressed exclusively by the particular
tumour.
• Collection of the specimen for the tumour marker
assay is easy.
• The assay itself is reproducible, rapid, and
inexpensive.
Currently, there is no one marker that fulfils all these
criteria for any cancer.

5. Classification of Markers
Tumour markers fall into three broad categories:
• Proteins Markers ;
• Genetic Mutations Markers ;
• Epigenetic Markers

6. Proteins were the first type of tumour marker identified
and hence are considered the so-called classic tumour
markers. For Eg:
Protein Tumour Markers
• Carcinoembryonic antigen (CEA)
• α-Fetoprotein
• Carbohydrate Antigen 19-9
• Prostate-Specific Antigen
• Carbohydrate Antigen 125
• Human Chorionic Gonadotropin in Testicular Germ Cell Tumors

7. Carcinoembryonic Antigen (CEA)
• CEA used clinically in patients with cancer of the colon
and rectum.
• It is an oncofetal protein that is normally present during
fetal life but can be seen in low concentration in
healthy adults.
• it is a glycoprotein

8. • CEA itself is secreted into the circulation and is also
found in the mucous secretions of the stomach,
small intestine, and biliary tree.
• Although its exact function is unknown, CEA has
been shown to be involved in cell adhesion and is
able to inhibit apoptosis induced by loss of
anchorage to the ECM
CEA contd…

9. • Normal serum levels are less than 2.5 ng/ml,
• Borderline if 2.5 to 5.0 ng/ml,
• Elevated if greater than 5.0 ng/ml.
Borderline levels occur with benign disorders such as:
• inflammatory bowel disease,
• pancreatitis,
• cirrhosis, and
• chronic obstructive pulmonary disease, and
smoking can also increase CEA—(the upper limit of normal in
smokers is considered 5 ng/Ml)
CEA - Testing

10. CEA - Prognosis
• Elevated CEA levels reflect the burden of tumour
present.
• The degree of CEA elevation correlates with increasing
stage of disease, and therefore CEA levels have
prognostic value.
• Preoperative serum CEA is an independent predictor
of survival—the higher the preoperative serum level,
the poorer the prognosis.

11. CEA contd…
• 5-year survival is higher in patients whose elevated
preoperative CEA normalized postoperatively.
• Finally, patients with elevated preoperative CEA
levels have higher recurrence rates than do those
with normal CEA levels.

12. CEA - Monitoring
• The most common application of CEA is to monitor
patients for recurrent disease.
• CEA is most sensitive for hepatic or retroperitoneal
metastasis and relatively insensitive for local,
pulmonary, or peritoneal involvement.
• Patients with advanced cancer whose CEA levels fall
during chemotherapy survive significantly longer

13. Verdict ??
• CEA is not useful as a screening test because of its
low sensitivity in early-stage disease.
• Elevated CEA levels occur in only 5% to 40% of
patients with localized disease.

14. α-Fetoprotein
• α-Fetoprotein (AFP) is used for the detection and
management of HCC.
• It is an oncofetal antigen
• It is synthesized by hepatocytes and endodermally
derived gastrointestinal tissues.

15. AFP - Testing
• The upper limit of normal for a healthy, non-pregnant
adult is less than 25 ng/Ml
• Levels are also raised in non-seminomatous testicular
cancer, for which it is a valuable tumour marker.
• Elevated levels are also seen in hepatitis, inflammatory
bowel disease, and cirrhosis.

16. AFP - Screening
• AFP has an estimated sensitivity of 25% to 75%, a specificity of
76% to 94%.
• The combination of AFP and ultrasound improves the efficacy of
screening
• In the United States, recent studies suggest that surveillance of
patients with HCV-related cirrhosis with a combination of AFP
and an imaging modality (either ultrasound or computed
tomography) would gain quality-adjusted life years at acceptable
cost.

17. AFP - Prognosis
• The AFP concentration reflects tumour size, with
levels higher than 400 ng/mL being associated with
larger tumours.
• As a result, it has been shown that AFP correlates
with stage and prognosis of disease.

18. AFP - Monitoring
• AFP has been shown to decline after resection or ablation.
• In patients whose AFP levels do normalize postoperatively,
a subsequent rise in AFP over the course of serial serum
measurements has been found to be the best indicator of
recurrent disease.
• Tumour re-growth after chemoembolization does not
correlate with rate of increase in AFP or tumour burden.

19. Contd…
• AFP levels usually decline in response to effective
chemotherapy.
• Monitoring of AFP therefore avoids prolonged use of
ineffective and potentially toxic chemotherapy.

20. Carbohydrate Antigen 19-9
• Carbohydrate antigen 19-9 (CA 19-9) is widely used as a
serum marker for pancreas cancer
• But its use is limited to monitoring response to therapy, not as
a diagnostic marker.
• Because CA 19-9 epitope is normally present within the
biliary tree. Biliary tract disease, both acute and chronic, can
elevate serum CA 19-9 levels.
• It is a mucin-type glycoprotein expressed on the surface of
pancreatic cancer cells.

21. CA 19-9 Testing
• CA 19-9 is detected with an immunoassay.
• The normal range of CA 19-9 in the blood of a
healthy individual is 0-37 U/mL
• CA 19-9 associated antigen levels are elevated in the
blood of many patients with pancreatic cancer.

22. CA19-9 - Limitation
• Negative Lewisa blood group antigen cannot
synthesize CA 19-9.
• Patients with benign biliary tract disease can have
levels up to 400 U/mL.
• High CA 19-9 levels can also be caused by non-
cancerous conditions such as gall stones,
pancreatitis, cystic fibrosis, and liver disease.

23. CA19-9 - Screening
• CA 19-9 is not useful as a screening modality because of
its low sensitivity in early-stage disease. With increasing
levels of CA 19-9, the diagnosis of pancreatic cancer
becomes more accurate.
• Levels higher than 1000 U/mL are almost diagnostic of
pancreatic cancer.

24. CA19-9 - Prognosis
• In patients with pancreatic cancer who have CA 19-9
detectable in their serum , the level has been shown
to correlate with tumour size.
• Of patients who undergo curative resection, those
whose CA 19-9 levels returned to normal survived
longer than those whose levels fell but never
normalized.

25. CA19-9 - Monitoring
• Serial measurement of CA 19-9 is used to monitor
response to therapy
• Besides pancreatic cancer, CA 19-9 levels are also
elevated in patients with other cancers, including
those of the biliary tree (95%), stomach (5%), colon
(15%), liver (HCC, 7%) and lung (13%).

26. Prostate-Specific Antigen
• Prostate-specific antigen (PSA) is a serine protease that
is formed in the prostatic epithelium and secreted into
the prostatic ducts.
• Its function is to digest the gel that is formed in seminal
fluid after ejaculation. Under normal circumstances,
only small amounts of PSA leak into the circulation.

27. Contd…
• With enlargement of the gland (e.g., in patients with
benign prostatic hyperplasia [BPH]) or distortion of
its architecture, serum PSA levels increase.
• Thus, PSA is considered a tissue-specific rather than
a prostate cancer–specific marker—patients who
have undergone curative radical prostatectomy, as
well as females, have no detectable PSA.

28. PSA - Testing
• PSA is detected with an immunoassay.
• serum PSA levels may be elevated include bph ,
prostatitis, prostatic massage, prostatic biopsy, and
digital rectal examination.

29. Contd….
• it has been found that the upper limit of the normal
range of PSA increases with age. The limit is 2.5
ng/mL for men aged 40 to 49 years, 3.5 ng/mL for
those 50 to 59, 4.5 ng/mL for those 60 to 69, and 6.5
ng/mL for men 70 years and older.
• The rate of increase in PSA in a normal 60-year-old is
0.04 ng/mL/yr.

30. PSA - Density
• PSA density is defined as the ratio of PSA to prostatic
volume, as measured by transrectal ultrasound or
magnetic resonance imaging.
• Higher PSA densities are more suggestive of malignancy
than BPH because the amount of PSA released per
gram of prostate cancer is significantly greater than that
released from normal prostatic tissue.

31. PSA - Screening
• PSA is widely used as a screening tool for prostate
cancer because it enables early detection and diagnosis
of this disease,

32. PSA - Monitoring
• After operative resection, the PSA level is expected
to normalize after 2 to 3 weeks.
• Normally it takes 3 to 5 months for PSA to normalize
after radiotherapy in ca prostate.
• In patients with advanced disease, PSA levels are also
used to monitor response to systemic therapy.

33. Carbohydrate Antigen 125
• Carbohydrate antigen 125 (CA 125) is a carbohydrate
epitope on a glycoprotein carcinoma antigen.
• It is present in the fetus and in derivatives of the
coelomic epithelium, including the peritoneum,
pleura, pericardium, and amnion.

34. Contd…
• In healthy adults, CA 125 has been detected by
immunohistochemistry in the epithelium of the
fallopian tubes, endometrium, and endocervix.
• However, neither adult nor fetal ovarian epithelium
expresses CA 125.

35. CA 125 - Testing
• CA 125 levels are measured with an immunoassay,
with the upper limit of normal set at 35 U/mL.
• Elevated levels are detected in ovarian cancer.
• cancer of the fallopian tube, endometrium, and
cervix.
• as well as in nongynecologic malignancies of the
pancreas, colon, lung, and liver.
• In Benign conditions CA 125 is elevated which are
endometriosis, adenomyosis, uterine fibroids, pelvic
inflammatory disease, cirrhosis, and ascites

36. CA 125 - Screening
• CA 125 is not useful as a screening tool for ovarian
cancer because of its poor specificity.

37. CA 125 - Prognosis
• Patients with elevated CA 125 levels at the time of
diagnosis have a worse prognosis than patients with
normal levels do.
• CA 125 levels—
• 50% of stage I patients,
• 70% of stage II patients,
• 90% of stage III patients, and
• 98% of stage IV patients

38. CA 125 - Monitoring
• Partial or complete response to therapy is associated
with a decrease in CA 125 levels.
• Increasing levels of CA 125 correlate with disease
recurrence and precede clinical or imaging evidence
of recurrence by a median of 3 months.
• CA 125 levels in peritoneal fluid may be more
sensitive than serum levels.

39. Contd…
• The upper limit of normal for peritoneal fluid CA 125
is 200 U/mL.

40. α-Fetoprotein and Human Chorionic
Gonadotropin in Testicular Germ Cell Tumors
• Nonseminomatous testicular cancers comprise
several different histologic types:
– embryonal carcinoma;
– syncytiotrophoblasts (choriocarcinoma);
– yolk sac tumors; and
– teratomas.

41. Contd…
• Marker expression can be predicted on the basis of
the predominant histologic type:
– human chorionic gonadotropin (HCG) is detected in more
than 90% of choriocarcinomas,
– whereas AFP is expressed by 90% to 95% of yolk sac
tumors,
– 20% of teratomas, and
– 10% of embryonal carcinomas.

42. Diagnosis
• The presence of a testicular tumour in combination
with an elevated level of AFP or HCG is suggestive of
testicular cancer, without being diagnostic.
• Elevated levels of these markers in a man younger
than 40 years without signs of a testicular tumour
may indicate extra-testicular germ cell cancer.

43. Prognosis
• An absolute AFP concentration greater than 500
ng/mL or an HCG level higher than 1000 ng/mL is
predictive of a poor prognosis.
• These tumour markers are useful in identifying
biologically distinct categories of morphologically
similar tumours

44. Monitoring
• In the majority of patients with nonseminomatous
germ cell tumors, tumor marker levels correlate with
response to chemotherapy.
• rate of marker decline can be used for early
identification of patients who will respond poorly to
chemotherapy.
• Half-lives longer than 3.5 days for HCG or longer than
7 days for AFP suggest that very aggressive therapy is
required.
• HCG level in urine is similar to that of serum .

45. DNA - Based Markers
• Specific mutations in oncogenes, tumor-suppressor
genes, and mismatch repair genes can serve as
biomarkers.
• These mutations may be:
•
– germline. e.g. ret proto-oncogene of MEN 2
– APC gene of FAP,
– somatic mutations such p53 mutations.
– Chromosomal abnormalities such as 9:22 translocation
that creates the bcr-abl oncogene (biomarkers).

46. Epigenetic Changes
• Testing for epigenetic changes is still at an early
discovery stage. But it has great potential because –
1. DNA assays for aberrant methylation are easier and
more sensitive than those for point mutations.
2. cancer-specific DNA methylation patterns can be
detected in tumour-derived free DNA in the
bloodstream and in epithelial tumour cells shed into
the lumen.

47. Contd…
• DNA-methylation profiles are more chemically and
biologically stable than RNA or most proteins. As a
result, they may be more reliably detected in diverse
biologic fluids.

48. Advances In Assays
• DNA Methylation biomarker studies have been
performed in a variety of cancers, including breast,
esophageal, gastric, colorectal, and prostate cancer.
• Combining DNA methylation assays may complement
existing screening methods with high sensitivity but
low specificity, such as PSA in prostate cancer.
• The use of panels of methylation targets in these
studies improved the clinical sensitivity of the assay.

49. Biomarkers and Biologically
Targeted Therapies
• Biomarker expression is increasingly being used,
independent of formal staging criteria, to decide
which patients receive biologically targeted
therapies.

50. Contd…
CANCER BIOMARKER THERAPY
Breast Estrogen receptor,
progesterone receptor
Tamoxifen/aromatase
inhibitors
Lymphoma CD20 Rituximab
Chronic myelogenous
leukemia (CML)
bcr-abl Imatinib
Gastrointestinal stromal
tumor (GIST)
c-kit Imatinib
Non–small cell lung cancer EGFR mutation Gefitinib
Breast HER2/neu Trastuzumab
From Ludwig JA, Weinstein JN: Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev
Cancer 5:845-856, 2005.

51. Thank
You