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Clinical Chemistry 2 (Lecture) > Circulating Tumor Markers: Basic Concepts and Clinical Applications (F) > Flashcards

Circulating Tumor Markers: Basic Concepts and Clinical Applications (F) Flashcards

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1
Q

What is the 2nd leading cause of death in developed countries?

A

Cancer (CA)

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2
Q

True or False

CA accounts for less than 2.7 M deaths annually

A

False, because CA accounts for more than 2.7 M deaths annually

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3
Q

What is CA (what is its principle)?

A

It is the uncontrolled growth of cells that can develop into a tumor & spread to other areas of body

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4
Q

What is the cause of formation and spreading (metastasis) of tumors?

A

Complex combination of inherited & acquired genetic mutations

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5
Q

In terms of the formation of CA, mutations include what?

A

Activation of:

1) Growth factors
2) Oncogenes
3) Inhibition of apoptosis
4) Tumor suppressor
5) Cell cycle regulation genes

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6
Q

CA is staged based on what?

A

1) Tumor size
2) Histology
3) Regional lymph node involvement
4) Presence of metastasis

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7
Q

How many are the stages of CA?

A

4 stages

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8
Q

What are the stages of CA?

A

1) I
2) II
3) III
4) IV

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9
Q

What are the events that happen in CA staging and progression?

A

1) Stage I
- > localized primary tumor
2) Stage II
- > invasion of primary tumor through epithelium and into blood vessels
3) Stage III
- > migration of tumor into regional lymph nodes
- > happens in the liver
4) Stage IV
- > metastasis and invasion of tumor to distant tissues
- > happens in the lung and liver

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10
Q

What are the fxns of tumor markers?

A

1) Detect and 2) monitor CA

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11
Q

What is the origin of tumor markers?

A

These are produced by tumor directly or as an effect of tumor on tissue

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12
Q

What are the types of tumor markers (include its principle and exs)?

A

1) Enzymes
- > levels of certain enzymes correlate w/ tumor burden
2) Serum proteins
- > such as β2-microglobulin & immunoglobulins
3) Hormones & metabolites
- > such as sp. markers of secreting tumors
4) Oncofetal antigens
- > such as carcinoembryonic and alpha-fetoprotein
5) Receptors
- > non-serologic
- > such as estrogen and progesterone receptors

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13
Q

What is the timeline of tumor marker use (include the tumor markers and the utility for each stage of the timeline)?

A

Screening
-> utility: biopsy indication
-> tumor marker: PSA
Diagnosis
-> utility: high lvls indicative of disease
-> tumor markers: metanephrines, HVA/VMA, prolactin, PTH, chromogranin A, cortisol, and ACTH
Prognosis
-> utility: high lvls associated w/ poor px; receptor status used for indication of chemotherapy
-> tumor markers: β2-Microglobulin, CA-125, CEA, LD, Her-2/neu, ER, and PR
Monitoring treatment
-> utility: monitor efficacy of chemotherapy; residual disease after surgery
-> tumor markers: CA-125, CA 19-9, CEA, AFP, hCG, PSA, and SPE
Detection of recurrence
-> utility: increased associated w/ relapse
-> tumor markers: CA 15-3, CA-125, CEA, AFP, hCG, and PSA

Screening -> Dx -> Px -> Monitoring treatment -> Detection of recurrence

Time element towards detection of recurrence from screening

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14
Q

What are the applications of tumor marker detection?

A

1) Screening
2) Px
3) Monitoring therapy effectiveness & disease recurrence

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15
Q

What is the principle of screening (as an application of tumor marker detection)?

A

Most tumor markers are found in normal cells, not just CA cells

Therefore, screening asymptomatic populations would result in detection of false (+)s, causing undue alarm and cost

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16
Q

True or False

All tumor markers are used to screen populations

A

False, because few tumor markers are used to screen populations

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17
Q

How can the susceptibility to breast, ovarian, and colon CA be determined?

A

These can be determined by identifying germline mutations in pts w/ a family history of these diseases

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18
Q

Breast and ovarian CAs are associated w/ what?

A

Germline BRCA1 and BRCA2 mutations

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19
Q

Colon CA is associated w/ what?

A

Adenomatous polyposis coli gene (APC)

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20
Q

In relation to px (w/c is 1 of the applications of tumor marker detection), tumor marker conc. gradually increases w/ what?

A

Tumor progression (reaching highest lvls when tumor metastasize)

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21
Q

Tumor marker lvls at dx can reflect what?

A

1) Presence of malignancy
2) Aggressiveness of tumor
3) Help predict outcome

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22
Q

In relation to monitoring therapy effectiveness and disease recurrence (w/c is 1 of the applications of tumor marker detection), when are the situations where tumor markers are observed?

A

After:

1) Surgical resection
2) Radiation
3) Chemotherapy

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23
Q

Effective therapy can result in what?

A

Decrease in tumor markers

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24
Q

Appearance of tumor markers after effective therapy can be used as what?

A

As a highly sensitive marker of recurrence

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25
Q

What are the lab considerations for tumor marker measurement?

A

1) Multiple tests should be performed (using same commercial kits)
2) Lack of standardization
3) Serially evaluate tumor markers (because they increase w/ time, whereas high normal values will not)

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26
Q

True or False

Standardization found for other common clinical assays generally does not exist for CA assays

A

True

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27
Q

Comparisons of results from different assays for a single pt can be treacherous due to differences in what?

A

1) Ab specificity
2) Analyte heterogeneity
3) Assay design
4) Lack of standard reference material
5) Calibration and kinetics
6) Variation in reference ranges

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28
Q

What are the methods for tumor markers?

A

1) Immunoassays
2) High-Performance Liquid Chromatography (HPLC)
3) Immunohistochemistry (IHC)
4) Enzyme assays

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29
Q

What is the most commonly used method to measure tumor markers?

A

Immunoassays

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30
Q

What is the characteristic of immunoassays?

A

It have many advantages (including ability to automate testing)

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31
Q

What are the factors in interpreting tumor marker immunoassays?

A

1) Linearity
2) Hook effect
3) Heterophile Abs

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32
Q

What is linear range?

A

It is the range of analyte concs. in w/c a linear relationship exists between analyte and signal

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33
Q

How is linearity measured (in connection to immunoassays)?

A

It is measured by analyzing sxs spanning reportable range

34
Q

What is hook effect?

A

It is the falsely low measurements as a result of excessively high tumor marker concs.

35
Q

What is the principle of hook effect?

A

Capture and label Abs are saturated, resulting in a lack of a “sandwich” formation, resulting in decrease in signal

36
Q

In relation to hook effect, what should be done to sxs exceeding linear range?

A

These should be diluted and retested

37
Q

What are heterophile Abs?

A

These are circulating Abs against animal Igs

38
Q

What is the action of heterophile Abs?

A

These can cause significant interference in immunoassays

39
Q

To whom are heterophile Abs occur?

A

These occur in pts given mouse monoclonal Abs

40
Q

What are the uses of HPLC?

A

It is the most widely used method to detect:

1) Catecholamines (and their metabolites in plasma and urine)
2) Neuroblastoma
3) Pheochromocytoma
4) Carcinoid tumors

41
Q

What is the principle of HPLC?

A

Analytes of interest are separated from plasma or urine, run over a column, and separated by physical characteristics

42
Q

In IHC, how are tests tumor markers detected?

A

These are detected directly within solid tissue

43
Q

What is the principle of IHC?

A

Slice of tissue is placed on glass slide and incubated w/ sp. Abs in solution to detect presence of Ags

44
Q

What is the principle of enzyme assays?

A

Detection of elevated circulating enzymes generally cannot be used to identify a sp. tumor or site of tumor

45
Q

What is the enzyme w/c is used as tumor marker that is exempted for enzyme assays?

A

Prostate specific antigen (PSA)

46
Q

Where is PSA exclusively found?

A

In diseased and benign prostate glands

47
Q

True or False

Before use of immunoassays and oncofetal Ags was common, enzyme detection was widely used

A

True

48
Q

What are the exs of enzymes used as tumor markers (in enzyme assays)?

A

1) Alkaline phosphatase (bone, liver, leukemia, and sarcoma)
2) Creatine kinase-BB (prostate, small-cell lung, breast, colon, and ovarian)
3) Lactate dehydrogenase (LDH) (liver, lymphomas, and leukemia)
4) PSA (prostate)

49
Q

What are the frequently ordered tumor markers?

A

1) Alpha-Fetoprotein (AFP)
2) Cancer Antigen 125 (CA-125)
3) Carcinoembryonic Antigen (CEA)
4) Human Chorionic Gonadotropin (hCG)
5) Prostate Specific Antigen (PSA)

50
Q

What is AFP?

A

It is an abundant serum protein synthesized by fetal liver and re-expressed in certain types of tumors

51
Q

To whom are AFP often elevated?

A

In pts w/:

1) Hepatocellular carcinoma
2) Germ cell tumors

52
Q

AFP is a 70-kd glycoprotein related to what?

A

Albumin

53
Q

What are the fxns of AFP?

A

1) It normally fxns as a transport protein

2) It is involved in regulating oncotic pressure in fetus

54
Q

What is the upper limit of normal for serum AFP?

A

~ 15 ng/mL in adults

55
Q

What are the clinical applications of AFP?

A

1) It is used for dx, staging, px, and treatment monitoring of hepatocellular carcinoma
2) It is also used for classification and monitoring therapy for testicular CA and for tumor staging

56
Q

How is AFP measured?

A

It is measured by / via a variety of immunoassays

57
Q

What are the uses CA-125?

A

1) It may be useful for detecting ovarian tumors at an early stage
2) It may also be useful for monitoring treatments w/out surgical restaging

58
Q

Where is CA-125 expressed?

A

1) Ovary
2) Other tissues of müllerian duct origin
3) Other tissues of ovarian carcinoma cells

59
Q

What is the clinical application of CA-125?

A

It is the only clinically accepted serologic marker of ovarian CA

60
Q

What is the methodology for CA-125?

A

Immunoassays using “OC 125” and “M11” Abs

61
Q

When is CEA discovered?

A

1960s

62
Q

What is CEA?

A

It is a prototypical ex of oncofetal Ag

63
Q

When is CEA expressed?

A

During development and re-expressed in tumors

64
Q

What are the uses of CEA?

A

1) It is most widely used tumor marker for colorectal CA
2) It is elevated in:
a. Lung tumors
b. Breast tumors
c. GI tumors

65
Q

What are the characteristics of CEA?

A

1) It is a large heterogenous glycoprotein

2) It has a MW of ~ 200 kDa

66
Q

CEA is involved in what?

A

1) Apoptosis
2) Immunity
3) Cell adhesion

67
Q

What are the clinical applications of CEA?

A

1) It is a tumor marker for colorectal CA
2) It is used for px
3) It is used for post-surgery surveillance
4) It is used to monitor response to chemotherapy

68
Q

True or False

In terms of methodology, for CEA, polyclonal Abs are historically used, but now, monoclonal anti-CEA Abs are used

A

True

69
Q

Due to high heterogeneity of CEA, what is essential?

A

It is essential that same assay be used for serial monitoring

70
Q

What is hCG?

A

It is a dimeric hormone secreted by trophoblasts in placenta

71
Q

What is the action of hCG?

A

To maintain corpus luteum during pregnancy

72
Q

What are the characteristics of hCG?

A

1) It is a 45-kd glycoprotein

2) It consists of alpha and beta subunits

73
Q

What are the clinical applications of hCG?

A

1) Px of ovarian CA
2) Dx of testicular CA
3) It is the most useful marker for gestational trophoblastic diseases

74
Q

What is the methodology for hCG?

A

1) Immunoassays w/ monoclonal capture

2) Tracer Abs

75
Q

What are the characteristics of PSA?

A

1) It is a 28-kd glycoprotein

2) It is produced only in epithelial cells of acini and in prostatic ducts

76
Q

What are the actions of PSA?

A

1) It regulates seminal fluid viscosity

2) It dissolves cervical mucous cap (allowing sperm to enter)

77
Q

Where can low lvls of PSA be detected?

A

In serum of healthy men

78
Q

What are the 2 major forms of PSA found circulating in the blood?

A

1) Free

2) Complexed

79
Q

What is the clinical application of PSA?

A

Annual screening of prostate CA in men over 50 yo and in younger men at high risk (family history)

80
Q

What is the normal range for PSA?

A

< 4 ng/mL

81
Q

What are the factors to take into account when testing for PSA?

A

1) Age
2) PSA velocity
3) Free PSA / total PSA ratios

82
Q

How is PSA measured?

A

It is measured by / via immunoassay using:

1) Enzyme
2) Fluorescence
3) Chemiluminescence
4) Automated immunoassay platform

Clinical Chemistry 2 (Lecture) (17 decks)

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