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Analytes > Tumour markers > Flashcards

Tumour markers Flashcards

1
Q

What is CA125?

A

Antigenic determinant on a high MW mucin-like glycoprotein. This glycoprotein is secreted by ovarian epithelial tumour cells, as well as by other pathological and non-pathological tissues of Mullerian-duct origin.
Recognised by OC125 - a MAb raised against an ovarian cancer cell line.

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2
Q

Indications for CA125 measurement

A
  1. Screening women with hereditary ovarian cancer syndromes in whom early intervention may be beneficial
  2. Investigation and DDx pelvic/adnexal masses - with US and menopausal status, to calculate RMI - Risk of Malignancy Index
  3. Monitoring for recurrence/progression of ovarian cancer.
  4. Screening of women with symptoms of ovarian malignancy - if >35 IU/mL, to proceed to US for RMI calculation.
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3
Q

Half life of CA 125?

A

5-10 days

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4
Q

Performance of CA 125 as a tumour marker?

A

50% sensitive for early stage ovarian cancer
~80% sensitive and specific for differentiating malignant and benign adnexal tumours

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5
Q

Causes of high CA125

A
  1. Gynae malignancy - ovarian, endometrial, fallopian tube
  2. Non-gynae malignancy - colon, rectum, liver, lung
  3. Non-malignant - menstruation, pregnancy, ovarian cysts, endometriosis, uterine fibromyomatoma, PID, ascites, peritoneal/pleural inflammation, cirrhosis
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6
Q

What is CA 19-9?

A

A high MW glycoprotein defined by the mouse mAb 116NS 19-9. Contains a sialylated Lewis-a epitope. 5-10% of the population will have the blood type Lewis a-b- and be unable to express CA 19-9.

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7
Q

Indications for CA 19-9

A

NOT for screening
1. Diagnosis of pancreatic and other GI cancers in conjunction with imaging, histopath
2. Prognostication pancreatic and other GI cancers (correlates with stage, resectability and OS in pancreatic ductile adenoca)
3. Monitoring response to treatment of pancreatic and other GI cancers
4. Detecting recurrence of pancreatic (CA 19-9 “velocity” over 4 weeks) and other GI cancers

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8
Q

Limitations of CA 19-9 measurement

A

Lewis-negative individuals do not express CA 19-9
Can be raised in benign conditions - obstructive jaundice of any causes
Values in RI do not exclude malignancy
Anti-reagent/anti-analyte antibodies - rare
Non-linearity in dilution - CA 19-9 tends to form aggregates
Variation between methods - serial monitoring by same platform
Interindividual variability depending on secretor genotype

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9
Q

Analytical methods CA 19-9

A

Immunoassay
No reference method

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10
Q

True or false: CA 19-9 RIs may be the same in F and M

A

FALSE. Concentrations significantly higher in F than M.

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11
Q

How is CA 19-9 used in prognostication of pancreatic cancer?

A
  1. Pre-op > 1000 kU/L associated with poorer outcome
  2. Post-op CA 19-9 < 200kU/L indicator of good outcome
  3. Post-op CA 19-9 decrease by >200 kU/L indicator of good outcome
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12
Q

How is CA 19-9 used in monitoring for recurrence of pancreatic ca?

A

Rise in CA 19-9 detectable several months before clinically or radiologically evident recurrence

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13
Q

How is CA 19-9 used for monitoring response to treatment of pancreatic ca?

A

Correlation between magnitude of decrease in CA 19-9 and overall survival and time to treatment failure.
Optimal testing interval and exact magnitude of change that is clinically significant still unclear

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14
Q

Effect of dilution on CA 19-9?

A

Non-linear. Dilution changes tertiary configuration. Exposes more sites for antibody binding and can cause higher apparent value.

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15
Q

Causes of increased CA 19-9

A
  1. Malignant - pancreatic, cholangiocarcinoma, GB ca, hepatocellular, gastric, colorectal, breast, ovarian, lung
  2. Benign GI disease - pancreatitis, cholecystitis, cirrhosis, hepatitis and acute hepatic necrosis, gallstones, cholestasis of any cause
  3. Other - lung disease (CF, pneumonia, tuberculosis, pleural effusion), PID, Hashimoto thyroiditis, RA, renal failure, SLE
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16
Q

Performance of CA 19-9 for detection of pancreatic ca?

A

Cut-off 37 kU/L 81% sensitive, 90% specific
Specificity increases as CA 19-9 rises - >1000kU/L specificity 99.8%
Poorly differentiated cancers produce lower quantities of CA 19-9

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17
Q

Another tumour marker that can be used as an alternative to CA 19-9 for patients who are Lewis a- b-?

A

CA 50

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18
Q

What is CEA?

A

Family of glycoproteins found in normal fetal GI tissue, but only in low concentrations in normal adult plasma. Increases with colorectal ca, as well as gastric, bronchial, uterine and ovarian ca and in lymphoma

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19
Q

Clinical utility of CEA

A

Monitor 3 monthly for 3 years for Dukes stage B or C disease (American Society of Clinical Oncology)
1. Longer apparent half-life (>4.5 days) after surgery suggests incomplete resection.
2. Rise of 1ug/L, even within reference limits, following initial fall after resection suggests recurrence/mets with sensitivity 80% spec 86%
NOT diagnostic/for screening
Concentration >50 ug/L effectively diagnostic of metastatic disease

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20
Q

Analytical methods for CEA

A

Immunoassay
No reference method
WHO reference material 73/601

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21
Q

Limitations of the CEA assay ?

A

Interferences: Heterophile antibody, hook effect
Variation: increased in smokers (2x non-smokers)
Disease specific: poorly differentiated tumours do not secrete CEA, detectable in benign conditions (IBD, chronic liver disease), detectable in other malignant conditions (gastric, cervical, NSCC lung)

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22
Q

What to do about incidental increase in CEA?

A

Based on clinical findings.
Consider repeat test in 1 month - rise suspicious for malignancy.

23
Q

Performance of CEA for colorectal ca dx?

A

30% sensitive and 40% specific!

24
Q

What is calcitonin?

A

A 32 amino acid peptide derived from procalcitonin. Secreted by parafollicular C cells of the thyroid in response to high calcium. No physiological role in non-pregnant, non-lactating adults. Possibly aids with skeletal protection in pregnant/lactating F and infants (increased in these populations).

25
Q

Actions of calcitonin in supraphysiologic, therapeutic doses?

A

Inhibit bone resorption
Decrease renal calcium reabsorption
Reduce plasma calcium

26
Q

Indications for calcitonin therapy?

A

Hypercalcaemia of malignancy
Bone loss due to immobilisation
Paget’s disease

27
Q

Pre-analytical factors for calcitonin measurement

A
  1. Heparin plasma or serum (but confirm with manufacturer kit info)
  2. On ice
  3. Separate within 30 min of collection
  4. Freeze plasma/serum until analysis
28
Q

Indications for calcitonin measurement

A
  1. Dx MTC (in conjunction with ultrasound and FNAC)
  2. Monitor treatment response for MTC
  3. Prognosticate likelihood of tumour recurrence
  4. Screening of patients with FHx MTC
  5. Pentagastrin/calcium stimulation test for investigate familial MTC, MEN 2A and B or mildly raised calcitonin
29
Q

Utility of CEA in MTC?

A

Not useful early in diagnosis
Monitoring post-thyroidectomy
Evaluating disease progression in patients with MTC

30
Q

Analytical methods for calcitonin?

A
  1. Two-site two-step immunoassays for monomeric calcitonin
    a) Siemens Immulite and Diasorin Liaison CLIA
    b) DIAsource ELISA
    c) Roche Elecsys ECLIA
    d) DIAsource immunoradiometric assays
  2. Historically, competitive RIA
  3. No reference method but WHO reference material 89/620 exists
31
Q

Sources of error in calcitonin measurement?

A

Haemolysis, icterus, lipaemia
Heterophile antibodies
Macrocalcitonin
Monoclonal Ab therapy can interfere
Delayed sample handling
Hook effect (older IRMA methods)
Utilising different methods for serial measurement
F < M, however, method dependent
Low calcitonin does not exclude metastatic disease.

32
Q

Diagnostic threshold for calcitonin in MTC?

A

60-100 ng/L (method dependent)

33
Q

Utility of doubling time of calcitonin?

A

Monitoring progression of MTC
Disease recurrence
Prognosis

34
Q

Treatment of MTC?

A

Total thyroidectomy and central compartment node dissection

35
Q

How is calcitonin used in monitoring response to treatment?

A

Measure calcitonin 15 days post-surgery (at earliest) and see gradual decline over 2 months
Biochemical cure for MTC defined as normalisation of calcitonin levels post-surgery

36
Q

How is the pentagastrin/calcium stimulation test used in MTC?

A

When screening for familial MTC/MEN2A/B, if serum calcitonin normal and individual negative for RET gene. Delivery of calcium/pentagastrin promotes release of calcitonin from parafollicular C cells. Measure calcitonin at 0, 2, 5 and 7-10 min intervals. Exuberant response (calciotnin >250ng/L in F and 500ng/L in M) suggestive of MTC

37
Q

Biochemical tests prior to MTC surgery?

A
  1. Calcitonin
  2. CEA
  3. Calcium and PTH (hyperparathyroidism)
  4. Plasma mets (R/O phaeo)
  5. RET gene analysis
38
Q

Causes of increased calcitonin

A
  1. Thyroidal disorders:
    - MTC
    - C-cell hyperplasia
    - Autoimmune thyroiditis
  2. Non-thyroidal:
    - Renal failure
    - Hypercalcaemia (hyperparathyroidism)
    - Lung ca
    - Hypergastrinaemia
    - Neuroendocrine tumours
  3. Drugs
    - PPIs
    - Glucocorticoids
    - Beta-blockers
    - Glucagon
39
Q

Performance of calcitonin for MTC?

A

> 100ng/L 100% PPV for MTC
Calcitonin screening for detection of MTC sensitivity 70-80%, spec 96-100%

40
Q

Clinical applications of tumour markers

A
  1. Screening
  2. Diagnosis
  3. Prognostication
  4. Predicting treatment response
  5. Monitoring response
  6. Detecting progression/recurrence post-treatment
41
Q

Example(s) of tumour marker(s) used for screening

A

FOBT for population screening of CRC
Screening of high risk populations (eg molar preg) with HCG for choriocarcinoma

42
Q

Example(s) of tumour marker(s) used for diagnosis

A

AFP used as an adjunct to US for HCC dx in pts with cirrhosis.
CA125 together with US and menopausal status for calculating RMI to differentiate between benign and malignant pelvic masses

43
Q

Example(s) of tumour marker(s) used for assessing prognosis

A

AFP, HCG and LDH in determining chemotherapeutic options for metastatic nonseminomatous germ cell tumours.

44
Q

Example(s) of tumour marker(s) used for predicting treatment outcome

A

ER, PR and HER positivity in breast cancer determines response to hormonal/trastuzumab therapies

45
Q

Example(s) of tumour marker(s) used for monitoring short term treatment response

A

50% decrease in CA125 defines treatment response in ovarian ca.
Serial monitoring of CEA and CA19-9 in CRC pts with liver mets mirrors imaging 91-94% of the time, reducing the reliance on imaging studies and minimising radiation exposure for the patient.

46
Q

Example(s) of tumour marker(s) used for monitoring for progression/recurrence

A

In non-metatstatic CRC, CEA monitoring improves overall survival and increases detection of asymptomatic recurrence amenable to curative surgery.

47
Q

6 essential requirements to validate a proposed tumour marker, before bringing it into clinical use

A
  1. Proposed sample collection and processing
  2. Analytical/technical validation
  3. Clinical validation (performance characteristics - sensitivity, specificity, prevalence, PPV, NPV, ROC curve analysis, accuracy)
  4. Demonstration of clinical value (ideally by randomised control trial)
  5. Achieving regulatory approval
  6. Postmarket evaluation (of the analytical system by IQC and EQA, and of the clinical utility)
48
Q

Requirements of an ideal tumour marker

A
  1. Detectable only in a given malignancy and absent in the healthy population or in nonmalignant conditions (ie, with clinical specificity and clinical sensitivity approaching 100%).
  2. Present in a readily acquired biological matrix (eg, serum, urine, tumor tissue).
  3. Present at concentrations proportional to tumor burden.
  4. Conveniently measured by a readily available, simple, reproducible, and inexpensive procedure.
  5. Beneficial to clinical care with a measurable effect on patient outcome.
49
Q

Difference between screening and diagnosis

A

Screening occurs in asymptomatic, unselected population.
Diagnosis occurs in symptomatic individual and is confirmation of a suspicion of disease.

50
Q

Wilson and Junger criteria for screening tests (WHO)

A

Disease Characteristics:
1. Important public health problem
2. Serious disease
3. Recognisable early premalignant stage
4. Well understood natural hx
Screening Test Characteristics:
1. Accurate and reliable
2. Acceptable to screened population
3. Part of ongoing surveillance system
4. Repeated at intervals depending on natural hx of disease
Treatment Characteristics
1. Acceptable and beneficial treatment available
2. Early treatment more beneficial than later treatment
3. Appropriate facilities for diagnosis, treatment
4. Agreed policy about who to screen and treat
5. Chance of physical or psychological harm should less than benefit
Cost Efficacy
1. Cost balanced against benefit provided

51
Q

Tumour markers increased by CKD

A

CA125, CA 15-3, CEA, HCG

52
Q

Tumour markers increased in pregnancy

A

AFP, HCG, CA125

53
Q

What is an “equimolar” PSA method?

A

A method that recognises free and complexed PSA equally well

Analytes (15 decks)

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