Types:
- Hormones:
- hCG
- Calcitonin
- Gastrin
- Prolactin
- Enzymes:
- Acid phosphatase
- Alkaline phosphatase
- PSA
- Metabolites
- Norepinephrine
- Epinephrine
- Normal proteins
- Thyroglobulin
- Oncofetal antigen
- CEA
- AFP
- Receptors
- ER
- PR
- EGFR
- Genetic changes
- Mutations
- Translocations
Ideal Tumour Marker:
- Specificity for a single type of cancer
- High sensitivity and specificity for cancerous growth
- Correlation of marker level with tumour size
- Homogenous (i.e. minimal post-translational modifications)
- Short half-life in circulation
Roles:
- Determine risk (PSA)
- Screening (Calcitonin, occult blood)
- Diagnosis (hCG, Catecholamines
- Estimate prognosis (CA125)
- Predict response to therapy (CA15-3, CA125, PSA, hCG)
- Monitoring for recurrence/progression (most widely used role)
- Therapeutic seleciton (her2/neu, kras)
Tumour markers in routine use
| Marker | Cancer |
|---|---|
| CA 15-3, 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 | Pheochromocytoa |
| Fecal occult blood | Colon cancer |
Normal Serum Levels
AFP:
- Hepatocellular carcinoma
- Germ cell tumors
- Non-seminomas: both AFP and hcG elevated in 90%
- Seminomas: AFP not elevated, hCG elevated in 30%
- Not directly related to tumour size
- Elevated in pregnancy, liver disease (hepatitis, cirrhosis, GI tumours)
- AFP tumour-specific glycoforms may improve specificity of AFP for HCC
CEA:
- CEA 150-300 kDA glycoprotein
- Elevated in smokers and elderly
- Elevated in breast, pancreatic, GI and lung cancer
- Breast cancer: used for detecting and monitoring metastatic disease
- Elevated in benign diseases: cirrhosis, emphysema and rectal polyps
- CEA: Not useful for CRC screening
- New more specific marker for CRC: TIMP-1 (Tissue inhibitor of metalloprotease)
CA 15-3/CA 27.29
- High molecular weight glycoprotein (Polymorphic epithelial mucin)
- Breast cancer marker:
- Correlate with stage and tumor size
- Prognosis and 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 and breast
- Elevated in other cancers: pancreatic, lung, ovarian, colorectal and liver
CA 125
-
200-2000 kDa glycoprotein
- Increased in benign diseases: pregnancy, endometriosis, ovarian cysts, PID, cirrhosis, hepatitis, pericarditis
- Increased in other cancers: lung, breast, GI, endometrial and pancreatic
- Synthesis modified by Taxol
Cytokeratin fragment 21-1
- Cytokeratins are intermediate filament structural proteins found in cytoskeleton of epithelial cells
- Increased CYFRA 21-1 seen in all histologic types of lung cancer but especially NSCLC
- CYFRA 21-1 is used for diagnosis, prognosis and monitoring after chemotherapy
- May be increased in benign respiratory disease, urological, gastrointestinal and gynaecological cancers
Thyroglobulin:
- Monitoring of the recurrence or metastasis of differentiated thyroid cancer (papillary/follicular)
Prostate specific antigen
-
PSA Forms/measurements:
- 55-95% PSA complexed with antichymotrysin (PSA-ACT)
- 5-45% free PSA (fPSA)
- Total PSA=fPSA +PSA-ACT
-
Total PSA ranges:
- 0-4 ng/mL = Low risk of PCA (22% positive)
- 4-10 ng/mL = diagnostic gray zone (PCA & BPH)
-
10 ng/mL = 40-50% with PCA
Enhancing Differential Diagnosis PCA – PSA velocity – increases over time – % fPSA – PSA density – tPSA/prostatic volume – Age-race- adjusted reference ranges
Free PSA (fPSA) • Unbound portion of PSA is inversely related to probability of prostatic carcinoma • Differentiation from carcinoma and BPH
When the total PSA is between 4 and 10 ng/mL:
| %Free PSA | Probability of carcinoma |
|---|---|
| 0 - 10 | 56% |
| 10 - 15 | 28% |
| 15 - 20 | 20% |
| 20 - 25 | 16% |
| > 25 |
Prostate specific antigen clinical applications
- Early detection in conjunction with DRE
- PSA >10 ng/mL with +DRE = Biopsy
- PSA 4-10 ng/mL and –DRE = Biopsy
- Determine success of radical prostatectomy
- Recurrence following treatment
- Monitoring hormonal treatment
Genetic tumor markers and disease:
Oncogenes:
- N-ras: leukemia
- K-ras: colon/ gastric
- C-erB-2: Breast/gastric
- N-myc: Breast/Neuro
- c-abl/bcr: CML
- bcl-2: leukemia/lymp
- HER-2/INT2/ATM/
- H-ras: Breast
- MCC: colon
Tumor Suppressors:
- p53: Breast/colon/lung
- RB1: Retinoblastoma
- WT1& 2: Renal
- BRCA1& 2: Breast/
- pancreatic/Ovarian
- BRCA1:prostate/stom.
- APC: Colorectal
- MTS1: Melanoma
- DCC: colon/gastric
Estrogen and progesterone receptors
- ER positive have more favorable prognosis within first 5 y after diagnosis
- Hormone therapy blocks binding of estrogen to estrogen
receptors:
- Block receptor using tamoxifen or aromatase inhibitors
- 60% of patients with primary tumors with ER/PR respond to hormone therapy
- ER/PR measured in tumor tissue by immunohistochemistry or ELISA (tumor tissues)
HER-2/neu (c-erbB-2)
- 185 kDa tyrosine kinase growth factor receptor
- Gene amplification/overexpession occurs in 30% patients & correlates with aggressive disease & shortened survival
- Moderate negative predictive factor for response to endocrine therapy or alkylating agents
- Strong predictive factor for response to trastuzumab (Herceptin)
- Methods approved by FDA: FISH and IHC
- 3+ : Positive
- 2: FISH
- 0/1: Negative
Other companion diagnostic tests:
| Biomarker | Drug | Cancer |
|---|---|---|
| Her2.neu | Trastuzumab | Breast ca |
| KRAS | Cetuximab, panitumumab | Colorectal |
| BRAF | Vemurafenib | Melanoma |
| ALK Fusion | Crizotinib | NSCLC |
| EGFR | Gefitinib, erlotinib | NSCLC |
| BCR-ABL translocation | Imatinib, dasatinib, nilotinib | CML |
RT-PCR for circulating tumor cells
- Prostate Cancer: PSA, PSMA
- Breast Cancer: Cytokeratin 19, CEA, MUC1, hMAM
- Melanoma: Tyrosinase, MART1, MAGE3, GAGE
mRNA Microarrays
- Large mRNA and DNA arrays (Affymetrix, Illumina) enable unfocused genomic signature analysis.
- Oncotype DX and Mamaprint enable prediction of therapeutic success in breast cancer.
- Tumor of Origin enables identification of the tissue origin of metastasis.
Oncotype Dx:
- 16 Cancer and 5 Reference Genes
- Proliferation:
- Ki-67
- STK15
- Survivin
- Cyclin B1
- MYBL2
- Estrogen:
- ER
- PR
- BCL2
- SCUBE2
- HER2:
- GRB7
- HER2
- INVASION:
- Stromelysin 3
- Cathepsin L2
- GSTM1
- BAG1
- CD68
REFERENCE GENES
- Beta-actin
- GAPDH
- RPLPO
- GUS
- TFRC
| Category | RS (0-100) |
|---|---|
| Low risk | RS <18 |
| Int risk | RS ≥18 and <31 |
| High risk | RS ≥31 |
Cancer Genomics Examples:
