Define the term cancer biomarker
A substance or process that is indicative of the presence of cancer in the body
What are the uses of cancer biomarkers in practice?
- Prediction (response to treatment)
What are the categories of biomolecules that can be cancer biomarkers
What are the genetic cancer biomarkers?
- DNA mutations
- mRNA expression
What are the epigenetic cancer biomarkers?
- DNA methylation
- Histone methylation
- miRNA gene silencing
What are the proteomic cancer biomarkers?
- Protein levels
What are the glycomic cancer biomarkers?
What sources can be tested for cancer biomarkers?
- Fine-needle aspirates
- Fresh tissue
- Frozen tissue
What are the features of an ideal cancer biomarker?
- Reflect kinetics
- Minimally invasive
- Clinical importance
What should a cancer biomarker be specific to?
- Disease type
- Disease stage
How sensitive should the ideal biomarker be?
Ideally should detect a single molecule
What should the ideal biomarker be predictive of?
- Treatment response
What factors are considered when deciding if a biomarker is robust?
What features must biomarkers have if they are to be used for cancer screening?
- Must be highly specific
- Must be able to clearly reflect different stages of the disease
- Must be easily detected without complicated medical procedures
- Method of screening must be cost effective
Why must cancer biomarkers used for screening be highly specific?
To minimise false positives and negatives
What markers are good targets for application of early screening?
Markers released to the serum and urine
What is prostate specific antigen produced by?
Epithelial cells of the prostate
What levels of PSA are considered suspicious?
What is required when PSA is 4-10ng/ml?
How is PSA used in risk stratification?
Used to stratify patients into low, intermediate, or high risk for having/developing metastatic disease, or dying of prostate cancer. It is used in conjunction with two other parameters - grade (Gleason grading) and stage (imaging)
Where is HPV detected?
Almost all cases of cervical cancer
How are cervical cells collected?
Using a Pap smear
Who is screened for cervical cancer in the UK?
Women aged 25 to 64 years - 25-49 years screened every 3 years, 50-64 screened every 5 years
How is cancer traditionally diagnosed?
Using tissue biopsy, on which immunohistochemistry and pathological evaluation are performed
What is the problem with using biopsy to diagnose cancer?
- Highly invasive
Define diagnostic biomarkers
Substances that are produced by cancer, or by other cells of the body, in response to cancer or certain benign conditions.
Are tumour markers made by normal cells?
Most are, however are produced much higher levels in cancerous conditions
Give 6 examples of diagnostic biomarkers
- Alpha-fetoprotein in liver cancer
- Cancer antigen 125 in ovarian cancer
- CA15-3 in metastatic breast cancer
- Carbohydrate antigen 19-9 in colorectal cancer
- Carcinoembryonic antigen in pancreatic cancer
- Prostate specific antigen in prostate cancer
Give an example of a genetic diagnostic biomaker
BCR-ABL in CML (chronic myelogenous leukaemia)
What % of patients with CML harbour a BCR-ABL translocation?
What drug targets BCL-ABL?
What is a prognostic biomarker?
Indicates the likely course of the disease in an untreated individual
What is the purpose of a predictive biomarker?
It identifies subpopulations of patients who are most likely to respond to a given therapy
Why are predictive biomarkers clinically useful?
- Predictive biomarker driven cancer therapy reduces the unnecessary treatment and adverse effects
- Can quickly highlight acquired resistance to therapy
Why is it important to reduce unnecessary treatment and adverse effects?
- Safer - Certain chemotherapy regimens result in death rates in the range of 0.5-2.0%, and 30-40% patients experience grade 3 or 4 toxic effects
- More clinical benefit
- More cost effective
Give three examples of predictive biomarkers
- ERBB2 amplification
- ECFR mutation
- BRAF mutation
What is ERBB2 mutation a marker for?
Highly aggressive breast cancers
What is ERBB2 amplification targeed by?
What is mutated EGFR indicative of?
Response to erlotinib in NSCLC
What is BRAF mutation indicative of?
Response to vemurafenib in metastatic melanoma
What is cell free DNA derived from?
- Active secretion
When are elevated levels of cell free DNA seen?
In tumour cell turnover
What somatic alterations might occur in cell free DNA?
- Point mutations
- Structural rearrangements
- Methylation of DNA
Give an example of where cell free DNA can be used as a prognostic biomarker
ESR1 mutations in metastatic breast cancer
What prognostic information can be determined from the presence of ESR1 cell free DNA?
- Those with the mutation who had prior exposure to AIs are resistant to therapy
- Reduced progression free survival in ES1 mutation positive patients
How do circulating tumour cells (CTCs) get into the bloodstream?
They are shed
What is the clinical use of CTCs?
- Can be prognostic and predictive
- Extremely useful monitoring tool
What is the problem with circulating CTCs as a clinical tool?
- Difficult to isolate
What tools can be used to analyse CTCs?
- Expression analysis
- Cell culture
What can circulating miRNAs be used as?
- Diagnostic biomarkers
- Prognostic biomarkers
- Predictive biomakers
What are the applications of miRNAs as diagnostic biomarkers?
- Monitor asymptomatic high-risk individuals
- Identification of early-stage cancer
- Discriminate between benign and malignant disease
What are the applications of miRNAs as prognostic biomarkers?
- Predict disease outcome
- Predict progression-free and overall survival
- Discriminate between benign and malignant disease
What are the applications of miRNAs as predictive biomakers?
- Monitor sensitivity to therapy and therapy response
- Aid treatment decisions