W8 Tumour markers (MAH) Flashcards
What is the definition of a tumour marker?
“A tumour marker is anything present in or produced by cancer cells or other cells of the body in response to cancer or certain benign conditions that provides information about a cancer, such as how aggressive it is, whether it can be treated with a targeted therapy, or whether it is responding to treatment”
4 types of diagnostic markers?
- Enzymes and Proteins e.g. Fibrin/fibrinogen
-Bladder cancer, measured in urine to monitor progression and response to treatment - Hormones and Hormone Receptors e.g. Somatostatin receptor
-Neuroendocrine tumours affecting the pancreas or gastrointestinal tract (GEP-NETs), diagnostic imaging of Somatostatin receptor to help determine treatment - Genetic and Molecular Markers e.g. JAK2 gene mutation
-Present in some Leukemias’ mutation present in blood and bone marrow confirms diagnosis - Circulating Tumour Cells (CTCs) e.g. CTCs of epithelial origin (CELLSEARCH)
-Found in blood samples of metastatic breast, prostate, and colorectal cancers used to inform clinical decision making, and to assess prognosis
Enzymes and Proteins:
Prostate-specific antigen (PSA):
What is it used in?
- PSA is a protein produced by normal &
prostate cancer cells. - Low levels are normal, increases with age
proportional to prostate size - A raised PSA level may suggest prostate
issues, but not necessarily cancer. - 5-alpha-reductase inhibitors such as
finasteride (proscar®) or dutasteride
(avodart®), can reduce PSA levels and give
a false test result.
Enzymes and Proteins:
Carcinoembryonic antigen (CEA)
What ca are these elevated?
Elevated in colorectal, pancreatic, and certain other cancers
- Blood [CEA] does not reflect tumour size
- Initial testing, patients with smaller and early-
stage tumours [CEA] = low to normal - Patients with more advanced tumours, or
metastases = initially high [CEA] - Following treatment, normal [CEA] = tumour
removed BUT a steadily rising [CEA] indicates
relapse - CEA in blood will not indicate cancer type
- CEA levels may be raised in non-cancerous
conditions e.g. Liver disease and inflammatory
bowel disease
Hormones and Hormone Receptors:
Oestrogen and progesterone receptors:
breast cancer diagnosis and treatment
- These are Sex hormones that regulate menstrual cycles and play an important role in
pregnancy. - Increased number of cycles increases risk
due to the increased exposure to oestrogen - Giving birth, breastfeeding and age at puberty and menopause all influence risk of
breast cancer. - Likely to respond to anti-hormone
treatment (tamoxifen) but response is less
likely if the tumour is also HER-2 positive.
Extra info:
Human Epidermal Growth Factor Receptor 2, responds to signals from its environment. Normally HER2 is responsible for the
healthy growth and development of cells.
However, when the HER2 protein is overexpressed on the cell surface of breast
cancer cells this leads to abnormal cell division and growth
Hormones and Hormone Receptors:
Human chorionic gonadotropin (hcg): elevated in some testicular and ovarian cancers
- Glycoprotein produced in pregnancy by the
placenta»_space; presence in urine = pregnancy test - HCG can be secreted by abnormal germ cell,
placental or embryonal tissues especially
seminomatous and non-seminomatous testicular tumours (NSGCT), ovarian germ cell tumours, gestational trophoblastic disease (GTD -hydatiform mole and choriocarcinoma) and benign or malignant non-testicular teratomas. - Supports diagnostics, correlates with stage and patients’ risk, and helps to monitor response to the treatment or predicts disease relapse
During therapy, a falling hCG level generally indicates that a tumour is responding to treatment
Genetic and Molecular Markers:
Mutations in which genes is ‘Associated
with increased risk of breast and ovarian
cancer?’
=Mutations in BRCA1 and BRCA2:
* BRCA = BReast CAncer gene
* Tumour suppressor genes
* BRCA1 is associated with the increased risk
of breast cancer. BRCA2 increases the risk of
breast, ovarian, prostate, pancreatic,
gallbladder, bile duct and skin (melanoma)
cancers.
* Predictive genetic testing available for BRCA
positive families (>1,800 mutations)
Circulating Tumour Cells (CTCs):
Detection of CTCs aid in prognosis and
monitoring of cancer progression.
What are CTCs?
- CTCs = tumour cells that spread by gaining
access to peripheral blood - Cancer metastasis is the primary cause of
death worldwide - Metastasis is a multistep process:
intravasation, colorectal ca (CRC) in terms of survival prediction, anticipating chemotherapy
resistance, and surgical planning
What is a prognostic marker?
“A prognostic biomarker is a clinical or biological characteristic that provides information on the likely patient health outcome (e.g. disease recurrence, progression free and overall survival), irrespective of the treatment. It is measured before treatment and identifies tumour-specific molecular or histopathological characteristics that are associated with long-term outcome or disease course, and is not treatment dependent
PROGNOSTIC MARKERS 3 examples?
- HER2/neu: Predicts breast cancer prognosis and response to targeted therapy.
- Ki-67: Indicates proliferation rate and predicts cancer aggressiveness.
- B-Type Natriuretic Peptide (BNP): Prognostic marker for lung and other cancers.
Human epidermal growth factor receptor 2 (HER2) HER2/neu oncogene
- 30% of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product.
- Overexpression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis.
- Because of its prognostic role as well as its ability to predict response to trastuzumab (Herceptin) breast tumors are routinely checked for overexpression of HER2/neu.
- Overexpression also occurs in other cancer such as ovarian cancer, stomach cancer, and biologically aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma
HER2/neu is important as the target of the monoclonal antibody trastuzumab (marketed as Herceptin)
HER2 receptor family signalling (for info)
There are four members of the HER2 receptor family, these are the targets of lapatinib, neratinib, pyrotinib and tucatinib. The HER2 extracellular domain has no known ligand and is activated by the formation of homo or
heterodimers (exemplified by a HER2-
HER3 heterodimer in the figure). These
dimers lead to phosphorylation of tyrosine kinase residues in the cytoplasmic domain which function as docking sites for proteins that activate the PI3K and MAPK signaling pathways downstream leading to cell cycle
progression and proliferation.
Ki-67 index test
- The grade of a large bowel or rectal neuroendocrine tumour (NET) tells you how much the cancer cells look like normal cells under a microscope.
- The Ki-67 or mitotic index are ways of describing how many cells are dividing
- A stain measures the Ki-67 value by counting % of cells undergoing mitosis thus actively proliferating
- UK uses WHO grading 1 to 3
- The grade of your cancer helps your doctor decide which treatment you need.
- Grade 1: The cells look normal. Tumours are usually slow growing and less likely to spread. -Ki-67 index of 2% or lower
This is a grade 1 NET (WD NET G1) - Grade 2: less normal in appearance; moderately differentiated tumours.
- Ki-67 index between 3% and 20%
This is grade 2 NET (WD NET G2). - Grade 3: cells look abnormal. They tend to grow quickly and are more likely to spread.
-Ki-67 index higher than 20%
This is either a grade 3 NET (WD NET G3) or a
neuroendocrine carcinoma (PD NEC G3).
PREDICTIVE TUMOUR MARKERS
What do they indicate?
2 types?
Predictive markers in oncology are features that indicate sensitivity or resistance to a specific type of therapy
- Epidermal Growth Factor Receptor (EGFR) Mutations: Predict response to EGFR inhibitors in lung cancer.
- Anaplastic Lymphoma Kinase (ALK) Rearrangements: Guide targeted therapy in non-small cell lung cancer.
They are used to help deterine treatments and prognosis.
What are the Limitations of cancer cell markers? (5)
- Poor sensitivity and specificity – screening not possible
- Lack specificity to tumour type
- Many are endogenous and altered in non-cancerous conditions
- Expression/mutation etc may not be altered in all patients with the same cancer
- Some cancers (to date) lack specific tumour marker
