lung cancer SD Flashcards
RF for lung cancer
cigarette smoking
passive smoking
occupational
- asbestos
- ionising radiation
- occupational RF
- air pollution
genetic predisposition
previous malignancies
genetic RF - old age, obesity, poor diet, physical inactivity, alcohol
Sx
chest discomfort/pain
trouble breathing
wheezing
blood in sputum
hoarseness
trouble swallowing
loss of appetite
weight loss for no reason
very tired
cough thatdoesn’t go away/worse over time
swelling in face/veins in neck
scans that can be used
x-ray
CT scan
PET-CT scan (positron emission tomography)
What scan is used to locate mass in a lung?
CT
PET-CT
bronchoscopy
- bronchoscope inserted through nose/mouth into trachea and lungs
- biopsy can be taken from lung for analysis
classifications of lung cancer
SCLC
NSCLC
small cell lung cancer
- mostly caused by smoking
- highly maligant
- spreads rapidly
- metastases when diagnosis made
- located in central airway
- tumours smaller in size compared to NSCLC
non-small cell lung cancer types
most common types:
- squamous cell carcinoma
- adenocarcinoma
- large cell cancers
squamous cell carcinoma
cancer in epithelial cells lining the lungs
typically in central portion of the lung and in airways
adenocarcinoma
- tumour originated from bronchial/alveolar epithelium
- most common type of LC in women who ever smoked
large cell cancers
- originate in larger cells of the lungs
- peripherally located
- eg. large clear cells
staging of lung cancer tumour
stage 1: <3cm, not spread, small
stage 2: 3-5cm, in lymph nodes in lungs,
stage 3: 5-7cm, in lymph nodes away from primary tumour, other organs/tissues, invading into chest wall/breast bone
stage 4: >7cm, spread to other lung, in many lymph nodes, metastasised to ANOTHER ORGAN
What are micro metastases?
metastses in another organ that can’t be seen on x-ray or CT scan
don’t have eough biomarkers yet
What can be used to diagnose LC if pathology not clear?
IHC - immuno histo chemistry
What are paraneoplastic syndromes assocated with LC?
secondary effetcs of the cancer
producing chemicals and hormones
paraneoplastic syndromes with LC
- ADH: inducing HYPONATRAEMIA
- ACTH: CUSHING syndrome
- parahormone, PTH related peptide, PGE, cytokines: HYPERCALCAEMIA
- calcitonin: HYPOPCALCAEMIA
- gonadotropins: GYNECOMASTIA
- serotonin, bradykinin: CARCINOID syndrome
common oncogenes in LC
KRAS
EGFR
tumour suppressor genes that are lost in LC
p53
RB1
p16
multiple loci on chromosome 3 (lots of tumour suppressor genes)
% of cases p53 lost in SCLC and NSCLC
SCLC 90%
NSCLC 50%
most prominent genetic alteration in LC
EGFR mutations
targeted therapies in NSCLC to target EGFR?
EGFR inhibitors
-> TKIs
How does EGFR drive cancer growth?
- activated oncogene
- drives cancer growth
- decreases apoptosis
- increased angiogenesis
TKIs and MAB used in NSCLC
Erlotinib
Gefitinib
Osimertinib
Cetuximab (MAB against EGFR)
How does cetuximab work?
- binds to outside of EGFR
- stops EGFR from dimerising
- inhibits KRAS
- slows down EGFR signalling & cellular growth
- leads to cell apoptosis
When does cetuximab become ineffective?
- if there’s mutant KRAS
- it becomes ineffective
- cancer cell will survive and proliferate
1st line Tx for NSCLC
- initially cetuzimab
- when that fails use TKIs
- 1st TKI = erlotinib
How does erlotinib work?
- TKI
- prevents EGFR phosphorylation
- inhibits MAPK
- tumour regression
- resistance in 10-14 mths
What mutation causes erlotinib resistanace?
T790M mutation
Where does T790M mutation occur?
in the ATP binding pocket
most common cause for TKI resistance (erlotinib, gefitinib, afatinib)
T790M mutation
Tx for T790M mutation
- Osimertinib (Targrisso)
- can bind to EGFR T790M
- binds to the mutated R
advantage with Osimertinib (Tagrisso)
- doesn’t bind to WT (wild type) EGFR
- only effects cancer cells and not normal cells
What type of drug is Osimertinib (Tagrisso)
irreversible EGFR-TKI
resistance mechanisms to Osimertinib (Tagrisso)
- MET-amplification
- EGFR C797S mutation
- HER2-amplification, PIK3CA and RAS mutations
EML4-ALK marker in NSCLC
ALK - R
EML - structural protein
NSCLC: genetic mutation activates ALK, leads to hyperphosphorylation & activation
genetic change forms a fusion protein:
- ALK fuses to EML4
- EML4-ALK fusion protein drives the protein fxn
EML4-ALK activates proliferation
-> 2 separate genes forming 1 gene
problem with EML4-ALK fusion protein
- it bypasses EGFR blockade
- inc proliferation and cell cycle
- dec apoptosis
TKI to target EML4-ALK
Crizotinib
Alectinib
drug used in LC if it has Ras mutation (G12C mutation)
Sotorasib (Ras inhibitor)
examples of immunotherapy that inhibit PD1 and activate the immune system to attack tumours producing antigens
Pembrolizumab (Keytruda)
Nivolumab (Opdivo)
Why can tumour cells express PD1?
to suppress T cells
PD-L1 inhibitors in LC
- tumour cells express PD-L1 to suppress T cells (PD-1 on T cell)
- PDL = programme death ligand
- PD-L1 inhibitors bind to PD-L1 and stop it binding to T cell
- activate immune system to attack tumours
