Non small cell lung cancer Flashcards
describe some characteristics of NSCLC
- Non-Small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers (Small cell lung cancer (SCLC) accounts for 15-20% of all lung cancers)
- Seen in smokers and non-smokers.
- Less aggressive than SCLC
- 5-year survival rate of 23%.
- More responsive to targeted therapies (relatively insensitive to chemo) than SCLC.
where does NSCLC typically arise from?
Arises from the epithelial cells of the lung or of the central bronchi to terminal alveoli
The histological type correlates with the site of origin. Therefore, where does adenocarcinoma and squamous cell carcinoma originate from?
Adenocarcinoma usually originates in peripheral lung tissue.
Squamous cell carcinoma (which is also called epidermoid carcinoma) forms in the lining of the bronchial tubes.
which is the most common form of lung cancer?
Adenocarcinoma is the most common form of lung cancer among both men and women.
what do large cell carcinomas refer to?
Large cell carcinomas refer to non-small cell lung cancers that are neither adenocarcinomas nor epidermoid cancers.
describe the staging of NSCLC using the TNM system
unlike small cell lung cancer, which is staged into limited or extensive: NSCLC is staged into stage 1, stage 2 and stage 3
what does TNM stands for?
T: size of the primary tumour
N: Status of the lymph node
M: metastasis presence
describe some of the mechanisms of NSCLC development
- Treatment decision for NSCLC patients has been historically based on the tumour histology classification
- However, with the novel sequencing technologies= we can extract the molecular profile of the tumours and create a gene list that are present in the effective patients
- NSCLC present KRAS mutations in many cases, followed by alterations in the EGFR gene–>BRAF gene–. other genes
- Almost all these genes are targetable
- Only problem: no targetable treatment for KRAS mutations but there lots of clinical trials testing inhibitors of MEK and other pathways where KRAS is involved
- EGFR: Erlotinib, gefitinib, afatinib, osimertinib
- BRAF: Dabrafenib, trametinib, vemurafenib
Going to focus on ALK oncoprotein fusion, BRAF and EGFR mechanisms of NSCLC and its treatment
what are the treatment strategies for NSCLC?
• Chemotherapy (when no known driver mutation) • Radiotherapy (in patients with no receptable disease--> local control can be achieved) • Surgery • Targeted treatments: EGFR antagonists BRAF inhibitors ALK inhibitors Anti-angiogenics (in combination)
describe the association of EGFR and NSCLC
- 10-20% NSCLC
- Mutations in EGFR gene cause protein/receptor overexpression
- Most common forms: del19 or exon 21 mutation (L858R)
- Associated with a worse prognosis
- HER1/EGFR gene encodes for part of the human epidermal growth factor receptor
- Receptor function requires receptor dimerization and growth factors binding
what can be used to predict non-responsiveness to molecular targeted therapies such as EGFR inhibitors?
KRAS is used and serves as a predictor of non-responsive to molecular targeted therapies such as EGFR inhibitor–> therefore when they’re mutated at the same time= useless to target EGFR as patient won’t respond to targeted therapy
describe EGF-EGFR signaling
- All the downstream pathways that are controlled by the activation of the EGF receptor
- EGFR acts as a tyrosine kinase: in the intracellular domain there is tyrosine kinase activity
- Tyrosine kinase activity includes phosphorylating its effectors’ tyrosine residues. For this phosphorylation it requires an ATP molecule (ATP–>ADP…uses phosphate group to phosphorylate tyrosine amino acid of its effectors)
- Tyrosine kinase activity of EGFR is within the intracellular domain–> the phosphorylation of downstream effectors causes the activation of so many pathways/signalling cascades that are going to control the cell proliferation, apoptosis, invasion and angiogenesis etc.
Name and describe some EGFR tyrosine kinase inhibitors (TKIs)
Iressa- commercial name (gefitenib) and Tarceva-commercial name (erlotinib)
- Initial results of phase 2 trials testing erlotinib and gefitinib in unselected patients were modestly positive but disappointing.
- BR.21 Phase III:erlotinib–> Median survival 6.7 vs 4.7 months, 8.8% response rate. Led to FDA approval of erlotinib as second/third line treatment after chemotherapy in NSCLC.
In BR.21 study, 10% of patients treated with either erlotinib or gefitinib were dramatic responders (responded really well) • Females+ • Adenocarcinoma + • Asian ethnicity + • Non-smokers
= they found they had a different type of mutation–> affecting the EGFR gene
There are mutations associated with drug sensitivity and others with drugs resistance i.e. patients that have the EGFR gene, don’t respond to erlotinib as they present some mutations that confer some resistance to the drug… one of the mutations is the T7090M
what is the difference between phase 2 and phase 3 clinical trials?
Phase II: try to find the main side effects of the treatment from the studied drug and its efficiency (no comparison of new treatment with gold standard treatment. Sample size is also smaller.
Phase III: larger sample than phase II (100s-1000s of patients), compare the new treatment with the traditional treatment (erlotinib vs chemotherapy)
what is T790M?
T790M is the most common mechanisms of resistance to EGFR TKI (60-70%) THEREFORE there is a need to find another treatment (third generation tyrosine kinase inhibitor that binds to the receptor even when there is T790M)
