Non small cell lung cancers Flashcards
NSLC characteristic
Non-Small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers.
Seen in smokers and non-smokers.
Less aggressive.
5-year survival rate of 23%.
More responsive to targeted therapies (relatively insensitive to chemo).
Arises from the epithelial cells of the lung or of the central bronchi to terminal alveoli.
The histological type correlates with site of origin.
Adenocarcinoma usually originates in peripheral lung tissue.
Squamous cell carcinoma usually starts near a central bronchus.
they begin in squamous cells- thin flat cells which look like fish scales when seen under the microscope
Histology of each type
Adenocarcinoma is the most common form of lung cancer among both men and women. Usually originates in peripheral lung tissue.
Squamous cell carcinoma (which is also called epidermoid carcinoma) forms in the lining of the bronchial tubes.
Large cell carcinomas refer to NSCLC that are neither adenocarcinomas nor squamous cell carcinoma.
Mechanisms of development
Mutations can be in
BRAF- dabrafenib, trametinib
EGFR- erlotiib gefitinb afatinib KRAS
KRAS doesn’t have targeted therapies atm. Numerous clinical trials using inhibitors of MEK and other pathways in combination
If no mutation present or KRAS, can use chemotherapy or immunotherapy
Treatment overview
Chemotherapy (when no known driver mutation) Radiotherapy Surgery Targeted treatments EGFR antagonists BRAF inhibitors ALK inhibitors Anti-angiogenics (in combination)
EGFR mutations and what can be done
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
- EGFR tyrosine kinase inhibitors (TKIs): Iressa (geftinib) and Tarceva (erlotinib)
Initial results of phase 2 trials testing erlotinib and gefitinib in unselected patients were modestly positive but disappointing.
BR.21 Phase III: 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 BR.21 study, 10% of patients treated with either erlotinib or gefitinib were dramatic responders Females Adenocarcinoma Asian ethnicity Non-smokers
- T790M is the most common mechanisms of resistance to EGFR TKI (60-70%).
3rd generation EFGR inhibitor: osimertinib.
Irreversibly binds to C797 in the ATP binding
site.
Well tolerated in clinical trials.
Approved for first and second line use, including
after resistance mediated by T790M mutations.
Anti-EGFR mAbs now include cetuximab, necitumumab, panitumumab and matuzumab
Competitive inhibition of ligands binding to the extracellular domain
Also form antibody-receptor complexes that are endocytosed and degraded
BRAF gene mutations in causing NSCLC
BRAF gene encodes for a serine/threonine kinase that belongs to the RAS-RAF-MEK-ERK axis that regulates cellular growth.
BRAF mutations in up to 2-3% of the NSCLC patients.
BRAF V600E account for 50% of the cases and affects to kinase domain.
Sorafenib and vemurafenib are kinase inhibitors that target oncogenic BRAF.
Efficient in melanoma but partial response in NSCLC.
ALK fusion oncogene: EML4-ALK
Present in 4% of patients with NSCLC.
Typically younger non-smokers lacking mutations in either EGFR and KRAS.
Crizotinib compete binding within the ATP-binding pocket of ALK.
Result of an inversion in chromosome 2p, which results in the fusion of the N-terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) with the kinase domain of ALK (anaplastic lymphoma kinase).
ALK acts on proto oncogene
fuses with eml4
fusion acts as an onocgene
fusion results in constitutive kinase activity causing carcinogenesis
Treatment for ALK fusion oncogene mutations
Crizotinib competes binding within the ATP-binding pocket of ALK.
Normally there is proliferation and survival upon binding to ALK
Permanent proliferation and inhibition of apoptosis
EML4-ALK fusion protein silenced by cirzotinib
Effect of blocking VEGF- VEGFR interactions
VEGF binds receptor allows activation of blood vessels that enables tumour cells to grow and expand, expanding to other regions to metastise
Bevacizumab (Avastin®) is a monoclonal antibody that binds to VEGF and prevents its binding to VEGF receptors on endothelial cells.
as a result tumour cells are starved and can’t grow s they can’t receive nutrients and oxygen
Avastin approved for metastatic non squamous non-small cell lung cancer in combination with platinum chemotherapy- ie for adenocarcinoma
Why use lipid biopsies
tumours are heterogenous- the moelcular sites of the primary tumour may not represent the rest of the sites in metastasis
so we can overcome this in liquid biopsies
these are alternatives to traditional biopisies- which have problems of sample size and heterogeneity
allow us to see molecular profiles of individual tumours
NSCLC summary
Non-Small Cell Lung Cancer (NSCLC) is any type of epithelial lung cancer other than small cell lung cancer (SCLC).
NSCLC develops in smokers and non-smokers and shows better prognosis.
The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma.
The most frequently altered genes in NSCLC are KRAS, EGFR and BRAF.
NSCLC are responsive to targeted therapies such as erlotinib (EGFR), sorafenib and vemurafenib (BRAF), crizotinib (ALK fusion oncogen) and bevacizumab (anti-angiogenic therapy).
