Non-small cell lung cancers Flashcards
NSCLC - 3 groups (3)
adenocarcinoma
squamous cell carcinoma
large cell carcinoma
NSCLC Characteristics (5)
- accounts for 80-85% of all lung cancers
- Seen in smokers and non-smokers
- Less aggressive.
- 5-year survival rate of 23% prognosis
- More responsive to targeted therapies (relatively insensitive to chemo)
Histology (5)
- Arises from the epithelial cells of the lung or of the central bronchi to terminal alveoli
- grown more slowly than other cancers
- The histological type correlates with site of origin.
- Adenocarcinoma usually originates in peripheral lung tissue.
- Squamous cell carcinoma usually starts near a central bronchus (lungs or either bronchi)
Adenocarcinoma
the most common form of lung cancer among both men and women.
Usually originates in peripheral lung tissue
Squamous cell carcinoma
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
Staging: TNM system (4)
Stage I: <3cm, N0, M0
Stage II: 3-7cm, N1, M1
Stage III: >7cm, N2, M2
Stage IIII: Invasion, N3, M3
based on TLM - Tumour size, Lymph Node and Metastasis
What are the 2 most common altered genes in NSCLC? (2)
EGFR and BRAF
Mechanisms of NSCLC development (and treatment) (5)
Crizotinib or 2nd generation ALK inhib - loads- ALK fusion
Numerous clinical trials using Mek or other pathway inhib’s in combination -KRAS
chemo or immuno -NONE
dabrfenib, tramentib, vemurafenib -BRAF
erlotinib, gefitinib, afatinib, osimertinib-EGFR
treatment (8)
- Chemotherapy (when no known driver mutation)
- Radiotherapy
- Surgery
- Targeted treatments (BRAF, EGFR, ALK fusion)
- EGFR antagonists
- BRAF inhibitors
- ALK inhibitors
- Anti-angiogenics (in combination)
EGFR (6)
- 10-20% NSCLC
- Mutations in EGFR gene cause protein/receptor overexpression or permanent activation
- Most common forms: del19 or exon 21 mutation (L858R).
- Associated with a worse prognosis
EGFR MoA (3)
- HER1/EGFR gene encodes for part of the human epidermal growth
factor receptor - Receptor function requires receptor dimerization and growth factors
binding (take ATP p-> transfer to Tyrosine kinase) - effectors = PI3K, RAS(RAF>MEK) : leads to prolif, apop, invasion + angio
EGFR tyrosine kinase inhibitors (TKIs) MoA
Iressa (geftinib) and Tarceva (erlotinib) - work by binding to ATP = prevent it’s interaction (phosphory of effectors)
EGFR trials (2)
- 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 dissapointments (5)
- 10% of patients treated with either erlotinib or gefitinib were dramatic responders (mutations in EGFR gene - that are associated w/ drug insensitivity)
- Females
- Adenocarcinoma
- Asian ethnicity
- Non-smokers
EGDR mutations sensitivity (2)
There are mutations associated with drug sensitivity and others with drugs resistance - thus geftinib and erlotinib sensitivity
T790M is the most common mechanisms of resistance to EGFR TKI (60-70%)
Osimertinib (4)
- 3rd generation EFGR inhibitor
- 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
Erlotinib vs standard chemo
Median Progression Free Survival was 9·7 months in the erlotinib group, compared with 5·2 in the standard chemotherapy group (p<0·0001)
= most efficient treatment in EGFR gene as log as they don’t carry the mutation
Anti-EGFR mAbs (3)
now include: cetuximab, necitumumab, panitumumab and matuzumab
- Competitive inhibition of ligands binding to the extracellular domain instead of intracellular
- Also form antibody-receptor complexes that are endocytosed and degraded
BRAF (4)
-BRAF gene encodes for a serine/threonine kinase that belongs to the RAS-RAF-MEK-ERK axis that regulates cellular growth
- 3 domains: CR1/2/3
- BRAF mutations in up to 2-3% of the NSCLC patients
- BRAF V600E account for 50% of the cases and affects to kinase domain (CR3)
- responds well to kinasei combined w/ or w/o MEKi
Sorafenib and vemurafenib (2)
-kinase inhibitors that target oncogenic BRAF (primary kidney, liver cancers + sometimes leukaemia)
- Efficient in melanoma but partial response in NSCLC
ALK fusion oncogene: EML4-ALK (4)
Result of an inversion in chromosome 2p = fusion of the N-terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) with the kinase domain of ALK (anaplastic lymphoma kinase)
- 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
Crizotinib (3)
Competes binding within the ATP-binding pocket of ALK
- small molecule inhib
- = doesn’t allow protein to phosphorylate substrates/effectors
= tumour disappears after 2 rounds w/ this
VEGF-VEGFR (2)
Allows and controls angiogenesis in tumours
Avastin (2)
-Bevacizumab (Avastin®) is a monoclonal antibody that binds to VEGF and prevents its binding to VEGF receptors on endothelial cells = tumour cells starved + cannot grow
-Avastin approved for metastatic non squamous non-small cell lung
cancer in combination with platinum chemotherapy
Progress in genomics: tissue is the issue. What are the challenges? (4)
- Location of tumour: lung tumours are often difficult to access.
- Biopsy: need sample of sufficient size and quality to isolate DNA
- Pre-analytical phase must be standardised.
- Difficulty in obtaining adequate samples (i.e. size and quality of specimen)
alternative???
liquid biopsies
Summary (5)
- 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)
