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Cardio/Resp > Non-small cell lung cancers > Flashcards

Non-small cell lung cancers Flashcards

1
Q

NSCLC - 3 groups (3)

A

adenocarcinoma
squamous cell carcinoma
large cell carcinoma

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2
Q

NSCLC Characteristics (5)

A
  • 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)
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3
Q

Histology (5)

A
  • 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)
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4
Q

Adenocarcinoma

A

the most common form of lung cancer among both men and women.
Usually originates in peripheral lung tissue

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5
Q

Squamous cell carcinoma

A

also called epidermoid carcinoma
Forms in the lining of the bronchial tubes

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6
Q

Large cell carcinomas

A

refer to NSCLC that are neither adenocarcinomas nor squamous
cell carcinoma

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7
Q

Staging: TNM system (4)

A

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

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8
Q

What are the 2 most common altered genes in NSCLC? (2)

A

EGFR and BRAF

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9
Q

Mechanisms of NSCLC development (and treatment) (5)

A

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

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10
Q

treatment (8)

A
  • Chemotherapy (when no known driver mutation)
  • Radiotherapy
  • Surgery
  • Targeted treatments (BRAF, EGFR, ALK fusion)
  • EGFR antagonists
  • BRAF inhibitors
  • ALK inhibitors
  • Anti-angiogenics (in combination)
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11
Q

EGFR (6)

A
  • 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
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12
Q

EGFR MoA (3)

A
  • 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
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13
Q

EGFR tyrosine kinase inhibitors (TKIs) MoA

A

Iressa (geftinib) and Tarceva (erlotinib) - work by binding to ATP = prevent it’s interaction (phosphory of effectors)

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14
Q

EGFR trials (2)

A
  • 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.
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15
Q

In BR.21 study dissapointments (5)

A
  • 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
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16
Q

EGDR mutations sensitivity (2)

A

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%)

17
Q

Osimertinib (4)

A
  • 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
18
Q

Erlotinib vs standard chemo

A

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

19
Q

Anti-EGFR mAbs (3)

A

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
20
Q

BRAF (4)

A

-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
21
Q

Sorafenib and vemurafenib (2)

A

-kinase inhibitors that target oncogenic BRAF (primary kidney, liver cancers + sometimes leukaemia)

  • Efficient in melanoma but partial response in NSCLC
22
Q

ALK fusion oncogene: EML4-ALK (4)

A

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
23
Q

Crizotinib (3)

A

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

24
Q

VEGF-VEGFR (2)

A

Allows and controls angiogenesis in tumours

25
Q

Avastin (2)

A

-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

26
Q

Progress in genomics: tissue is the issue. What are the challenges? (4)

A
  • 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)
27
Q

alternative???

A

liquid biopsies

28
Q

Summary (5)

A
  • 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)

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