Lung cancer Flashcards
What are the two main groups of lung cancer?
Small cell lung cancer (SCLC)
Non-small cell lung cancer (NSLC)
small cell lung cancer
- approx 15% of cases
- associated with a worse prognosis
- effects neuroendocrine cells
- strongly associated with tobacco smoking
Non-small cell lung cancer
- approx. 85% of cases
- variable prognosis; dependent on subtype
what are the 3 main types of NSCLC?
- adenocarcinoma; mucus cells
- squamous cell carcinoma; squamous cells
- large cell carcinoma; large, abnormal cells
what are the other types of lung cancers?
- lymphomas
- sarcomas
- mesotheliomas
- secondary lung cancer; metastasis
10 risk factors of lung cancer
- tobacco smoke
- air pollution
- occupation
- radon gas
- asbestos & other carcinogens
- radiation exposure
- dietary factors
- family history
- aging
- genetics
incidences of lung cancer in men and women
males and females: 13%
mortality rate of lung cancer
21.1%
- associated with low survival rates
SCLC characteristics
- 90% chance due to smoking
- aggressive (rapid metastasis to brain, liver, bone)
- high mortality (1 year prognosis)
- more responsive to traditional cancer therapies (chemotherapy)
NSCLC characteristics
- in smokers and non-smokers
- less aggressive
- 5 year survival rate of 23%
- more responsive to targeted therapies (relatively insensitive to chemo)
SCLC histology
- typically, centrally located, arising in peribronchial locations
- thought to develop from neuroendocrine cells
what is SCLC composted of?
sheets of small, round cells with dark nuclei, scant cytoplasm and fine, granular nuclear chromatin
NSCLC histology
histology correlates with site of origin
- adenocarcinoma usually originates in peripheral lung tissue
- squamous cell carcinoma usually near a central bronchus
what is NSCLC arise from?
epithelial cells of the lung or of the central bronchi to terminal alveoli
where does adenocarcinoma originate?
in the peripheral lung tissue
(also most common form of lung cancer)
where does squamous cell carcinomas form?
in the lining of the bronchial tubes
what are large cell carcinomas?
refers to NSCLC that are neither adenocarcinomas nor squamous cell carcinoma.
what are the genetics of lung cancer?
- different types of lung cancer = different profiles in terms of their genetics
- there are broader patterns observed within SCLC and NSCLC but also different between subsets (e.g. adenocarcinoma vs squamous cell)
- further differentiation between molecular types, between individials and even different cells within the tumour
- classic complexity observed in all cancers.
what is commonly mutated in SCLC?
TSGs
Key oncogenes in NSCLC
KRAS, EGFR, BRAF, NF1
key oncogenes in SCLC
KRAS, EGFR, BRAF, NF1 (but at lower %s)
SCLC: loss of tumour suppressor function
- mutations in TP53 gene; 80-90% of primary tumours
- point mutations and small deletions of PTEN gene; 10% of primary tumours
- others include alterations in RB1; 55-65%
SCLC; gain in oncogenic mutations
amplification of c-MYC; 9% of primary tumours
how many cancers contain TP53 mutations
over 50%
- most commonly affected TSG
- due to missense mutations in the DNA binding domain
what is MYC?
family of genes which encode for TFs that regulate cell growth & metabolic genes
- amplification of c-MYC = poor prognosis
Molecular changes due to MYC genes
increase in:
- transcription
- mitochondrial biogenesis and function
- rRNA and protein biosynthesis
- glycolysis and anaplerosis
changes in microRNA
Cellular changes due to MYC genes
increase in:
- cellular proliferation
- metabolic transformation
- metastatic capacity
- glutaminolysis
NSCLC; loss of tumour suppressor function
mutations in TP53 gene; 50%
- lower in adenocarcinoma vs squamous cell
NSCLC; gain in oncogenic mutations in adenocarcinoma
- KRAS; 29%
- EGFR; 14%
- BRAF; 7%
- ERBB2 (HER2); 4%
multistep process of carcinogenesis
initiation
- normal cell; impacted by chemical, radiation or virus
- initiation cell
promotion
- preneoplastic cell
progression
- neoplastic cell
metastasis
- malignant tumor
what are the tumour suppressors in lung carcinogenesis?
- p53
- RB1
- PTEN
- others
what are the oncogenic drivers during lung carcinogenesis?
- KRAS
- EGFR
- c-MYC
- ERBB2
- BRAF
what causes an increase in inflammation?
increase in;
- ROS
- Electrophilic metabolites
describe the process of carcinogenesis in lung cancer
normal lung epithelial cell is exposed to carcinogens, increase in inflammation, DNA repair fails, DNA adducts formation and epigenetic alterations happen creating a genetically altered epithelial cell.
Lack of apoptosis, cell cycle arrest or anti-inflammation causes continutation of gene mutations. Cell growth and proliferation leads to a tumour growth with then creates a lung metastasis.
what are the symptoms of lung cancer?
- persistent cough
- fatigue
- shortness of breath (dyspnea)
- coughing up blood (hemoptysis)
- weight loss
- pain when breathing
- wheezy
- repeated chest infection
process of a simplified diagnostic pathway
- GP assessment
- scans
- biopsy
- MDT assessment and staging
radiology: chest x-ray
- sometimes challenging to interpret
- will give an indication but needs CT and biopsy to help confirm lung cancer
- location of abnormality can help narrow down the type
- small cell and squamous cell tend to be central
- adenocarcinoma and large cell tend to be peripheral
- can help with staging
CT scans and PET-CT scans
- higher resolution
- can provide more detail and help define size, location and spread more effectively
- tend to be employed after initial chest x-ray to provide more informaiton
- helps with staging and diagnosis
staging of SCLC
limited staging:
- cancer found in one side of the chest, involving just one part of the lung and nearby lymph nodes
- chemo + radio to cure
extensive staging:
- cancer has spread to other regions of the chest or other body parts
- chemo to control (not cure)
staging of NSCLC
more extensive staging that covers tumor size, lymph nodes affected and how much it has metastasised.
percutaneous needle biopsy
tissue or fluid
bronchoscopy biopsy
trachea and large airways
endobronchial ultrasound (EBUS)
lymph nodes
thoracoscopy
deeper and smaller spots in the lung
mediastinoscopy
mediastinal lymph nodes
metastasis
- approx 50% of lung cancer is metastatic at diagnosis
- SCLC; 70% are metastatic at diagnosis
- associated with poor survival outcomes at stage 4 for NSCLC and extensive for SCLC
what are common metastatic sites?
- brain
- bones
- liver
- peripheral lymph nodes
- adrenal glands
traditional therapeutic approach for SCLC
- surgery for non-metastatic; lobectomy, pneumonectomy, wedge resection
- chemotherapy (etoposide/cisplastin)
- radiotherapy
traditional therapeutic approach for NSCLC
- chemotherapy (when unknown driver mutation)
- radiotherapy (or chemoradiotherapy)
- surgery
- targeted treatments; EGFR antagonists, BRAF inhibitors, ALK inhibitors, anti-angiogenics (in combination)
surgery
- potential cure for early stage lung cancer
BUT - tumour cells may remain
radiotherapy
- can be used as an intent to cure treatment for early NSCLC
BUT - toxicity and poor outcomes for advanced disease
platinum based chemotherapy
- available as first line therapy, numerous combinations
BUT - toxic and prone to tumour resistance
targeted therapy
- relatively effective against tumors with defined mutations
BUT - not available for most lung cancer patients, tumours develop resistance
immunotherapy
- specific tumor killing with potentially less toxicity. lots of potential strategies
BUT - development of autoimmune reactions, expensive
targeted therapies
- design to interact with their targets
- act on specific molecular targets associated with cancer
- cytostatic
- many are oral agents
chemotherapy
- indetified because they kill cells
- act on all rapidly dividing cells
- cytotoxic
- mainly intravenous, some oral agents
Treatments for SCLC
- combinations of chemo ; limited approach
- loss of TSG not as amenable for therapeutic targeting
- difficulty restoring function despite research
- c-MYC targeted therapeutics in preclinical development, issues with targeting TFs slowly being improved
- immunotherapy potential
what are topoisomerase inhibitors?
- enzymes involved in DNA winding, prevent DNA replication
- Topo type 1; cut one strand
- Topo type 2; cut both strands
what are platinum-based agents?
- cross-linking of DNA, inhibits repair and DNA synthesis
what can be combined chemotherapy?
etoposide/ irinotecan (topo) +cisplastin/ carboplatin (platinum)
NSCLC therapy
- surgery first choice if limited
- can be assisted by neoadjuvant approach radio/chemotherapy
- targeted therapies effective is molecular subtype is known
- depends on cancer stage.
EGFR tyrosine kinase inhibitors (TKIs)
- Iressa (geftinib)
- Tarceva (erlotinib)
what is ALK?
anaplastic lymphoma kinase is gene that can become an oncogene in cancer
what is EML4?
echinoderm microtubule-associated-protein like 4
EML4-ALK
ALK is the oncogene activated by EML4 in lung cancer.
use of crizotinib for treatment
- crizotinib competes binding within the ATP-binding pocket of ALK to stop the ALK from being abnormally activated due to fusion with EML4.
immunotherapy
wide range of potential and existing therapies;
- cytokines
- cancer vaccines
- checkpoint inhibitors
- monoclonal antibodies
- adoptive cell therapy (CAR-T cell therapy)
immunotherapy trials
- PD1 inhibitors; Pembrolizumab & Nivolumab
- PD-L1 inhibitors; Atezolizumab
