Lung cancer Flashcards
Describe 3 histological classifications of lung cancer and their properties.
1) Small cell: Faster proliferation, smaller cytoplasm, neuroendocrine origin (Feyrter cells), ectopic hormone production.
2) Squamous cell carcinoma: Originates from metaplastic bronchial epithelium. Tobacco smoke. Decreasing trend.
3) Adenocarcinoma: Surfactant secreting type II alveolar cells. Tobacco smoke/non-smokers. Increasing trend.
What types of genetic alterations take place in lung cancers?
1) Point mutations and small deletions: EGFR
2) Copy number alterations (loss of heterozygosity, amplification): p53, Rb
3) Gene fusion (kinase domain under control of fused gene promoter): ALK
List 3 types of gene mutated in lung cancers.
Tumor suppressor genes: p53, Rb - difficult to target therapeutically
Receptor tyrosine kinases: EGFR, ALK, HER2 (ERBB2), ROS1, RET - most studied for targeted therapy.
Signaling cascade: RAS, MAPK pathways
What are the factors contributing to tumor heterogeneity?
Driver mutation: EGFR, ALK
Branch mutation: APOBEC deaminase (RNA editing enzyme that’s overexpressed in smoking related cancers). Contributes to subclonal mutation.
Describe how interactions with microenvironment contribute to therapeutic resistance.
1) Stromal alterations: VEGF secretion by tumor cells leads to neovascularization
2) Immune avoidance: Mutations in factors in antigen presentation (upregulation of PD-L1)
Describe 3 categories of non-targeted cytotoxic chemotherapy.
1) DNA crosslinker: Cisplatin. Interferes with mitosis, induces apoptosis through DNA damage.
2) Nucleotide analog: Gemcitabine. Replaces cytidine (C)
3) Anti-microtubule agent: Docetaxel. Destabilizes microtubule assembly, induce apoptosis.
List genes that can be tested for mutations in current clinical practice of NSCLC.
EGFR, ALK rearrangements, ROS1
Understand the mechanisms and nomenclatures of targeted therapy drugs.
- mab = monoclonal antibody
- nib = kinase inhibitor
What are the strategies identifying novel mutations in cancer using next generation sequencing?
1) Whole genome sequencing: most comprehensive, but high cost. Identifies multiple mutations, but difficulty identifying the driver.
2) Exome sequencing: Based on hybrid capture technique. Cost efficient, but limited to known exons, missing non-coding regulatory mutations.
3) Whole transcriptome sequencing: Analyzes expressed RNA and can identify novel exons, structural mutations such as fusion. Highest errors and editing in RNA bases, requires RNA handling.
Describe the endpoints in open-label, phase 2, single arm clinical trials in targeted agents?
Goal of phase 2 clinical trial is to determine safety (placebo vs new drug vs conventional drug).
Endpoint is to get response rate of ~30%
Can be done with no control: Hard to find enough patients for negative control group. compare to previous results of other therapies of NSCLC
T/F: Small cell lung cancers generally have better prognosis than non-small cell lung cancers.
False, small cell lung cancers have more proliferative cells and are more aggressive.
T/F: There is an increasing trend in squamous cell carcinomas associated with smoking.
False, increasing trend is in adenocarcinomas.
T/F: Increased APOBEC expression contributes to higher frequency of driver mutations in adenocarcinomas.
False, APOBEC contributes to branch mutations, not driver.
T/F: Almost all EGFR specific TKIs eventually develop resistance.
True
TNM staging
T: Size of the tumor and extent of invasion to nearby tissues.
N: Lymph node
M: Metastasis
Example: T1N0M0 => Stage 1
