Lung cancer Flashcards
What are the most common oncogenic drivers in NSCLC?
EGFR, KRAS, BRAF, ALK, MET
Why is EGFR tested in NSCLC?
10% of cases have EGFR driver
Patients with EGFR activating mutations are eligible for EGFR TKIs such as erlotinib and gefitinib
What is the consequence of EGFR mutations in lung cancer?
Cause upregulation of EGFR/MAPK signalling pathway –> increased proliferation
Where are EGFR mutations most often located?
Tyrosine kinase domain, exons 18-21
What are the 2 most common EGFR activating mutations?
Leu858Arg
Exon 19 deletion
What is the most common cause of EGFR-TKI resistance?
What is the consequence of it?
Thr790Met
Eligible for treatment with 3rd generation TKI, osimertinib
What is the challenge associated with testing for EGFR resistance mutations?
Often at much lower frequency than driver mutations - requires assay with increased sensitivity, e.g. ddPCR
Limit of detection is determined by cfDNA copy number
ddPCR can detect T790M down to 0.1% allele fraction but in many patients there is not enough DNA to reach this level of sensitivity
Why is KRAS tested in NSCLC?
Patients with G12C variant are eligible for sotorasib KRAS inhibitor
Why is MET tested in NSCLC?
Patients with MET exon 14 skipping mutations have been shown to be sensitive to MET inhibitor
What is the consequence of MET exon 14 skipping?
Loss of juxtamembrane binding domain - decreases ubiquitination (process that marks proteins for degradation)
Prolonged activation of MET and upregulation of MAPK pathway –> increased signalling –> increased proliferation
Why are ALK and ROS1 tested?
Small subset of patients have ALK or ROS1 rearrangements resulting in fusion genes with oncogenic activity.
How are ALK and ROS1 rearrangements tested for?
IHC as first line
ROS1 confirmed by RNA fusion panel
ALK confirmed by FISH
Why is testing ctDNA particularly useful in NSCLC?
~25% patients unsuitable for biopsy, biopsy inadequate or too ill for biopsy
EGFR+ patients respond well to EGFR TKIs, EGFR- respond much worse to EGFR TKIs (than to standard chemo)
What is the advantage of using ctDNA when testing for EGFR TKI resistance?
Avoid need for a second biopsy - original diagnostic biopsy cannot be used as T790M only arises after treatment with EGFR targeted therapy
What is the testing pathway for EGFR TKI resistance?
ctDNA testing for Thr790Met
Positive –> osimertinib
Negative –> tissue biopsy –> test for Thr790Met
Negative on biopsy –> standard chemo
