Diagnostic Methods

Question 1

What are the two most common mutations that drive non-small cell lung cancer (NSCLC)?

Answer 1

• No mutation detected 55.7%
• KRAS 22.9%
• EGFR 14.8%

**considered oncogenic driver mutations

Question 2

What are the characteristics/downfalls of EGFR dideoxy sequencing?

Answer 2

• 2 day workflow
• multiple steps and labor intensive
• insertions/deletions can be difficult to precisely interpret
• sensitivity ~20% (bad)

Question 3

Why is determining the variant of a gene important clinically?

Answer 3

The variant will impact therapy (usually determined with next gen sequencing) by affecting a patient’s sensitivity/resistance to certain drugs

Question 4

How do you treat an inaccessible target differently than an accessible target?

Answer 4

Inaccessible targets (e.g. exon 20 insertion, exon 20 T790M) require a “wider net” with cytotoxic therapy

Accessible targets (e.g. exon 19 deletion, exon 20 L858R) can be precisely targetted with EGFR TKIs or other drugs

Question 5

What is afatinib?

Answer 5

A second generation EGFR TKI approved for first line therapy for EGFR mutant lung cancer (e.g. exon 19 deletion or L858R mutation)

**also available; gefitinib and erlotinib

Question 6

What are three ways one can acquire TKI resistance?

Answer 6

1. EGFR T790M mutation (modifies ATP affinity, drug binding properties, and shifts inhibitory curves)
2. Activation of bypass signaling cascades (MET and HER2 amplification)
3. Phenotypic and genomic neuroendocrine transformation (silences the expression of or dependence on EGFR)

Question 7

What is osimertinib?

Answer 7

A third generation EGFR TKI available for patients resistant to 1st/2nd gen EGFR TKIs (e.g. from T790M mutation)

Question 8

What drives resistance to EGFR TKIs?

Answer 8

Tumor plasticity and selection pressure drive adaptation which leads to resistance

Question 9

What are the first generation EGFR TKIs? Second gen? What mutations are these effective against?

Answer 9

1st gen: Gefitinib and Erlotinib

2nd gen: Afatinib

**all effective against:

Exon 19 deletion and Exon 21 L858R

Question 10

What is the main third generation EGFR TKI? What mutation is this effective against?

Answer 10

Osimertinib

**effective against Exon 20 T790M mutation