What amino acids are involved in EGFR (Epidermal Growth Factor Receptor) mutations for Non-Small Cell Lung Cancer (NSCLC) treatment?

EGFR Mutations in NSCLC: Key Amino Acid Positions

The clinically significant amino acids involved in EGFR mutations for NSCLC treatment are primarily L858 (leucine at position 858), amino acids 747-750 in the LREA motif, G719 (glycine at position 719), L861 (leucine at position 861), S768 (serine at position 768), and T790 (threonine at position 790). 1

Common Sensitizing Mutations (85% of EGFR mutations)

Exon 19 Deletions (~45% of cases)

• In-frame deletions around the LREA motif involving amino acid residues 747 to 750 1
• These deletions predict excellent response to EGFR TKIs with response rates of 55-80% 2

Exon 21 L858R Point Mutation (~40% of cases)

• Arginine substitution for leucine at amino acid position 858 (L858R) 1
• This single amino acid substitution is the second most common activating mutation 1

Uncommon Sensitizing Mutations (~10% of cases)

Exon 18 G719X (~3% of cases)

• Glycine at position 719 mutated to various amino acids (G719X) 1
• Afatinib shows 77.8% response rate for this mutation 3

Exon 21 L861Q (~2% of cases)

• Glutamine substitution for leucine at position 861 (L861Q) 1
• Afatinib demonstrates 56.3% response rate 3

Exon 20 S768I (~2% of cases)

• Isoleucine substitution for serine at position 768 (S768I) 1
• Afatinib achieves 100% response rate specifically for S768I mutations 3, 4

Resistance Mutations

T790M (Acquired Resistance)

• Methionine substitution for threonine at position 790 (T790M) 1
• Develops in approximately 60% of patients progressing on first/second-generation TKIs 2
• Requires third-generation TKIs like osimertinib 3, 5

Exon 20 Insertions (4-10% of cases)

• In-frame insertion mutations within exon 20 1
• These are resistant to standard EGFR TKIs (gefitinib, erlotinib, afatinib) with response rates of only 3-8% 1
• Require specialized agents like amivantamab or mobocertinib 1, 5

Clinical Testing Algorithm

Broad screening of exons 18-21 using next-generation sequencing (NGS) is mandatory to identify all clinically significant amino acid mutations 1, 5

Key amino acid positions to screen:

• Exon 18: G719 (glycine at 719) 1
• Exon 19: amino acids 747-750 (LREA motif deletions) 1
• Exon 20: S768, T790, and insertion sites 1
• Exon 21: L858, L861 1

Treatment Selection Based on Amino Acid Mutations

For L858R or exon 19 deletions (amino acids 747-750):

• Osimertinib is the preferred first-line agent 1, 2

For S768I, G719X, or L861Q:

• Afatinib or osimertinib are both preferred options 3, 5
• Consider afatinib specifically for S768I due to 100% response rate 3, 4

For T790M (threonine 790 to methionine):

• Third-generation TKIs (osimertinib, almonertinib, furmonertinib) are required 1, 3

For exon 20 insertions:

• Avoid standard EGFR TKIs; use amivantamab or mobocertinib after platinum-based chemotherapy 1, 5

Critical Pitfalls to Avoid

• Do not assume all mutations at the same amino acid position respond identically - distinct response rates occur even for mutations at the same genomic location 1
• Do not use afatinib for exon 20 insertion mutations - these amino acid insertions confer resistance 3, 5
• Do not rely on single-gene testing - compound mutations involving multiple amino acid positions occur in ~20% of samples and require comprehensive NGS 1