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EGFR and KRAS Mutations in ALK-Positive Lung Adenocarcinomas: Biological and Clinical Effect

Nora Sahnane1, Milo Frattini2, Barbara Bernasconi1

  • 1Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.

Clinical Lung Cancer
|September 19, 2015
PubMed
Abstract

Insights

Double-positive lung adenocarcinoma (ADC) with anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are not rare. Patients with ALK/EGFR mutations may respond better to crizotinib than erlotinib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements are typically mutually exclusive with epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in lung adenocarcinoma (ADC).
  • Sporadic cases of double-positive (DP) ADC, harboring both ALK rearrangements and EGFR/KRAS mutations, have been reported.
  • Understanding the biology and clinical implications of DP ADC is crucial for optimizing targeted therapy.

Purpose of the Study:

  • To identify and characterize double-positive (DP) cases in therapy-naive ALK-rearranged ADC.
  • To investigate the biological features of DP ADC.
  • To evaluate the clinical response of DP ADC patients to tyrosine kinase inhibitors (TKIs).

Main Methods:

  • Selection of 42 ALK-positive ADCs from a multicentric series of 301 ADC cases.
  • Mutational analysis of EGFR (exons 18-21) and KRAS (codons 12-13) using Sanger and/or pyrosequencing.
  • Fluorescent in situ hybridization (FISH) to assess EGFR and KRAS copy number.
  • Evaluation of TKI treatment response in DP patients using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Main Results:

  • Eight of 42 ALK-positive ADCs (19%) were identified as DP, with concomitant EGFR (3 cases) or KRAS (5 cases) mutations.
  • All DP cases exhibited copy number gains in EGFR or KRAS due to polysomy or gene amplification, with mutant allele-specific imbalance in amplified cases.
  • Among 4 treated patients, 2 EGFR-mutant DP patients showed a better response to crizotinib than erlotinib, while 2 KRAS-mutant DP patients had variable responses to crizotinib.

Conclusions:

  • The incidence of DP ADC is significant and warrants attention.
  • Patients with ALK/EGFR-mutant DP ADC may benefit more from crizotinib compared to erlotinib.
  • The efficacy of TKIs in ALK/KRAS-mutant DP ADC remains uncertain, suggesting a need for integrated targeted therapy approaches.
Keywords:
ALK rearrangementsCrizotinibEGFR mutationsErlotinibKRAS mutations

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