title: EGFR and KRAS Mutations in ALK-Positive Lung Adenocarcinomas: Biological and Clinical Effect.
abstract: BACKGROUND
  In lung adenocarcinoma (ADC), anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements are mutually exclusive with epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. However, the existence of double-positive (DP) patients have been sporadically described. We identified DP cases in therapy-naive ALK-rearranged ADC and characterized the biology of these tumors to better understand the clinical response to tyrosine kinase inhibitors (TKIs).
  
  
  METHODS
  We selected 42 ALK-positive ADCs from a multicentric series of 301 cases of ADCs. A mutational analysis was performed using Sanger and/or pyrosequencing to address exons 18-21 of EGFR and codons 12-13 of the KRAS gene. In addition, the KRAS and EGFR copy number was investigated using fluorescent in situ hybridization. DP patients were treated with TKIs, and their response was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria.
  
  
  RESULTS
  Eight of 42 ALK-positive ADCs (19%) demonstrated a concomitant mutation in the EGFR (3 cases) or KRAS (5 cases) genes and were classified as DP. All DP cases displayed copy number gains in the EGFR or KRAS gene because of polysomy or gene amplification. In the latter cases, a mutant allele-specific imbalance was observed. Four patients were treated with TKIs. The 2 EGFR-mutant DP patients demonstrated a better response to crizotinib compared with erlotinib. The 2 KRAS-mutant DP patients experienced opposite responses to crizotinib.
  
  
  CONCLUSIONS
  The incidence of DP ADC is not negligible. Patients with ALK/EGFR might benefit more from crizotinib compared with erlotinib administration, although the efficacy of TKIs in patients with ALK/KRAS remains unclear. An integrated targeted therapy should be considered for patients with DP ADC.
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy. Electronic address: n.sahnane@gmail.com.
authors.forename: Nora
authors.initials: N
authors.lastname: Sahnane
authors.affiliation: Institute of Pathology, Locarno, Switzerland.
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bernasconi
authors.affiliation: Department of Oncology, Clinica Luganese, Lugano, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zappa
authors.affiliation: Oncology Institute of Southern Switzerland, Mendrisio, Switzerland.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Schiavone
authors.affiliation: Oncology Institute of Southern Switzerland, Mendrisio, Switzerland.
authors.forename: Luciano
authors.initials: L
authors.lastname: Wannesson
authors.affiliation: Department of Oncology, Ospedale di Busto Arsizio, Busto Arsizio, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Antonelli
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Balzarini
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.affiliation: Institute of Pathology, Locarno, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzucchelli
authors.affiliation: Unit of Pathology, Ospedale di Circolo di Varese, Varese, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tibiletti
authors.affiliation: Institute of Pathology, Locarno, Switzerland.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Martin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ALK rearrangements; Crizotinib; EGFR mutations; Erlotinib; KRAS mutations