title: Concordant and Discordant EGFR Mutations in Patients With Multifocal Adenocarcinomas: Implications for EGFR-Targeted Therapy.
abstract: Adenocarcinoma remains the most common subtype of lung cancer in the United States. Most patients present with tumors that are invasive and often metastatic, but in some patients, multiple precursor in situ or minimally invasive adenocarcinoma tumors develop that can be synchronous and metachronous. These precursor lesions harbor the same spectrum of genetic mutations found in purely invasive adenocarcinomas, such as EGFR, KRAS, and p53 mutations. It is less clear, however, whether separate lesions in patients who present with multifocal disease share common underlying genetic driver mutations.
  
  
  
  Here we review the relevant literature on molecular driver alterations in adenocarcinoma precursor lesions. We then report 4 patients with multifocal EGFR mutant adenocarcinomas in whom we performed molecular testing on 2 separate lesions.
  
  
  
  In 2 of these patients, the mutations are concordant, and in 2 patients, the mutations are discordant. A review of the literature demonstrates increasing evidence that lesions with discordant mutations may confer a more favorable prognosis because they are unlikely to represent metastases.
  
  
  
  Our findings suggest that the emergence of the dominant EGFR driver alteration is often independent between lesions in patients with multifocal adenocarcinomas, and thus the same targeted therapy may not be effective for all lesions. However, genetic testing of multiple lesions can help to distinguish separate primary tumors from metastatic disease.
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Jody C
authors.initials: JC
authors.lastname: Chuang
authors.affiliation: Division of Thoracic Surgery, Stanford University School of Medicine, Stanford, California.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Shrager
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Wakelee
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California. Electronic address: jwneal@stanford.edu.
authors.forename: Joel W
authors.initials: JW
authors.lastname: Neal
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D011379:Prognosis
chemical_list: D066246:ErbB Receptors
keywords: Bronchioloalveolar carcinoma; EGFR (epidermal growth factor receptor); KRAS; Minimally invasive adenocarcinoma; Multifocal adenocarcinoma; Non-small cell lung cancer