title: Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).
abstract: OBJECTIVE
  Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment.
  
  
  METHODS
  Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.
  
  
  RESULTS
  High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).
  
  
  CONCLUSIONS
  Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity.
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cushman
authors.affiliation: Alliance Statistical and Data Center, Durham, North Carolina.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Ace J
authors.initials: AJ
authors.lastname: Hatch
authors.affiliation: Alliance Statistical and Data Center, Durham, North Carolina.
authors.forename: Ivo
authors.initials: I
authors.lastname: Shterev
authors.affiliation: Alliance Statistical and Data Center, Durham, North Carolina.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Sibley
authors.affiliation: Alliance Statistical and Data Center, Durham, North Carolina.
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.affiliation: University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
authors.affiliation: Alliance Statistical and Data Center, Durham, North Carolina.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.affiliation: Duke University Medical Center, Durham, North Carolina. anixon@duke.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D000068818:Cetuximab / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab