title: Combined Epiregulin and Amphiregulin Expression Levels as a Predictive Biomarker for Panitumumab Therapy Benefit or Lack of Benefit in Patients With RAS Wild-Type Advanced Colorectal Cancer.
abstract: OBJECTIVE
  RAS wild-type (wt) status is necessary but not sufficient for response to anti-epidermal growth factor receptor (EGFR) agents in advanced colorectal cancer (aCRC). RNA expression of EGFR ligands epiregulin (EREG) and amphiregulin (AREG) may correlate with EGFR-targeted therapy efficacy in aCRC, so may represent a much-needed additional predictive marker for these drugs.
  
  
  OBJECTIVE
  To examine a novel ligand model in a randomized clinical trial of panitumumab, irinotecan, and ciclosporin in colorectal cancer (PICCOLO) with with the a priori hypothesis that high tumor expression of either AREG or EREG would predict panitumumab therapy benefit in RAS-wt patients; and low expression, lack of efficacy.
  
  
  METHODS
  Prospectively planned retrospective biomarker study from the PICCOLO trial, which tested the addition of panitumumab to irinotecan therapy in patients with KRAS wt aCRC who experienced failure with prior fluoropyrimidine treatment. The analysis was conducted between 2012 and 2014. A predefined dichotomous model classified tumors as "high expressor" (either EREG or AREG in top tertile for messenger RNA level) or "low expressor" (neither EREG nor AREG in top tertile). Ligand expression was assessed as a prognostic and predictive biomarker. Expression of AREG/EREG and RAS and BRAF mutations were assessed in archival tumor tissue.
  
  
  METHODS
  Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS).
  
  
  RESULTS
  Of the 696 PICCOLO trial patients in the irinotecan-vs-irinotecan with panitumumab randomization, 331 had sufficient tumor tissue available and measurement of ligand expression was successful in 323. High ligand expression was not prognostic for OS (hazard ratio [HR], 0.79 [95% CI, 0.58-1.09]; P = .15) or PFS (HR, 0.93 [95% CI, 0.68-1.27]; P = .64). The primary population had RAS wt aCRC (n = 220); for RAS wt patients with high ligand expression, median (interquartile range [IQR]) PFS was 8.3 [4.0-11.0] months (irinotecan with panitumumab) vs 4.4 [2.8-6.7] months (irinotecan alone); HR, 0.38 [95% CI, 0.24-0.61]; P < .001). In RAS wt patients with low ligand expression, median (IQR) PFS was 3.2 [2.7-8.1] months (irinotecan with panitumumab) vs 4.0 [2.7-7.5] months (irinotecan); HR, 0.93 [95% CI, 0.64-1.37]; P = .73; interaction test results were significant [P = .01]). Less marked effects were seen for response rate (interaction P = .17) and OS (interaction P = .11).
  
  
  CONCLUSIONS
  High ligand expression is a predictive marker for panitumumab therapy benefit on PFS in RAS wt patients; conversely, patients with low ligand expression gained no benefit. The current "opt-in" strategy for anti-EGFR therapy in all patients with RAS wt aCRC should be questioned. Expression of EREG/AREG is a useful biomarker for anti-EGFR therapy; optimization for clinical use is indicated.
  
  
  BACKGROUND
  isrctn Identifier: ISRCTN93248876.
authors: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Jenny F
authors: JF
authors: Seligmann
authors: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Faye
authors: F
authors: Elliott
authors: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Susan D
authors: SD
authors: Richman
authors: Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
authors: Bart
authors: B
authors: Jacobs
authors: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Gemma
authors: G
authors: Hemmings
authors: Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom.
authors: Sarah
authors: S
authors: Brown
authors: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Jennifer H
authors: JH
authors: Barrett
authors: Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
authors: Sabine
authors: S
authors: Tejpar
authors: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Philip
authors: P
authors: Quirke
authors: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Matthew T
authors: MT
authors: Seymour