Combined Epiregulin and Amphiregulin Expression Levels as a Predictive Biomarker for Panitumumab Therapy Benefit or Lack of Benefit in Patients With<i>RAS</i>Wild-Type Advanced Colorectal Cancer
Authors: Jenny F. Seligmann, Faye Elliott, Susan D. Richman, Bart Jacobs, Gemma Hemmings, Sarah Brown, Jennifer H. Barrett, Sabine Tejpar, Philip Quirke, Matthew T. Seymour
Journal: JAMA Oncology (2016)

<h3>Importance</h3> <i>RAS</i>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. <h3>Objective</h3> 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<i>RAS</i>-wt patients; and low expression, lack of efficacy. <h3>Design, Setting, and Participants</h3> Prospectively planned retrospective biomarker study from the PICCOLO trial, which tested the addition of panitumumab to irinotecan therapy in patients with<i>KRAS</i>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<i>RAS</i>and<i>BRAF</i>mutations were assessed in archival tumor tissue. <h3>Main Outcomes and Measures</h3> Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS). <h3>Results</h3> 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];<i>P</i> = .15) or PFS (HR, 0.93 [95% CI, 0.68-1.27];<i>P</i> = .64). The primary population had<i>RAS</i>wt aCRC (n = 220); for<i>RAS</i>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];<i>P</i> &lt; .001). In<i>RAS</i>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];<i>P</i> = .73; interaction test results were significant [<i>P</i> = .01]). Less marked effects were seen for response rate (interaction<i>P</i> = .17) and OS (interaction<i>P</i> = .11). <h3>Conclusions and Relevance</h3> High ligand expression is a predictive marker for panitumumab therapy benefit on PFS in<i>RAS</i>wt patients; conversely, patients with low ligand expression gained no benefit. The current "opt-in" strategy for anti-EGFR therapy in all patients with<i>RAS</i>wt aCRC should be questioned. Expression of EREG/AREG is a useful biomarker for anti-EGFR therapy; optimization for clinical use is indicated. <h3>Trial Registration</h3> isrctn Identifier:ISRCTN93248876