Association of Tumor <i>HER3</i> Messenger RNA Expression With Panitumumab Efficacy in Advanced Colorectal Cancer
Authors: Jenny F. Seligmann, Ace J. Hatch, Susan D. Richman, Faye Elliott, Bart Jacobs, Sarah Brown, Herbert Hurwitz, Jennifer H. Barrett, Philip Quirke, Andrew B. Nixon, Matthew T. Seymour
Journal: JAMA Oncology (2017)

<h3>Importance</h3> Epidermal growth factor receptor (EGFR) (HER1) signaling depends on ligand binding and dimerization with itself or other HER receptors. We previously showed in a randomized trial that high EGFR ligand expression is predictive of panitumumab benefit in advanced colorectal cancer. Tumor expression of HER3 may further refine the<i>RAS</i>wild-type (wt) population benefitting from anti-EGFR agents. <h3>Objective</h3> To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab. <h3>Design, Setting, and Participants</h3> The study was a prospectively planned retrospective biomarker study of pretreatment samples from the PICCOLO trial that tested the addition of panitumumab to irinotecan therapy in patients with<i>KRAS</i>wt advanced colorectal cancer who experienced failure with prior fluoropyrimidine treatment. HER3 was assessed as a prognostic marker, then as a predictive biomarker in patients with<i>RAS</i>wt, first as a continuous variable and then as a binary (high vs low) variable. Relationship with MEK-AKT pathway mutations and EGFR ligands epiregulin and amphiregulin (EREG/AREG) were also assessed. <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> In 308 patients (mean age at randomization, 61.6 years; 193 men) higher HER3 was weakly prognostic for OS (hazard ratio [HR] per 2-fold change, 0.91; 95% CI, 0.83-0.99;<i>P</i> = .04) but not PFS (HR, 0.93; 95% CI, 0.83-1.05;<i>P</i> = .25). Higher HER3 was predictive, being associated with prolonged PFS on irinotecan plus panitumumab (IrPan) (HR, 0.71; 95% CI, 0.61-0.82;<i>P</i> &lt; .001), but not irinotecan (HR, 0.96; 95% CI, 0.82-1.13;<i>P</i> = .65) in patients with<i>RAS</i>wt, with significant interaction between biomarker and treatment (<i>P</i> = .001). Similar interaction was seen for OS (<i>P</i> = .004). In an exploratory binary model, dividing the population at the 66th percentile, HER3 was predictive of panitumumab benefit: in patients with high HER3 expression, median PFS was 8.2 months (IrPan) vs 4.4 months (irinotecan) (HR, 0.33; 95% CI, 0.19-0.58;<i>P</i> &lt; .001). Patients with low HER3 expression gained no benefit in PFS: 3.3 months (IrPan) vs 4.3 months (irinotecan) (HR, 0.96; 95% CI, 0.67-1.38;<i>P</i> = .84), with significant interaction (<i>P</i> = .002). The binary model was also predictive for OS, with significant interaction (<i>P</i> = .01). Combining HER3 and ligand data, patients with HER3-high, AREG/EREG-high tumors gained markedly from panitumumab (PFS HR, 0.24; 95% CI, 0.11-0.51;<i>P</i> &lt; .005 and OS HR, 0.36; 95% CI, 0.18-0.73;<i>P</i> = .004). Conversely, patients with HER3-low, AREG/EREG-low tumors did not benefit (PFS HR, 1.14; 95% CI, 0.73-1.79;<i>P</i> = .57 and OS HR, 1.44; 95% CI, 0.92-2.26;<i>P</i> = .11). <h3>Conclusions and Relevance</h3> High HER3 expression identified patients with<i>RAS</i>wt who gained markedly from panitumumab, and those who did not, with statistically significant biomarker-treatment interactions for PFS and OS. This finding provides insight into the mechanism of anti-EGFR agents and is of potential clinical utility.