IMPORTANCE: 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 RAS wild-type (wt) population benefitting from anti-EGFR agents. OBJECTIVE: To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab. DESIGN, SETTING, AND PARTICIPANTS: 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 KRAS 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 RAS 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. MAIN OUTCOMES AND MEASURES: Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS). RESULTS: 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; P = .04) but not PFS (HR, 0.93; 95% CI, 0.83-1.05; P = .25). Higher HER3 was predictive, being associated with prolonged PFS on irinotecan plus panitumumab (IrPan) (HR, 0.71; 95% CI, 0.61-0.82; P < .001), but not irinotecan (HR, 0.96; 95% CI, 0.82-1.13; P = .65) in patients with RAS wt, with significant interaction between biomarker and treatment (P = .001). Similar interaction was seen for OS (P = .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; P < .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; P = .84), with significant interaction (P = .002). The binary model was also predictive for OS, with significant interaction (P = .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; P < .005 and OS HR, 0.36; 95% CI, 0.18-0.73; P = .004). Conversely, patients with HER3-low, AREG/EREG-low tumors did not benefit (PFS HR, 1.14; 95% CI, 0.73-1.79; P = .57 and OS HR, 1.44; 95% CI, 0.92-2.26; P = .11). CONCLUSIONS AND RELEVANCE: High HER3 expression identified patients with RAS 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.
IMPORTANCE: 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 RAS wild-type (wt) population benefitting from anti-EGFR agents. OBJECTIVE: To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab. DESIGN, SETTING, AND PARTICIPANTS: 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 KRAS 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 RAS 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. MAIN OUTCOMES AND MEASURES: Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS). RESULTS: 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; P = .04) but not PFS (HR, 0.93; 95% CI, 0.83-1.05; P = .25). Higher HER3 was predictive, being associated with prolonged PFS on irinotecan plus panitumumab (IrPan) (HR, 0.71; 95% CI, 0.61-0.82; P < .001), but not irinotecan (HR, 0.96; 95% CI, 0.82-1.13; P = .65) in patients with RAS wt, with significant interaction between biomarker and treatment (P = .001). Similar interaction was seen for OS (P = .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; P < .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; P = .84), with significant interaction (P = .002). The binary model was also predictive for OS, with significant interaction (P = .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; P < .005 and OS HR, 0.36; 95% CI, 0.18-0.73; P = .004). Conversely, patients with HER3-low, AREG/EREG-low tumors did not benefit (PFS HR, 1.14; 95% CI, 0.73-1.79; P = .57 and OS HR, 1.44; 95% CI, 0.92-2.26; P = .11). CONCLUSIONS AND RELEVANCE: High HER3 expression identified patients with RAS 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.
Authors: Jean-Yves Douillard; Kelly S Oliner; Salvatore Siena; Josep Tabernero; Ronald Burkes; Mario Barugel; Yves Humblet; Gyorgy Bodoky; David Cunningham; Jacek Jassem; Fernando Rivera; Ilona Kocákova; Paul Ruff; Maria Błasińska-Morawiec; Martin Šmakal; Jean Luc Canon; Mark Rother; Richard Williams; Alan Rong; Jeffrey Wiezorek; Roger Sidhu; Scott D Patterson Journal: N Engl J Med Date: 2013-09-12 Impact factor: 91.245
Authors: Jeffrey A Engelman; Pasi A Jänne; Craig Mermel; Joseph Pearlberg; Toru Mukohara; Christina Fleet; Karen Cichowski; Bruce E Johnson; Lewis C Cantley Journal: Proc Natl Acad Sci U S A Date: 2005-02-24 Impact factor: 11.205
Authors: Stephanie M Cushman; Chen Jiang; Ace J Hatch; Ivo Shterev; Alexander B Sibley; Donna Niedzwiecki; Alan P Venook; Kouros Owzar; Herbert I Hurwitz; Andrew B Nixon Journal: Clin Cancer Res Date: 2014-12-17 Impact factor: 12.531
Authors: E Tzahar; H Waterman; X Chen; G Levkowitz; D Karunagaran; S Lavi; B J Ratzkin; Y Yarden Journal: Mol Cell Biol Date: 1996-10 Impact factor: 4.272
Authors: Natalia V Sergina; Megan Rausch; Donghui Wang; Jimmy Blair; Byron Hann; Kevan M Shokat; Mark M Moasser Journal: Nature Date: 2007-01-07 Impact factor: 49.962
Authors: Susan D Richman; Katie Southward; Philip Chambers; Debra Cross; Jennifer Barrett; Gemma Hemmings; Morag Taylor; Henry Wood; Gordon Hutchins; Joseph M Foster; Assa Oumie; Karen G Spink; Sarah R Brown; Marc Jones; David Kerr; Kelly Handley; Richard Gray; Matthew Seymour; Philip Quirke Journal: J Pathol Date: 2016-01-29 Impact factor: 7.996
Authors: Matthew T Seymour; Sarah R Brown; Gary Middleton; Timothy Maughan; Susan Richman; Stephen Gwyther; Catherine Lowe; Jennifer F Seligmann; Jonathan Wadsley; Nick Maisey; Ian Chau; Mark Hill; Lesley Dawson; Stephen Falk; Ann O'Callaghan; Kim Benstead; Philip Chambers; Alfred Oliver; Helen Marshall; Vicky Napp; Phil Quirke Journal: Lancet Oncol Date: 2013-05-29 Impact factor: 41.316
Authors: Marc Peeters; Frédéric Forget; Meinolf Karthaus; Manuel Valladares-Ayerbes; Alberto Zaniboni; Gaston Demonty; Xuesong Guan; Fernando Rivera Journal: ESMO Open Date: 2018-02-24
Authors: Annabel H S Alig; Volker Heinemann; Michael Geissler; Ludwig Fischer von Weikersthal; Thomas Decker; Kathrin Heinrich; Swantje Held; Lena Weiss; Laura E Fischer; Nicolas Moosmann; Arndt Stahler; Ivan Jelas; Annika Kurreck; Jobst C von Einem; Anke C Reinacher-Schick; Andrea Tannapfel; Clemens Giessen-Jung; Sebastian Stintzing; Dominik P Modest Journal: Cancers (Basel) Date: 2022-01-21 Impact factor: 6.639
Authors: Marc Peeters; Timothy Price; Julien Taieb; Michael Geissler; Fernando Rivera; Jean-Luc Canon; George Pentheroudakis; Reija Koukakis; Peter Burdon; Salvatore Siena Journal: Br J Cancer Date: 2018-07-17 Impact factor: 7.640