Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

// Alberto Ocaña 1 , Laura Díez-González 1 , Azucena Esparís-Ogando 3, 4 , Juan Carlos Montero 3 , Eitan Amir 2 , Atanasio Pandiella 3 1 Translational Research Unit, Albacete University Hospital, Albacete, Spain 2 Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada 3 Cancer Research Center (CIC-IBMCC), CSIC-University of Salamanca, Salamanca, Spain 4 IBSAL, Salamanca, Spain Correspondence to: Alberto Ocaña, e-mail: albertoo@sescam.jccm.es Keywords: neuregulin, anti-HER3, prognostic value, predictive role Received: February 20, 2016      Accepted: March 28, 2016      Published: April 08, 2016 ABSTRACT Background: Neuregulins (NRG) are a family of epidermal growth factor ligands which act through binding to HER3 and HER4 receptors. NRGs are widely expressed in solid tumors. Their prognostic significance or their role as predictors of benefit from anti-HER3 therapy is not known. Results: Of 29 included studies, 7 studies reported the association between NRG and outcome. NRG was most commonly expressed in breast, prostate, colon and bladder cancers. NRG expression was not associated with either OS or PFS (HR: 3.47, 95% CI 0.78–15.47, p = 0.10 and HR: 1.64, 95% CI 0.94–2.86, p = 0.08, respectively). In 4 placebo controlled trials of anti-HER3 therapy, the addition of anti-HER3 antibodies to control therapy in unselected patients was not associated with improved PFS (HR: 0.88, 95% CI 0.75–1.04. p = 0.14). However, in patients with high NRG expression, there was significantly delayed progression (HR: 0.35, 95% CI 0.23–0.52, p < 0.001). Anti-HER3 antibodies were associated with increased risk of diarrhea, nausea and rash. Methods: A search of electronically available databases identified studies exploring clinical outcomes based on NRG expression, as well as placebo-controlled trials of HER3-directed therapy reporting results based on NRG expression status. Data were combined in a meta-analysis using generic inverse variance and random effects modeling for studies reporting the hazard ratio (HR) for overall (OS) or progression-free survival (PFS). Mantel-Haenszel random-effect modeling was used for odds ratio (OR) for 3-year and 5-year OS and PFS. Conclusions: NRG expression is not associated with either OS or PFS, but is a predictor of benefit from anti-HER3 antibodies.