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

Abstract

BackgroundNeuregulins (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.ResultsOf 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.MethodsA 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.ConclusionsNRG expression is not associated with either OS or PFS, but is a predictor of benefit from anti-HER3 antibodies.

Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non–small cell lung cancer

“…NRG1 was found to be associated with responses to ERRB3/HER3 inhibitory antibodies in a variety of tumor types (28, 29) and with resistance to cetuximab in colon cancer (30) . NRG1 was not independently associated with survival (29) , suggesting it is predictive of therapeutic benefit rather than prognostic.…”

Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients

“…has become the focus of research attention because of its overexpression in various cancers, including breast, urinary bladder, colorectal, prostate, and lung cancers [6]. In breast cancer, NRG1 overexpression was observed in approximately 30-80% of cases.…”

“…Because of the close relationship between NRG1 and HER3, NRG1 expression has been suggested as a predictive biomarker for HER3 inhibition [6,11]. In addition, NRG1 can promote resistance to HER2-targeted therapy through activation of HER3 and PI3K/Akt signaling both in vivo and in vitro [9,34,35].…”

“…NRG1 is the predominant ligand of HER3 and HER4. Through binding to HER3, it functions in specific regulation of cell proliferation and organ development [6,7]. Additionally, NRG1 can induce carcinoma development and promote metastasis [7].…”

“…Heterodimer containing HER3 can activate the following two key signaling pathways: mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt [12]. In various cancers, HER3/HER2/PI3K/Akt signaling promotes tumor cell proliferation and survival [6,12,13]. Several studies have demonstrated associations between HER3 protein expression and poor survival in various cancers including GC [14][15][16][17].…”