title: Phospho-ERK1/2 levels in cancer cell nuclei predict responsiveness to radiochemotherapy of rectal adenocarcinoma.
abstract: Locally advanced rectal adenocarcinoma is treated with radiochemotherapy (RCT) before surgery. The response to RCT is heterogeneous and consensus regarding reliable predictors is lacking. Since the ERK pathway is implicated in radioprotection, we examined pretreatment biopsies from 52 patients by immunohistochemistry for phosphorylated ERK (pERK). Immunostaining for pERK was considerably enhanced by use of alkaline demasking. Nuclear staining occurred in both cancer cells and stromal cells. Blind-coded sections were scored by 2 independent investigators. In patients showing no residual tumor after RCT (TRG1), staining for pERK in cancer, but not stromal, cell nuclei was significantly weaker than in patients showing a poor RCT response (TRG1 vs TRG4: p = 0.0001). Nuclear staining for pERK predicted poor responders, as illustrated by receiver operating characteristic curves with an area under curve of 0.86 (p = 0.0007) and also predicted downstaging (area under curve: 0.76; p = 0.01). A number of controls documented the specificity of the optimized staining method and results were confirmed with another pERK antibody. Thus, staining for pERK in cancer cell nuclei can predict the response to RCT and may help spare poor responders this treatment. These results also raise the question whether inhibitors of ERK activation may serve as response modifiers of RCT.
authors.affiliation: Department of Pathology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Holck
authors.affiliation: Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.
authors.forename: Hans Jørgen
authors.initials: HJ
authors.lastname: Nielsen
authors.affiliation: Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Pedersen
authors.affiliation: Department of Pathology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.|Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.
authors.forename: Lars-Inge
authors.initials: LI
authors.lastname: Larsson
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D002467:Cell Nucleus / Q000378:metabolism; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis*; D010766:Phosphorylation; D012372:ROC Curve; D012004:Rectal Neoplasms / Q000473:pathology* / Q000628:therapy; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERK; immunohistochemistry; phosphorylation; radiochemotherapy; rectal carcinoma