Multi-candidate immunohistochemical markers to assess radiation response and prognosis in prostate cancer: results from the CHHiP trial of radiotherapy fractionation.

Background: Protein markers of cellular proliferation, hypoxia, apoptosis, cell cycle checkpoints, growth factor signalling and inflammation in localised prostate tumours have previously shown prognostic ability. A translational substudy within the CHHiP trial of radiotherapy fractionation evaluated whether these could improve prediction of prognosis and assist treatment stratification following either conventional or hypofractionated radiotherapy.
Methods: Using case:control methodology, patients with biochemical or clinical failure after radiotherapy (BCR) were matched to patients without recurrence according to established prognostic factors (Gleason score, presenting PSA, tumour-stage) and fractionation schedule. Immunohistochemical (IHC) staining of diagnostic biopsy sections was performed and scored for HIF1α, Bcl-2, Ki67, Geminin, p16, p53, p-chk1 and PTEN. Univariable and multivariable conditional logistic regression models, adjusted for matching strata and age, estimated the prognostic value of each IHC biomarker, including interaction terms to determine BCR prediction according to fractionation.
Findings: IHC results were available for up to 336 tumours. PTEN, Geminin, mean Ki67 and max Ki67 were prognostic after adjusting for multiple comparisons and were fitted in a multivariable model (n = 212, 106 matched pairs). Here, PTEN and Geminin showed significant prediction of prognosis. No marker predicted BCR according to fractionation.
Interpretation: Geminin or Ki67, and PTEN, predicted response to radiotherapy independently of established prognostic factors. These results provide essential independent external validation of previous findings and confirm a role for these markers in treatment stratification.
Funding: Cancer Research UK (BIDD) grant (A12518), Cancer Research UK (C8262/A7253), Department of Health, Prostate Cancer UK, Movember Foundation, NIHR Biomedical Research Centre at Royal Marsden/ICR.
Competing Interests: Declaration of interests DD reports personal fees from The Institute of Cancer Research, during the conduct of the study; In addition, DD has a patent EP1933709B1 issued. EH reports grants from Cancer Research UK, during the conduct of the study; grants from Accuray Inc., grants from Varian Medical Systems, grants and non-financial support from Astra Zeneca, grants and non-financial support from Janssen-Cilag, grants and non-financial support from Bayer, grants from Roche Products Ltd, grants and non-financial support from Merck Sharp & Dohm, grants from Prostate Cancer UK, grants and non-financial support from Aventis Pharma Limited (Sanofi), outside the submitted work. AW reports a fellowship from Cancer Research UK during the conduct of the study as well as subsequent funding from AstraZeneca and imCORE. BG, HT, CG, CS, FD, CC and NS have nothing to disclose.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)