A miRNA Signature Predicts Benefit from Addition of Hypoxia-Modifying Therapy to Radiation Treatment in Invasive Bladder Cancer - Beyond the Abstract

Organ preservation tri-modality therapy for locally advanced bladder cancer involves transurethral resection of the bladder tumor followed by radiotherapy with a radiosensitizer. The radiosensitizer could be hypoxia-modifying therapy or chemotherapy.1 Both approaches achieve similar survival benefits, but a predictive biomarker would enable a personalized and optimized choice.1 Our group develops hypoxia-associated, tumor type-specific gene expression signatures. The signatures are prognostic in multiple cohorts and predict benefits from having hypoxia-modifying therapy with radiotherapy.

Our signatures and others that entered the clinical arena (e.g. Oncotype DX, MammoPrint) measure mRNA expression, which comprises <5% of the total RNA produced by cells. There is increasing interest in biomedical sciences in non-coding RNA (e.g. miRNA) and their role in regulating gene expression. As miRNAs are small (~22 nucleotides) they are more stable than mRNAs and so less likely to undergo degradation following tissue preservation in formalin and storage in paraffin. Therefore, we aimed to derive a miRNA hypoxia signature in invasive bladder cancer and compare its performance with our previously published 24-gene mRNA-based bladder signature.2,3

We developed the signature using The Cancer Genome Atlas (TCGA) data and a list of candidate seed miRNAs that were up-regulated under hypoxia in at least two of four bladder cancer cell lines. The seed genes were filtered to identify those most likely to reflect hypoxia in bladder cancer samples. This filtering involved testing for similarity with a signature developed to assess hypoxia in multiple tumor types. A 14-miRNA signature was derived. The 14 miRNA signature was prognostic in the TCGA dataset used to develop the signature, showed a trend in a TCGA test data set, and was prognostic in an independent cohort of 62 muscle-invasive bladder cancer patients. Final testing involved the BCON trial that randomized bladder cancer patients to radiotherapy only or with hypoxia-modifying carbogen and nicotinamide (CON). The 14-miRNA signature predicted benefit from CON and performed similarly to our 24-mRNA signature. Patients classified as having hypoxic tumors using a combination of the two signatures had a 3-year overall survival rate of ~25% following radiotherapy alone, which increased to ~65% with the addition of CON. As tumor hypoxia is associated with a poor prognosis irrespective of treatment (surgery, radiotherapy), the study shows the potential of gene signatures to select MIBC patients with hypoxia-modifying therapy. Our next step is to test the combined signature in a prospective clinical trial.

Written by: Mairah T. Khan, Ananya Choudhury, and Catharine M.L. West

Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester, UK

  1. Song YP, McWilliam A, Hoskin PJ, Choudhury A. Organ preservation in bladder cancer: an opportunity for truly personalized treatment. Nat Rev Urol. 2019;16(9):511-22.
  2. Hall JS, Taylor J, Valentine HR, Irlam JJ, Eustace A, Hoskin PJ, et al. Enhanced stability of microRNA expression facilitates classification of FFPE tumour samples exhibiting near total mRNA degradation. Br J Cancer. 2012;107(4):684-94.
  3. Yang L, Taylor J, Eustace A, Irlam JJ, Denley H, Hoskin PJ, et al. A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High-Risk Bladder Cancer Patients. Clin Cancer Res. 2017;23(16):4761-8.

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