A Luminal Non-Coding RNA-Based Genomic Classifier Confirms Favourable Outcomes in Patients with Clinically Organ-Confined Bladder Cancer Treated with Radical Cystectomy - Beyond the Abstract

In 2017, the Cancer Genome Atlas (TCGA) bladder cancer program undertook a large, multi-omic molecular profiling effort to characterize muscle-invasive bladder cancer (MIBC). In this study, the TCGA used the long non-coding RNA transcriptome to divide their luminal-papillary mRNA subtype into two biologic subgroups with distinct prognosis, suggesting additional granularity to subtyping may have further clinical utility.¹

Long non-coding RNAs (lncRNAs) are mRNA-like transcripts that range in length from 200 nucleotides to over 100 kilobases and lack open reading frames so they are not translated into proteins. Although the biological functions of many lncRNAs remain unclear, their expression patterns have been associated with biological or disease states, facilitating opportunities for biomarker development.² Nevertheless, Since the TCGA is based on a population of patients, there was a need to develop a single-sample genomic classifier for identifying these cancers from personal patient gene expression profiles.

As such, we expanded upon these initial TCGA findings and further explored the utility of lncRNA expression profiling in a follow-up study from 2019, characterizing a biologically distinct subset of luminal muscle-invasive bladder cancer associated with favorable prognosis. Within the luminal subtype, there was a distinct group that differed from other luminal cases in terms of biological signatures related to less aggressive behavior including wild type p53 activity and increased hedgehog signaling. Tumors with luminal favorable signature also have lower immune signature scores and higher tumor purity scores, suggesting these tumors are immune cold. This observation may be in line with the mechanism described in detail by Tate et al., who suggested that PPARG is likely to be important for inducing the immune cold phenotype in luminal bladder tumors.³

Whereas previous studies found lower levels of upstaging for tumors with luminal subtype relative to non-luminal subtype,⁴ the present study which evaluated patients with clinically organ-confined bladder cancer who underwent immediate cystectomy without neoadjuvant therapies reported both favorable survival outcomes and the lowest rates of pathological upstaging for the luminal favorable tumor subgroup. As such, it can be hypothesized that these luminal bladder cancers might be managed with immediate radical cystectomy rather than undergo neoadjuvant therapy if the disease is clinically localized. Interestingly, future trials evaluating these observations in a prospective fashion are eagerly awaited. In context, the GUSTO trial spares neoadjuvant therapy in MIBC classified as luminal-papillary by the TCGA model⁵ and LUMBER-NAC will evaluate sparing NAC in GSC luminal cT2N0 MIBC.⁶

While the number of systemic therapeutic regimens is emerging, luminal subtypes have also been demonstrated to be associated with higher expression of targets for antibody drug conjugates, such as NECTIN4.⁷ Moreover, since luminal favorable bladder cancers express the highest FGFR3-activity scores, they may benefit from targeted therapies such as FGFR inhibitors. As such, future molecular profiling of tumors treated with neoadjuvant targeted therapies is encouraged to shed light on whether luminal-type tumors are the ideal candidates for these novel therapeutic regimens.

1. Erasmus University Medical Center, Rotterdam, The Netherlands
2. Veracyte Inc. United States of America
3. Department of Urology, University of Texas Southwestern, United States of America

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