ASCO GU 2017: Keynote Lecture, Emerging Impact of Genomics on the Clinical Management of Bladder Cancer

Orlando, Florida USA (UroToday.com) David McConkey, Johns Hopkins School of Medicine, gave the keynote lecture regarding genomics and bladder cancer. Genomics can inform diagnosis and prognostication. Collaborative efforts and completion of large-scale genomics projects have led to the most recent checkpoint blockade in advanced bladder cancer. Whole transcriptome profiling has provided a much more granular description of bladder cancer. Molecular subtypes of muscle-invasive bladder cancer are separated into basal and luminal subtypes. Basal correlate to the triple negative breast cancers which is an ominous finding. Basal and luminal cells arise from basal and luminal epithelium which may be distinguished by immunohistochemistry (IHC), respectively. Validation of the IHC data are forthcoming. The genomic subtypes urobasal A correlate with unstable luminal tumors. UroA and contain distinct long non-coding RNA signatures which may aid in identifying these tumors.

Bladder cancer variants present diagnostic and clinical challenges. Basal tumors contain squamous features with micropapillary tumors being ‘luminal’ with distinct gene signatures. Thus, the genomics may aid in diagnosis of these tumors. Clinical features of basal tumors are more prevalent in women and more advanced. Identification of DNA repair alterations are a marked advancement in the selection of treatment in patients. When assessing outcomes in a large meta-dataset, p-53 and luminal subtypes had poor chemotherapy response confirmed in the TCGA cohort. Basal bladder cancer cells are more sensitive to chemotherapy. The reason for these varying response to chemotherapy are being explored. The COXEN trial is further assessing these findings prospectively. Is response to checkpoint blockade predictable? Findings supporting this assumption are loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. PPAR gamma may inhibit T cell infiltration which are noted in luminal subtypes which may have important biological implications in non-muscle invasive bladder cancer.

Immune infiltration in matched BCG-resistant tumors are being explored including the assessment of gene therapy using rAd-IFN instillation to induce T cell infiltration in refractory tumors. Inhibiting FGFR3 may also promote T cell infiltration. In summary, benefit from neoadjuvant chemotherapy may be predictable with genomics. The immune landscape in luminal tumors could present challenges for the efficacy of immune checkpoint blockade.

Presenter: David McConkey, Johns Hopkins School of Medicine

Written By: Stephen B. Williams, MD, Assistant Professor, The University of Texas Medical Branch at Galveston, Galveston, TX and Ashish M. Kamat, MD, Professor, The University of Texas MD Anderson, Houston, TX

at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA

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