EAU 2018: RNA Sequencing Identifies 3 Different Molecular Grades and Immune Checkpoint Cascades with Distinct Clinical Behavior in Non-Muscle Invasive Bladder Cancer
While there has been growing data on the molecular classification of muscle-invasive bladder cancer, into distinct molecular subtypes that are associated with clinical response and outcomes, there has been insufficient exploration into NMIBC. To that effect, the authors of this study completed whole transcriptomic (WT) analysis of 178 bladder tumours (158 NMIBC and 20 MIBC or metastatic) using formalin fixed paraffin embedded (FFPE) tissues, incorporating messenger RNA expression, splice variants, gene fusion, mutation detection and immune checkpoint inhibitor cascades. Conventional pathological grading for both WHO 1973 (grade 1, 2 and 3) and 2004 (low grade-LG vs high grade-HG) classifications was reviewed by 3 different expert uro-pathologists. They validated their findings using an independent RNA-Sequencing dataset (n=209, Hedegaard et al. 2016 Cancer Cell).
Unsupervised clustering of data from RNA-Seq distinguished three molecular subtypes of NMIBC, termed Molecular Grade Related Index (MGRI) 1, MGRI2 and MGRI3. MGRI1 was comprised of almost exclusively LG tumours, while MGRI3 clustered with primarily HG MIBC tumours. MGRI2 was a mix of LG and HG tumors.
Review of the samples by expert uro-pathologists demonstrated kappa values for interobserver variability of 0.40 (1973 WHO histological grading) and 0.78 (2004 classification), which is quite poor. The MGRI classification may help reduce this variability by taking the subjectivity out of the grading.
Looking at clinical outcomes, MGRI was a strong predictor of clinical outcomes. MGRI independently predicted progression to MIBC (n=138, HR=2.96, 95%CI=1.70-5.13, p=1.20x10-04). Five year progression-free survival in a combined data set (n=347) differed significantly for MGRI1 (100%) vs MGRI2 (92.2%) vs MGRI3 (73.5%, p=1.99x10-05, Gray’s test). Importantly, patients with MGRI1 never progressed to more advanced disease!
This data suggests that molecular grading can help overcome the deficiencies of the current pathologic grading schemes and help better identify patients with NMIBC at risk of progression.
In a separate preliminary analysis, the authors began to explore the role of the immune checkpoint cascades in NMIBC. They assessed each of the key immune checkpoint targets, but also compiled all major genes in each cascade as a separate index. While none of the individual genes was associated with risk of recurrence or progression, the PD-1 ICC (index of all the genes involved in the PD-1 pathway), was an independent predictor of recurrence. Hence, the authors suggest that evaluation of the entire pathway may be more important than any one gene in the setting of NMIBC. However, this is still preliminary data.
Presented by: Thenappan Chandrasekar, MD Clinical Fellow, University of Toronto
Co-Authors: Zlotta A.1, Shen J.2, Noon A3, Jiang H4, Ehrlich A5, Kuk C.5, Ni R.6, Sukhu B.6, Chan K.6, Roupret M.7, Seisen T.7, Comperat E.8, Sweet J.9, Kulkarni G.1, Fleshner N.1, Azad A.6, Van Der Kwast T.9 , Wrana J.6
Author Information:
1. University of Toronto, Dept. of Surgical Oncology, Toronto, Canada
2. Mount Sinai Hospital, Dept. of Surgical Oncology, Toronto, Canada
3. University of Sheffield, Dept. of Urology, Sheffield, United Kingdom,
4. University Health Network, Dept. of Statistics, Toronto, Canada,
5. University of Toronto, Dept. of Surgical Oncology, Toronto, Canada
6. Mount Sinai Hospital, Dept. of Pathology, Toronto, Canada
7. Universit. Pierre et Marie Curie, Dept. of Urology, Paris, France
8. Universit. Pierre et Marie Curie, Dept. of Pathology, Paris, France
9. University Health Network, Dept. of Pathology, Toronto, Canada
Written by: Thenappan Chandrasekar, MD Clinical Fellow, University of Toronto, twitter: @tchandra_uromd at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark