Methods:
In this study, DNA was extracted from 40 microns of formalin fixed paraffin embedded (FFPE) specimens from refractory CDC (46 cases) and RMC (24 cases). Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of > 800X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. Microsatellite instability status (MSI) was determined on 114 loci.
Results:
All CDC patients were older and more frequently male (Table 1). Sickle cell trait was identified in both CDC and RMC, but far more frequently associated with RMC. All CDC and RMC patients had clinically advanced Stage III and IV tumors with the primary tumor used for CGP in 70% of cases and a metastasis biopsy was sequenced in 30%. All CDC and RMC cases were intermediate (Grade 3) or high grade (Grade 4). In both tumor types, the genetic alteration/tumor was relatively low and there were no VHL genetic alteration. SMARCB1 genetic alteration were significantly more frequent in RMC than CDC but common in both tumors. Targeted therapies for kinase (EGFR, RET) and MTOR (NF2, TSC2) pathways were more frequent in CDC than RMC. At 1.8 mut/Mb, the median TMB was low for both tumor types with none of the cases showing ≥2 0 mut/Mb. None of the CDC or RMC cases featured MSI-high status.
Table 1 – Comparison of CDC and RMC cases:
Conclusions:
In addition to their histologic differences, the frequencies and types of genetic alterations seen in CDC differ significantly from those seen in RMC. The opportunities for biomarker driven targeted therapies for both CDC and RMC appear limited with rare opportunities to target genetic alterations in TKGFR and MTOR pathways for CDC. Similarly, the relatively low TMB and absence of MSI-High status in CDC and RMC also predicts that these tumors may be resistant to immunotherapies.
Presented by: Gennady Bratslavsky, NY, USA
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan, at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA