Introduction:

TMPRSS2:ERG gene fusions are the most frequent genomic alteration in prostate cancer. However, its role in selecting therapies in castrate resistant prostate cancer (CRPC) is less understood. We performed comprehensive genomic profiling (CGP) to learn whether sub-categorization of TMPRSS2:ERG fusion status would impact therapy opportunities in patients with CRPC.

Methods:

DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections of 2,424 castrate resistant acinar prostate cancer. CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci.

Results:

The genomic alterations (GA) per tumor frequencies was not significantly different between the two groups of CRPC. Amplifications and rare other short variant alterations in AR were not significantly different within the TMPRSS2:ERG fusion positive and negative CRPC. TP53 GA were significantly higher in TMPRSS2:ERG positive versus TMPRSS2:ERG negative CRPC. GA frequencies in PTEN were more frequent in TMPRSS2:ERG positive than TMPRSS2:ERG negative tumors (p<0.0001). TMPRSS2:ERG negative CRPC had higher TMB levels than TMPRSS2:ERG positive group (p=0.04). MSI-high status was more frequent in the TMPRSS2:ERG negative CRPC (p=0.01).

Conclusion:

TMPRSS2:ERG fusion positive status is associated with additional other genomic alterations in castrate resistant disease. In addition, CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMPRSS2:ERG positive and TMPRSS2:ERG negative CRPC. Given the higher levels of TMB and MSI-high status in TMPRSS2:ERG negative CRPC, TMPRSS2:ERG wild type may be a potential biomarker for immunotherapy response.

Funding: N/A