There are several known mechanisms in CRPC patients, including hyper-mutated phenotype in approximately 5% of PC in published cohorts, mismatch repair (MMR) gene mutations, and microsatellite instability (MSI). MSI and MMR loss has been found to be correlated to immunotherapy. Emerging data in CRPC links response to anti-PD1 therapy and MSI. This is relevant as Pembrolizumab has been recently approved by the FDA for all cancers with MSI or MMR loss based on 5 phase I/II trials. Should we therefore perform routine testing of MSI and/or MMR loss in all CRPC patients, based on these trials?
Androgen receptor (AR) mutations, AR amplification, AR structural re-arrangements, and AR splice variants are associated with resistance to AR directed therapies. When treatment resistance is identified, metastatic biopsies should be considered. We know that treatment resistance after primary and secondary hormonal therapies involve reactivation of the AR. It is still not clear whether less AR resistance will occur with the earlier use of abiraterone for metastatic PC.
One extreme non-AR driven CRPC phenotype, which is the castration resistant small cell /neuroendocrine PC. These are treated like small cell lung cancers, with platinum. These manifest clinically aggressive disease, with visceral metastasis, and low PSA progression. In these specific tumors, it has been noted that there is lower AR expression and signaling. Interestingly, this unique PC evolved clonally from prostate adenocarcinoma during CRPC progression.
Dr. Beltran summarized her lecture with some further aspects that we should explore in the future. These include gene expression, epigenetics, metabolism, tumor microenvironment, immune response, hereditary/germline factors, and pharmacogenetics. It is important we take the next step and extend information from emerging research cohorts and single patient examples to larger populations.
Presented by: Himisha Beltran
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre.Twitter: @GoldbergHanan at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal