In recent years, there have been major advances with increasing complex landscape. Multiple systemic agents have been shown to increase survival. Castrate resistant prostate cancer (CRPC) remains nuclear steroid hormone receptor-driven. There have been developments with better imaging and biomarkers for prostate cancer (tumor genomics, MRI, PET-PSMA, circulating tumor cells, and cell-free DNA). Our understanding or prostate cancer biology has also improved. We now understand that there is inter-patient heterogeneity that is likely to result in molecular treatment stratification. Myeloid-derived suppressor cells (MDSC) fuel tumor growth through the IL-23/RORy axis. Lastly, there have been multiple active agents in development that may warrant molecular stratification. These include PARP inhibitors and Cis-platinum chemotherapy that have been effective for tumors with DNA repair gene mutations, immunotherapy for tumors with mismatch repair (MMR) defects, and CDK12 mutations, and PSMA targeted radioimmunoconjugates for tumors expressing PSMA.
Prostate cancer is a highly diverse and heterogeneous group of diseases. Significant inter-patient heterogeneity exists as well, with BRCA1 defects, MMR defects, ATM loss, CDK12 mutations, PTEN loss, SPOP mutations, WNT aberrations, RB1/TP53 small cell, RAS/RAF mutations, and others.
Dr. De Bono continued and delved deeper, describing some of the mutations and their significance in more detail.
- MMR defects: These occur in 3-5% of CRPC tumors. For these mutations to have a significant effect, both gene alleles need to be lost. New Generation Sequencing (NGS) and immunohistochemistry are needed to identify these mutations. Some of these tumors might respond well to immunotherapy.
- Other DNA repair defects: These occur in 25-30% of CRPC tumors. These include high fidelity homologous recombination genes including BRCA2, BRCA1, PALB2, RAD51, and others. Loss of function of both alleles of the gene is required to impart PARP/Cis-platinum sensitivity.
- ATM loss occurs in 5-15% of CRPC tumors. This mutation is also sensitive to PARP inhibitors.
- CDK12 biallelic loss is associated with high tumor infiltrating lymphocytes (TIL) and immunotherapy response.
- PTEN loss - This is a very poor prognostic factor, with preliminary data that suggest that this associated with benefit from AKT inhibitor and no response to abiraterone
- SPOP mutations - are prevalent in 5-10% of CRPC tumors, and they are sensitive to abiraterone
- RB1 loss –Is associated with TP53 mutation (usually an early event), and also results in increased SOX2. It is found in pretreatment tumors but increases with endocrine resistance. 35% of hormone-sensitive prostate cancer tumors have some evidence of RB1 loss, while 56% of CRPC have an RB1 loss. It may be associated with loss of BRCA 2/RNAseH2B, and can have platinum or PARP inhibitor sensitivity
- AR-variant 7 (ARV7) – data is confounded by the fact that circulating tumor cells (CTC( with ARV7 mutation associates with high CTC count, so ARV7 is highly prognostic due to high CTCs. This mutation is usually rare in primary prostate cancer. It usually occurs early in the CRPC setting and is expressed after the beginning of androgen deprivation therapy (ADT) before treatment with abiraterone or enzalutamide. More than 80% of CRPC patients express this mutation. It is associated with response and survival when androgen receptor therapy is initiated, but it appears more prognostic than predictive.
- Circulating tumor cells (CTCs) analyses enable identification of single tumor cells, with an analysis the provides more precision to detect deletions accurately. It identifies intra-patient heterogeneity and enables pooling and barcoding of DNA. The RNA analyses from CTCs are still not optimized, and the low number of CTCs are a major limitation. It is possible to identify these cells using apheresis, a procedure that is well-tolerated and takes approximately two hours.
In summary, biomarker-driven disease stratification is gradually becoming a standard. The National Comprehensive Cancer Network (NCCN) guidelines have already mandated germline testing for advanced prostate cancer. Multiplex analyses of multiple biomarkers will be required. Orthogonal assays, such as NGS may be necessary as well. Advanced prostate cancer is constantly in a state of evolution, and the acquisition of genomic analyses at disease progression is something that needs to be seriously considered.
Presented by: Johann S. De Bono, Head of Division and Team Leader, Regius Professor of Cancer Research and a Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, Great Britain
References:
1. Mateo J et al. NEJM 2015
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany