ESOU 2019: Treatment of Positive Pelvic Lymph Nodes: Genomics

Prague, Czech Republic ( The assessment of genomics as part of the treatment of men with positive lymph nodes was presented by Dr. Kristiansen from Germany. He notes that the molecular classification of localized prostate cancer is a diverse landscape but predominantly made up of TMPRSS2-ERG, TP53, PTEN, SPOP mutants, CHD1, and ETS rearrangements. In this presentation, Dr. Kristiansen briefly highlighted several of these important genes.

PTEN (phosphatase and tensin homolog gene) is an inhibitor of PI3K signaling, is deleted in 40% of prostate cancers, and is an inactive mutation in 5-10% of tumors. PTEN loss has prognostic significance in that patients with homo- or heterozygous loss of PTEN have worse PSA-recurrence free survival compared to those with normal PTEN.

ETS-gene fusions are recurrent gene fusions of androgen-regulated genes with ETS genes, most commonly the TMPRESS2-ERG combination. These rearrangements are found in 30-80% of prostate cancers and provide mechanistic evidence for the importance of tumorigenesis (with AR/PTEN/c-Myc). For example, in mouse models, aberrant ERG expression cooperates with loss of PTEN to promotes cancer progression in the prostate. TMPRSS2-ERG fusion-positive patients in several studies have been associated with greater PSA recurrence-free survival compared to TMPRSS2-ERG fusion negative tumors. PTEN and ERG are also useful as a marker for intraductal carcinoma, as these tumors are often PTEN-negative and ERG-positive.

SPOP (speckle-type POZ protein) is the most common point mutation in prostate cancer at 6-13% prevalence; it is a substrate binding member of the Cullin-3 based ubiquitin ligase complex. In mouse models, SPOP mutations induce invasive adenocarcinoma in PTEN-negative tumors, as well as activate AR and PI3K signaling pathways. The BET-proteins are SPOP substrates; BRD4 is a tumorigenic substrate in vivo and in vitro. SPOP mutations lead to BET-accumulation and induce resistance towards BET-inhibitors. BRD4-accumulation amplifies AKT signaling and AKT-inhibitors overcome resistance against inhibition.  Dr. Kristiansen posed the question: is there any role for AR splice variants in locally advanced prostate cancer? In his opinion, probably not as there are very low levels of AR alterations in hormone naïve patients.

Turning to the commonly used prognostic transcript signatures (Oncotype Dx, Prolaris, and Decipher), there is recent evidence that the genomic make-up varies widely among prostate cancer foci. Wei et al.1 found considerable variability in genomic alterations among prostate cancer cores, and between RNA- and DNA-based genetic platforms. Heterogeneity was found in the molecular grouping of individual prostate cancer foci and the activity of gene sets underlying the assays for risk stratification and androgen receptor activity. More recent studies have suggested no difference between isolated GG1 tumors and GG1 tumors with high-grade components elsewhere, although these studies require validation. According to the World Health Organization, “tumor heterogeneity and sampling biases remain major unsolved problems with all molecular tests.”

Dr. Kristiansen concluded his presentation with several take-home messages:

  • Molecular diagnostics in localized prostate cancer is evolving
  • There is specific interest in the role of PTEN
  • Based on the current evidence, there is an unlikely role for ARv7 in localized disease
  • Tumor heterogeneity is a major obstacle, particularly for the current commercial biomarker tests

Presented by: Glen Kristiansen, MD, Full Professor and Chairman, Institute of Pathology, University Hospital, Bonn, Germany 

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 16th Meeting of the European Section of Oncological Urology, #ESOU19, January 18-20, 2019, Prague, Czech Republic

1. Wei L, Wang J, Lampert E, et al. Intratumoral and Intertumoral Genomic Heterogeneity of Multifocal Localized prostate cancer impacts molecular classification and genomic prognosticators. Eur Urol 2017 Feb;71(2):183-192.

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