SIU 2018: Interpretation and Clinical Implication of Cancer Genetics in Uro-Oncology - Prostate Cancer

Seoul, South-Korea (UroToday.com) In this session, Dr. Byun highlighted the current status of cancer genetics in the prostate cancer realm. Naturally, this is a very broad topic to cover in 15 minutes, so he highlighted some key topics without delving too much into the details. In the summary below, those key points are highlighted.

The landscape of PCa continues to change rapidly. This diagram, already somewhat outdated, demonstrates the spectrum of PCa managed by urologists and medical oncologists. 
Progression of PCa and the Development of mCRPC

There are numerous commonly altered genes in the PCa spectrum, and their function has been slowly delineated through numerous studies. Some of the most common ones include: AR, ATM, BRCA1/2, ERG, MLL1-3, MYC, PTEN, RB1, TP53.

Numerous studies have demonstrated the added benefit of mutational signatures to clinical risk stratifiers in predicting outcomes, yet, translating that to clinical practice has been difficult. We also know that tumor microenvironment contributes to treatment response and resistance … and may confound the effect of genetics and genomics alone.

While there is value to understanding cancer genomics from PCa development all the way to progression to mCRPC, we need to add clinical application to this knowledge. It comes in 2 ways: develop prognostic/predictive biomarkers and to identify druggable targets to develop new therapies for localized and advanced prostate cancer.

The flowchart of PCa biomarkers and where they fit in:
Flowchart of Genomic PCa Biomarkers
1. Susceptibility biomarkers
  • Includes SNPs, rare germline mutations, STHLM3 (Stockholm 3) model
  • These help identify men in a specific population that should undergo screening – helps increase yield of PSA screening in a higher risk population
  • Especially true in Asian countries when PCa risk is lower and general PSA screening is NOT recommended
  • His group has been working on exome-based GWAS studies in the Korean population to help improve screening
2. Biomarkers of Disease Risk
  • Includes: MI-Prostate score, %fPSA, 4K score, PHI, SelectMDx, ExoDx, PCA3, ConfirmDx
  • These help identify who to biopsy after being screened
3. Risk stratification after biopsy
  • Includes: Oncotype Dx, Prolaris, Decipher
  • These help determine need for adjuvant therapy or decision on primary treatment
4. Biomarkers of treatment response
  • Includes: AR-V7 status (predicts response to oral ARAT’s), DNA repair gene mutations (predicts response to PARP inhibitors or chemotherapy)
  • There are numerous ongoing trials looking at PARP inhibitors in this setting (CRPC)
  • These help determine which systemic therapy to utilize in advanced disease
He briefly highlighted the recent data on germline genetic mutations (Pritchard et al, NEJM) that demonstrated that 12% of men with metastatic prostate cancer had germline genetic mutations. 

There are numerous germline assays and somatic mutation assays now available – yet, this is not standardized. Important to work with genetic counselor to understand the implications of the test results. The two slides below highlight the available germline (first slide) and somatic (second slide) tests available in the United States.

Germline Commercial tests available:
Commercial Germline / Genetic Testing

Somatic commercial tests available:
Commerical Genomic Testing Tumor Profiling Companies

There is obviously much more the genomic landscape of prostate cancer, but this was a nice summary of where these tests fit in and how they can impact diagnosis and management.

Presented by: Seok Soo Byun, South Korea

Written By: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University Twitter: @tchandra_uromd, @TjuUrology at the 38th Congress of the Society of International Urology - October 4- 7, 2018 - Seoul, South Korea
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