Washington, DC USA (UroToday.com) At the 20th Annual Meeting of the Society of Urologic Oncology, Dr. Daniel Spratt reviewed the evolving role of genomic biomarkers in localized prostate cancer. The definition of high-risk localized prostate cancer was conceived approximately 20 years ago and has had few modifications since. The 2019 NCCN guidelines define this disease entity as follows: Gleason scores 8-10, cT3-4 disease, and PSA > 20 ng/ml. Other methods of subclassification using clinical features include the CAPRA, D’Amico, Hopkins, Zumsteg, and Nguyen nomograms just to name a few. While many of these nomograms (notably CAPRA) have excellent prognostic value, once patients are categorized within a subgroup, there is a certain loss of discriminatory power.
High-risk cancers are not created equal, and there is certainly heterogeneity with respect to their natural history and response to treatment. Some high-risk cancers are not lethal; the SPCG-4: radical prostatectomy versus watchful waiting (WW) trial showed that only 35% of high-risk men on WW die of prostate cancer by 18 years, and 20% of men on WW die of other causes with no metastases or use of ADT. Similarly, some high-risk cancers are “indolent” once treated. RTOG 9202 EBRT + 4 months versus 28 months ADT showed high levels (>80%) of metastasis-free probability at 20 years.
Dr. Spratt describes that of all high-risk prostate cancer cases, 20% are indolent, 50% are indolent with standard treatment, 10% need standard treatment intensification, and 20% need novel treatment strategies. Within high risk disease, clinical nomograms have a limited ability to predict who will harbor biologically significant disease—10-year metastasis AUC is 0.45 for NCCN and 0.60 for CAPRA. There is a need for additional methods that will improve granularity and discriminatory power.
The biology of high-risk localized prostate cancer is different from metastatic prostate cancer, with few known common DNA alterations. In locoregional disease, only 1-2% share common mutations (Rb1, ATM, AR, and most prominently BRCA2), and a high proportion (40-50%) of patients without any mutations develop recurrence, suggesting that mutations do not explain all high-risk phenotypes. Alternatively, the entire prognostic signature of mRNA expression can be evaluated, and studies that have done so have demonstrated significant mRNA expression heterogeneity.
There are known patterns of protein expression that have been associated with tumor behavior. Androgen receptor (AR) expression has been shown to correlate with metastatic potential. Low AR-active tumors have very high metastatic potential and are the tumors that are often not cured with definitive therapy. These aggressive clinical entities comprise 10% of prostate cancer and require novel and/or more aggressive treatment strategies.
In summary, mutations do occur in high-risk localized prostate cancer, but are uncommon and do not explain the majority of clinical observations. RNA testing demonstrates significant heterogeneity in this clinical entity and has been shown to outperform standard clinical (e.g. clinical nomograms) and pathologic variables. Many other emerging areas of relevant biology are not yet elucidated (e.g. IncRNA, epigenetics). The use of genomic biomarkers may help further sub-stratify patients with high-risk local prostate cancer and allow appropriate selection for novel or intensified treatment.
Presented by: Daniel Spratt, MD Associate Professor Laurie Snow Research Professor of Radiation Oncology Associate Chair, Clinical Research Chair, Genitourinary Clinical Research, Rogel Cancer Center Director, Spine Oncology Program, Rogel Cancer Center
Written by: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, @selmasic at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC