ASCO GU 2018: The Clinical Role of Germline and Somatic Genomics and the Risk-Stratification of Localized Prostate Cancer

San Francisco, CA ( Dr. Rob Bristow, previously at the Princess Margaret Cancer Centre, Toronto, Canada, is now at the University of Manchester as the Director of the Manchester Cancer Research Center. With an expertise in advanced prostate cancer, he is the invited keynote speaker. Today, he provided a tour-de-force review of the current literature focusing on germline and somatic mutational landscape in prostate cancer, specifically localized prostate cancer.

He provided a rapid review of the key developments in this field, including some of his groups work in the area. Below is a brief summary of the talk.

Tumor Complexity and Genomics - There is a need for better risk stratification in non-indolent, localized prostate cancer. This has led to the development of numerous genomic tests in this disease space. However, its uncertain where we go with these genomic markers.

Currently, there is a distinct divide between clinically localized T1-T4 N0M0 prostate cancer and metastatic T1-T4 N1 M1. The former is curable, but the latter is now. The latter is treated with systemic therapies, and there is increasingly a trend to bring those treatments into the former. Additionally, there is a lot of work being done to help prevent the transition from the former to the latter, and hence, a lot of work in the grey space between.

Currently, as new prognostic assays are developed, they help identify at risk patients for worse outcomes – if negative, there is no change to management. However, if these tests are positive, there is an intensification of the planned treatment. However, in order for these prognostic tests to become predictive factors, the intensification of treatment needs to actually result in better outcomes!

He specifically called out a paper by Cucchiara et al as an excellent review of the current genomic tests available in the localized prostate cancer setting. The citation is as follows: Cucchiara V, Cooperberg MR, Dall'Era M, Lin DW, Montorsi F, Schalken JA, Evans CP. Genomic Markers in Prostate Cancer Decision Making. Eur Urol. 2017 Nov 9. pii: S0302-2838(17)30975-2. doi: 10.1016/j.eururo.2017.10.036. [Epub ahead of print] Review.

He then spent some focused time on the genomic classifier (GC), as some of his work utilized this in this disease space. Specifically, prior studies demonstrated that GC predicted metastases rates following RP. One of his poster presentations at this conference then utilized the GC to predict biochemical recurrence based on pre-radiotherapy biopsy pathology. He also highlighted another abstract by Nguyen et al (“Prospective analysis of 4,474 prostate biopsies to evaluate potential treatment management impact of combined clinical-genomic risk classification”, Abstract 39 – summary available online), which evaluated the impact of Decipher genomic test on decision making.

He spent some time on the role of newer tests that have begun to examine other changes in PCa, including stromal microenvironment. A study by Wo, Wang and Collins (2018 European Urology) found that they were able to predict metastatic spread in patients with localized prostate cancer based on stromal tissue rather than cancer tissue. This highlights the importance of the surrounding environment on clinical outcomes.

There are numerous risk stratification strategies currently being evaluated. He highlighted the importance of team science, and the involvement of multiple disciplines to complete good research in this field.

He then highlighted some of the work his lab has been involved in. A recent paper identified that tumor genomic and microenvironmental heterogenenity predicted 5-year BCR-free survival. Another one of his papers found that evaluation of pre-treatment biopsy pathology and recurrence after radiotherapy treated with salvage RP revealed that there the focus of recurrent disease was present on pre-treatment biopsy. This likely suggests a radio-resistant focus of cancer that has now had a chance to progress without any direct competition. Better identification of these tumor cells may allow for better selection for primary surgical management.

He then examined the coexisting relationship between tissue hypoxia, presence of intraductal carcinoma (IDC) and SCHLAP-1 mutations. Absence of all three was associated with very low metastatic spread or PSA relapse. However, patients with all 3, termed “nimbosus” or latin for “gathering of clouds,” had very high (40%) 10-year risk of distant metastases and 25% change of relapse within 18 months.

Lastly, he addressed briefly the interest in the germline and somatic mutations, such as BRCA, which can drive aggressive prostate cancer especially in younger men. BRCA2 seems to be the most aggressive, predisposing to very aggressive prostate cancer.

Despite this rapid overview of the up-to-date development of germline and somatic genomics and the Risk-Stratification of Localized Prostate Cancer, there is still a lot of work to be done to shift the focus from prognostication to predictor, and more importantly to change management.

Speaker: Rob Bristow, Manchester Cancer Research Center, University of Manchester, UK

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA