The value of Genomic Profiling at diagnosis in Poor Prognosis & Metastatic Prostate Cancer

What is it about?

The study explored the upfront evaluation of genomic mutation yield at the time of first diagnosis in men with poor prognosis prostate cancer that has a significant relapse rate despite radical therapy and poor cancer survival. The study used data from pre-biopsy imaging, guided biopsies, and modern prognostic ( Cambridge Prognostic Group/ metastatic) categorisation to confirm high yields of pre-existing cancer mutations by using pre-biopsy selection criteria of high PSA and MRI features and that samples for sequencing can be obtained without disrupting the standard diagnostic histopathology work-up. The study identified DNA damage repair (DDR) pathogenic mutations in five individuals, with four harbouring BRCA2 and one ATM, and PTEN mutations in four men, with a further three present in PI3K-related gene subunits, as well as one mutation in MTOR. The study found that specific genomic signatures may add value in management decisions and ascertaining likely future disease trajectory and survival outcomes. The UK NHS Genomics in Medicine initiative now offers selected DDR mutation profiling as part of commissioned cancer services.

Featured Image

Photo by digitale.de on Unsplash

Photo by digitale.de on Unsplash

Why is it important?

The research is important because it demonstrates for the first time in a standard clinical pathway, the feasibility and potential benefits of using baseline genomic profiling to guide personalised therapy in men with newly diagnosed CPG4/5 (poor prognosis) and primary metastatic metastatic prostate cancer. The study shows that knowledge of genomic status may help in managing treatment for this demographic of men with a high probability of treatment failure and development of disease progression. The research also confirms for the first time high yields of aggressive cancer detection by using pre-biopsy selection criteria of high PSA and MRI features and that samples for sequencing can be obtained without disrupting the standard diagnostic histopathology work-up. Key Takeaways: 1. The study confirms high yields of cancer mutation detection by using pre-biopsy selection criteria of high PSA and adverse MRI features and that samples for sequencing can be obtained without disrupting the standard diagnostic histopathology work-up. 2. This method results in high yields of genetic abnormalities. DNA damage repair (DDR) pathogenic mutations were detected in five individuals, with four harbouring BRCA2 (one germline) and one ATM (Table S2 ). All were in men with CPG 4-5/metastatic disease, representing 14% (5/37) of this sub-cohort, a much higher proportion than previously reported in unselected cohorts of newly diagnosed men. 3. PTEN mutations were identified in four men and a further three were present in PI3K-related gene subunits, as well as one mutation in MTOR (total 8/52, 15%; Table S2 ). Seven were in men with CPG 4-5 or metastatic disease representing 19% of this subcohort (7/37). 4. The research demonstrates the potential benefits of using genomic profiling at an early stage in the diagnostic pathway to guide personalized therapy in men with aggressive disease which is likely to have a poor prognosis, relapse quickly and progress to require treatment escalation.

Perspectives