The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited

Area of Science:

• Oncology
• Genomics
• Prostate Cancer Research

Background:

• Metastasis is increasingly viewed as a disease spectrum, not a binary state.
• Oligometastasis, a state of limited metastatic burden, may benefit from local therapies.
• Current definitions of oligometastasis rely solely on numerical lesion counts.

Purpose of the Study:

• To characterize the somatic mutational landscape in metastatic castration-sensitive prostate cancer (mCSPC).
• To identify a biological definition of oligometastatic CSPC based on mutational profiles.
• To correlate genomic alterations with disease progression and outcomes.

Main Methods:

• Retrospective analysis of mCSPC patients undergoing clinical-grade tumor sequencing.
• Classification of patients into biochemically recurrent, oligometastatic, polymetastatic, or de novo metastatic groups.
• Assessment of driver mutation frequencies and their association with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).

Main Results:

• Driver mutations in TP53, WNT, and cell cycle genes increased across the mCSPC spectrum.
• TP53 mutations were linked to shorter rPFS and time to CRPC in oligometastatic disease.
• TP53 and DNA double-strand break repair mutations correlated with a higher number of metastases and poorer outcomes.

Conclusions:

• Somatic mutational profiles offer a biological definition of metastatic disease spectrum.
• This approach can complement numerical definitions of oligometastasis.
• Genomic insights may refine treatment strategies for mCSPC.