Genetics-Driven, Intensity-Modulated Adaptive Management of Patients With Metastatic Prostate Cancer

Survival differs markedly between men with metastatic prostate cancer (mPC) confined to lymph nodes (LNM) versus bone (BM). We examined whether site-specific genomic alterations-and their combinations-explain this disparity and could inform intensity-modulated follow-up or therapy.

Clinical and targeted-sequencing data for 1011 men with mPC in the cBioPortal for Cancer Genomics registry were analyzed (LNM-only = 622; BM-only = 389). Genes altered in > 5% of tumors (two-sided p < 0.05) were assessed individually and in every possible multigene cluster for associations with overall survival (OS). Survival was evaluated with Kaplan-Meier curves and the difference in restricted mean survival time (dRMST) to pinpoint the first significant curve divergence. Synthetic-lethal (SL) interactions were explored via the SLOAD database.

In total, 18 of 184 profiled genes (9.8%) exceeded the 5% alteration threshold. FOXA1 was enriched in BM, whereas TMPRSS2, ERG, PTEN, ZFHX3, CDK12, and KMT2C were enriched in LNM (p < 0.05). Among 9143 tested gene clusters, 65 were associated with inferior OS; 48 occurred in the LNM subgroup, 17 in the combined cohort, and none in the BM alone. High-risk clusters showed first OS divergence 10-60 months after diagnosis of metastasis. SLOAD identified 615 putative SL pairs involving these genes.

We identified 65 site-specific multigene clusters-chiefly in lymph node-only mPC-that underlie the survival gap between nodal and bone metastases. These signatures suggest a 10-60-month interval that may lend itself for intensity-modulated follow-up. We also discovered hundreds of synthetic-lethal gene-alteration pairs, opening future research opportunities in combinatorial therapeutic targeting.