Integrative Multi-Region Molecular Profiling of Primary Prostate Cancer in Men with Synchronous Lymph Node Metastasis

Prostate cancer is a highly heterogeneous disease, with variable clinical trajectory and response to therapy. In cases of primary, localized prostate cancer, it is common to find multiple distinct tumor foci, each exhibiting considerable histologic and genomic variability both within and between tumors. Despite this knowledge, identifying the "biologically dominant" lesion responsible for driving aggressive clinical behavior in multifocal primary prostate cancer remains elusive.

For a given patient, knowledge of which clone (or clones) is most likely to give rise to metastasis has the potential to inform management, including selection of surveillance versus treatment, risk stratification using tissue-based prognostic biomarkers, evaluating appropriateness for focal therapies, and for development of novel treatment strategies.

In this study, targeted next-generation RNA and DNA sequencing was used to perform molecular profiling of 103 primary prostate cancer and 28 lymph node metastasis samples from 18 men after radical prostatectomy and lymph node dissection. Phylogenetic trees were constructed to trace the clonal evolution of primary prostate cancer to synchronous lymph node metastasis.

Our analysis showed significant intra- and inter-tumoral heterogeneity among the primary prostate cancer samples, with relative homogeneity among the lymph node metastases in a given patient. Several pathological features, including high histologic grade, presence of cribriform pattern, and extra-prostatic extension, were consistently associated with lymph node metastasis. Notably, the highest-grade region of a primary tumor did not always correspond to the lymph node metastatic clone, indicating that histologic grade alone is not a definitive predictor of metastatic potential. Shared alterations in established oncogenic drivers were also seen among primary tumor foci and lymph node metastasis samples, though these were not found to be the sole drivers of aggressive biology according to phylogenetic analysis.

This study underscores the complexity of primary, localized prostate cancer, demonstrating that anatomic, histopathological, and genomic factors play crucial roles in determining metastatic potential. Currently, reliably identifying the biologically dominant nodule in multifocal prostate cancer represents a significant clinical challenge. This analysis shows that retrospective clonal mapping of isolated lymph node metastasis in primary prostate cancer is feasible. Emerging technologies for molecular profiling in larger cohorts are needed to determine the primary prostate cancer nodule most likely to cause harm a priori.

Written by: Udit Singhal, MD, Srinivas Nallandhighal, MS, & Simpa S. Salami, MD, MPH

Department of Urology, Michigan Medicine, Ann Arbor, MI, USA

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