Abstract 5311: Tracking prostate cancer progression by deep whole genome sequencing of primary tumors and longitudinal circulating tumor DNAs.

Abstract Background: Although prostate cancer (PCa) generally has a high survival rate, some patients develop aggressive disease. Identifying reliable markers of progression and therapeutic response is essential for improving management. Cell-free DNA (cfDNA) in blood provides a minimally invasive means to monitor tumor evolution through liquid biopsy. In this study, we compared primary tumors from severe PCa patients versus long-term disease-free individuals to identify genomic alterations linked to aggressiveness. We also tracked tumor-shared alterations in circulating tumor DNA (ctDNA) and discovered exclusive modifications emerging during progression. Methods: Banked fresh frozen prostate tissues from radical prostatectomy cases (lethal PCa=80, disease-free=35) were processed to identify tumor foci and macro-dissect cores of high cellularity (75%) for DNA extraction. Serial plasma collections from six lethal cases were used to isolate cfDNA. Sequencing of tumors, matched germline blood DNAs, and cfDNAs was performed to identify copy number variations (CNVs) and mutations. Results: Already established and novel CNVs were found in tumors of both lethal and disease-free cases. Comparing their CNVs showed shared alterations associated with PCa development and disease recurrence, also pinpointing genomic signatures specifically associated with PCa severity. Clinical analysis of lethal cases revealed genomic deletions associated with rapid recurrence, metastases, castration-resistance, and short overall survival. Longitudinal cfDNA analysis unveiled rising ctDNA fractions when patients reached the metastatic and late stages. Although genomic amplifications were rare in primary tumors, they were common during progression. Tumor-shared alterations were found in the ctDNA during progression, along with newly discovered ctDNA-exclusive modifications. Furthermore, clonal ctDNA alterations became sub-clonal during treatment and re-emerged in the blood two years later in relation to treatment resistance. Evidence of tumor-shared and unique clonal evolutions was identified in the advanced disease stages, speaking for intra-tumoral and metastatic cellular heterogeneity. Conclusion: The identification of novel genomic changes in tumor DNA and ctDNAs in advanced disease is enhancing our knowledge of PCa severity. Findings on ctDNA underscore the significance of longitudinal liquid biopsy for monitoring disease progression. They could contribute to the development of novel diagnostic tests that enable earlier, more effective treatment and ultimately reduce PCa lethality. Citation Format: Samira Rahimirad, Eleonora Scarlata, Lucie Hamel, Seta Derderian, Ginette McKercher, Fadi Brimo, Fred Saad, Armen Aprikian, Simone Chevalier. Tracking prostate cancer progression by deep whole genome sequencing of primary tumors and longitudinal circulating tumor DNAs abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5311.