Comparative analysis on genomic features of prostate cancer patients with and without treatment-emergent neuroendocrine prostate cancer: Perspective from liquid biopsy and tissue-based next generation sequencing.

Abstract

e17067 Background: Treatment-emergent neuroendocrine prostate cancer (t-NEPC) serves as a highly aggressive variant of prostate cancer. Genomic features of t-NEPC remained to be further explored. Methods: A total of 398 patients underwent targeted genomic sequencing, with 123 patients harboring t-NEPC and 275 patients without it. Among them, 251 patients received liquid-based sequencing (82 t-NEPC(+) and 169 t-NEPC(-)), and 227 patients received tissue-based sequencing (62 t-NEPC(+) and 164 t-NEPC(-)). Pathogenic somatic/germline variations and rearrangements were included for analysis. Results: For the total cohort, t-NEPC (+) presented more AURKA (t-NEPC(+) vs. t-NEPC(-): 5.7%[7/123] vs. 1.1%[3/275], p=0.012) and CDK12 (13%[16/123] vs. 5.8%[16/275], p=0.026) mutations over the t-NEPC(-). TP53 alterations were comparable (20.3%[25/123] vs. 19.6%[54/275], p=0.892). ERG rearrangement was more frequently observed in the t-NEPC(+) compared to the t-NEPC(-) (14.6%[18/123] vs. 8%[22/275], p=0.048) and was validated by external Immunohistochemistry results (ERG over-expression rate: 25.4%[32/126] vs. 16.6%[48/290], p=0.042). In t-NEPC(+) population, liquid biopsy showed significantly more AR variations (25.9%[21/81] vs. 4.8%[3/63], p=6E-4) but less MYC (2.5%[2/81] vs. 12.7%[8/63], p=0.021), FOXA1 (0%[0/81] vs. 14.3%[9/63], p=4E-4) and FANCA (0%[0/81] vs. 4.8%[4/63], p=6E-4) mutations compared to the tissue-based sequencing. Similar findings were observed in the t-NEPC (-) cohort. Conclusions: t-NEPC was featured by elevated CDK12 alterations and ERG rearrangement rate. For both t-NEPC(+) and t-NEPC(-) populations, combined results from tissue-based sequencing and liquid biopsy were recommended to provide a more comprehensive mutational landscape and facilitate subsequent therapeutic decision-making.