RESUMEN
Multiparametric magnetic resonance imaging (mpMRI) and MRI/ultrasound fusion-targeted prostate biopsy (FB) have excellent sensitivity in detecting significant prostate cancer (sPC). FB platforms can be distinguished by rigid (RTB) or elastic image registration (ETB). We compared RTB and ETB by analyzing sPC detection rates of both RTB and ETB at different stages of the surgeons' learning curve. Patients undergoing RTB between 2015-2017 (n = 502) were compared to patients undergoing ETB from 2017-2019 (n = 437). SPC detection rates were compared by Chi-square-test on patient-basis. Combination of transperineal systematic biopsy and each TB served as reference and sub-analyses were performed for different grades of surgeon's experience. In the RTB subgroup, 233 men (46%) had sPC, compared to 201 (46%) in the ETB subgroup. RTB alone detected 94% of men with sPC and ETB 87% (p = 0.02). However, for at least intermediate-experienced surgeons (>100 FB), no differences occurred between RTB and ETB. In the total cohort, at least intermediate-experienced surgeons detected significantly more sPC (10%, p = 0.008) than novices. Thus, targeted transperineal MRI/TRUS-FB with a RTB registration system showed a similar sPC detection rate to ETB in experienced surgeons but a superior sPC detection rate to ETB in the total cohort. Low-experienced surgeons seem to benefit from RTB.
RESUMEN
BACKGROUND: Mutations in DNA damage repair genes, in particular genes involved in homology-directed repair, define a subgroup of men with prostate cancer with a more unfavorable prognosis but a therapeutic vulnerability to PARP inhibition. In current practice, mutational testing of prostate cancer patients is commonly done late i.e., when the tumor is castration resistant. In addition, most sequencing panels do not include TP53, one of the most crucial tumor suppressor genes in human cancer. In this proof-of-concept study, we sought to extend the clinical use of these molecular markers by exploring the early prognostic impact of mutations in TP53 and DNA damage repair genes in men with primary, nonmetastatic prostate cancer undergoing radical prostatectomy (RPX). METHODS: Tumor specimens from a cohort of 68 RPX patients with intermediate (nâ¯=â¯11, 16.2%) or high-risk (nâ¯=â¯57, 83.8%) disease were analyzed by targeted next generation sequencing using a 37 DNA damage repair and checkpoint gene panel including TP53. Sequencing results were correlated to clinicopathologic variables as well as PSA persistence or time to PSA failure. In addition, the distribution of TP53 and DNA damage repair gene mutations was analyzed in three large publicly available datasets (TCGA, MSKCC and SU2C). RESULTS: Of 68 primary prostate cancers analyzed, 23 (33.8%) were found to harbor a mutation in either TP53 (nâ¯=â¯12, 17.6%) or a DNA damage repair gene (nâ¯=â¯11, 16.2%). The vast majority of these mutations (22 of 23, 95.7%) were detected in primary tumors from patients with high-risk features. These mutations were mutually exclusive in our cohort and additional data mining suggests an enrichment of DNA damage repair gene mutations in TP53 wild-type tumors. Mutations in either TP53 or a DNA damage repair gene were associated with a significantly worse prognosis after RPX. Importantly, the presence of TP53/DNA damage repair gene mutations was an independent risk factor for PSA failure or PSA persistence in multivariate Cox regression models. CONCLUSION: TP53 or DNA damage repair gene mutations are frequently detected in primary prostate cancer with high-risk features and define a subgroup of patients with an increased risk for PSA failure or persistence after RPX. The significant adverse impact of these alterations on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.
