Abstract
Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. To date there is no understanding of whether this variability can influence management decisions for patients with prostate tumors. Here, we present a single case from a clinical trial of neoadjuvant intense androgen deprivation therapy. A patient was diagnosed with a large semi-contiguous tumor by imaging, histologically composed of a large Gleason score 9 tumor with an adjacent Gleason score 7 nodule. DNA sequencing demonstrates these are two independent tumors, as only the Gleason 9 tumor harbors single-copy losses of PTEN and TP53. The PTEN/TP53-deficient tumor demonstrates treatment resistance, selecting for subclones with mutations to the remaining copies of PTEN and TP53, while the Gleason 7 PTEN-intact tumor is almost entirely ablated. These findings indicate that spatiogenetic variability is a major confounder for personalized treatment of patients with prostate cancer.
Highlights
Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones
Using the TMPRSS2:ERG fusion as a putative early driver of tumorigenesis, based on its expression in all right-sided tumor foci (B2, B3, R2, and R3), we modeled that the IDC-P and invasive foci identified in the radical prostatectomy (RP) descended from IDC-P and invasive foci sampled on biopsy
Here, we describe a patient with high-risk prostate cancer treated by neoadjuvant intense androgen deprivation therapy (ADT) and surgery
Summary
Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. Retrospective DNA sequencing studies have demonstrated that 80–90% of prostate cancers comprise multiple spatially separate (distinct) regions, with occasional development of two independent clones within the same tumor[1,2] This multifocality is a well-recognized problem for diagnosis, and to date there has been no understanding of whether this variability can influence personalized management decisions. Observations that AR-targeting agents (such as abiraterone and enzalutamide) improve overall and metastasis-free survival in patients with hormone-sensitive and nonmetastatic disease, respectively, suggests that earlier intense inhibition of AR may further improve outcomes[4,5,6] To this end, the effect of introducing intense androgen deprivation therapies in the neoadjuvant setting has been explored in a series of clinical trials at several cancer centers[7]. While comprehensive molecular profiling of multiple specimens from a single patient is uncommon for many biomarker-driven therapies, we propose that success of genomically driven trials and treatment strategies may require complete assessment of larger tumors prior to application of precision therapies
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