Intratumoral and Intertumoral Genomic Heterogeneity of Multifocal Localized Prostate Cancer Impacts Molecular Classifications and Genomic Prognosticators

Abstract

Background Next-generation sequencing is revealing genomic heterogeneity in localized prostate cancer (CaP). Incomplete sampling of CaP multiclonality has limited the implications for molecular subtyping, stratification, and systemic treatment. Objective To determine the impact of genomic and transcriptomic diversity within and among intraprostatic CaP foci on CaP molecular taxonomy, predictors of progression, and actionable therapeutic targets. Design, setting, and participants Four consecutive patients with clinically localized National Comprehensive Cancer Network intermediate- or high-risk CaP who did not receive neoadjuvant therapy underwent radical prostatectomy at Roswell Park Cancer Institute in June–July 2014. Presurgical information on CaP content and a customized tissue procurement procedure were used to isolate nonmicroscopic and noncontiguous CaP foci in radical prostatectomy specimens. Three cores were obtained from the index lesion and one core from smaller lesions. RNA and DNA were extracted simultaneously from 26 cores with ≥90% CaP content and analyzed using whole-exome sequencing, single-nucleotide polymorphism arrays, and RNA sequencing. Outcome measurements and statistical analysis Somatic mutations, copy number alternations, gene expression, gene fusions, and phylogeny were defined. The impact of genomic alterations on CaP molecular classification, gene sets measured in Oncotype DX, Prolaris, and Decipher assays, and androgen receptor activity among CaP cores was determined. Results and limitations There was considerable variability in genomic alterations among CaP cores, and between RNA- and DNA-based platforms. Heterogeneity was found in molecular grouping of individual CaP foci and the activity of gene sets underlying the assays for risk stratification and androgen receptor activity, and was validated in independent genomic data sets. Determination of the implications for clinical decision-making requires follow-up studies. Conclusions Genomic make-up varies widely among CaP foci, so care should be taken when making treatment decisions based on a single biopsy or index lesions. Patient summary We examined the molecular composition of individual cancers in a patient’s prostate. We found a lot of genetic diversity among these cancers, and concluded that information from a single cancer biopsy is not sufficient to guide treatment decisions.

The Heterogeneity of Prostate Cancer: A Practical Approach

“…However, studies on the genetic similarities of different tumor foci in 1 patient are lacking, and intertumoral heterogeneity should probably be placed in the same set as interpatient heterogeneity, meaning that multifocal tumors in 1 patient are unique. This thesis has found some ground in the scientific works on multifocal prostate cancer [33,34,49]. …”

Rationale for the development of alternative forms of androgen deprivation therapy

“…Many studies have evaluated their role in patients’ outcome after radical prostatectomy, risk for biochemical recurrence, response to ADT, and lethal CaP development (reviewed in (Bostrom, et al 2015)) and have reached different conclusions. The reason for the discrepancies between these studies is not entirely clear, but is likely related at least in part to differences in TMPRSS2-ERG fusion status among and within intraprostatic foci of localized CaP (Boutros, et al 2015; Svensson, et al 2011; Wei, et al 2016). Inconsistent association between TMPRSS2-ERG status and post-operative risk for CaP progression may, thus, be due to inadequate tissue sampling.…”

“…It is likely, however, that these may have pronounced effects on AR’s function and underlie the heterogeneity that has been observed for AR transcriptional output in patient specimens. As for genomic CaP heterogeneity in general, this variability is more pronounced in localized ADT-naïve CaP than in metastatic CaP that has recurred under ADT (Kumar, et al 2016; Wei et al 2016). In addition to alterations that directly affect components and contributors to AR transcription complexes, the expression and mutational status of other genomic markers, can affect AR’s transactivation function.…”

Tissue-based biomarkers in prostate cancer

“…A recent study by Wei et al is illustrative of the challenge. [118] The authors analyzed inter and intratumoral heterogeneity in four patients with prostate cancer by performing next-generation sequencing (whole-exome sequencing, copy number alteration, and RNA sequencing) on multiple prostate cancer foci from within the radical prostatectomy specimens of these patients. The clonal evolution of prostate cancer demonstrated significant early divergence and genomic heterogeneity within each specimen.…”