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Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer.

ABSTRACT: Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by testing the classifier's performance in a multifocal context. We analyzed 106 cancer samples from 85 distinct cancer foci within 39 patients. By somatic mutation data from whole-exome sequencing and targeted qualitative and quantitative gene expression assays, 31% of the patients were uniquely classified into one of the seven TCGA classes. Further, different samples from the same focus had conflicting classification in 12% of the foci. In conclusion, the level of both intra- and interfocal heterogeneity is extensive and must be taken into consideration in the development of clinically useful molecular classification of primary prostate cancer.

SUBMITTER: Carm KT

PROVIDER: S-EPMC6753093 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer.

Carm Kristina Totland KT Hoff Andreas M AM Bakken Anne Cathrine AC Axcrona Ulrika U Axcrona Karol K Lothe Ragnhild A RA Skotheim Rolf I RI Løvf Marthe M

Scientific reports 20190919 1

Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by test ...[more]

PMID: 31537872

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Project description:BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.

Project description:PURPOSE:Very high-risk prostate cancer (PC) is associated with poor response to local and systemic treatments; however, few cases have been molecularly profiled. We studied clinical outcomes and molecular profiles of patients with clinically localized primary Gleason pattern 5 PC. PATIENTS AND METHODS:Clinicopathologic features, targeted somatic and germline sequencing, and PTEN, TP53, and ERG status by immunohistochemistry were assessed in patients undergoing surgery from 2005 to 2015; 60 consecutive patients were identified with Gleason score 5 + 4 = 9 or 5 + 5 = 10 PC after radical prostatectomy with available tissue and clinical follow-up. Clinicopathologic and genomic parameters were correlated with biochemical relapse, metastasis-free survival, time to castration resistance, and overall survival using Cox proportional hazards models. RESULTS:Of patients with somatic sequencing data and clinical follow-up, 34% had DNA repair gene mutations, including 22% (11 of 49) with homologous recombination and 12% (six of 49) with mismatch repair gene alterations. Homologous recombination mutations were germline in 82% (nine of 11) of patients. In addition, 33% (16 of 49) had TP53 mutation, and 51% (29 of 57) had PTEN loss. Overall, 43% developed metastasis, with a time to castration resistance of 12 months. On multivariable analysis of clinicopathologic variables, only ductal/intraductal histology (hazard ratio, 4.43; 95% CI, 1.76 to 11.15; P = .002) and seminal vesicle invasion (hazard ratio, 5.14; 95% CI, 1.83 to 14.47; P = .002) were associated with metastasis. Among genomic alterations, only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis, and neither remained significant in multivariable analyses. These data are retrospective and hypothesis generating. CONCLUSION:Potentially actionable homologous recombination and mismatch repair alterations are observed in a significant proportion of patients with very high-risk PC at the time of radical prostatectomy. These findings could inform the design of prospective trials in this patient population.

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Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer.

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Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer.

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