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Prostate cancer

Abstract

Prostate cancer is a complex disease that affects millions of men globally, predominantly in high human development index regions. Patients with localized disease at a low to intermediate risk of recurrence generally have a favourable outcome of 99% overall survival for 10 years if the disease is detected and treated at an early stage. Key genetic alterations include fusions of TMPRSS2 with ETS family genes, amplification of the MYC oncogene, deletion and/or mutation of PTEN and TP53 and, in advanced disease, amplification and/or mutation of the androgen receptor (AR). Prostate cancer is usually diagnosed by prostate biopsy prompted by a blood test to measure prostate-specific antigen levels and/or digital rectal examination. Treatment for localized disease includes active surveillance, radical prostatectomy or ablative radiotherapy as curative approaches. Men whose disease relapses after prostatectomy are treated with salvage radiotherapy and/or androgen deprivation therapy (ADT) for local relapse, or with ADT combined with chemotherapy or novel androgen signalling-targeted agents for systemic relapse. Advanced prostate cancer often progresses despite androgen ablation and is then considered castration-resistant and incurable. Current treatment options include AR-targeted agents, chemotherapy, radionuclides and the poly(ADP-ribose) inhibitor olaparib. Current research aims to improve prostate cancer detection, management and outcomes, including understanding the fundamental biology at all stages of the disease.

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Fig. 1: Anatomy and histological structure of the human prostate gland.
Fig. 2: Global geographical incidence and mortality of prostate cancer.
Fig. 3: Prostate cancer stages and progression.
Fig. 4: Genetic alterations in prostate cancer.
Fig. 5: Androgen and/or AR dependence and prostate cancer progression.
Fig. 6: Histological features of prostate cancer.
Fig. 7: Overview of prostate cancer management.
Fig. 8: Possible future precision medicine approach to prostate cancer management.

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Acknowledgements

R.J.R and R.G.B. are supported by core funding grants from Cancer Research UK (CRUK), Manchester Institute and CRUK Manchester Centre. R.G.B. is also supported by the CRUK Manchester RadNet and ACED grants, the NIHR Manchester Biomedical Research Council and Prostate Cancer UK through a Movember Centre of Excellence. C.O. is supported by the European Society of Medical Oncology (ESMO) with the aid of a grant from Roche. K.E.K. is supported by grants from Celgene, Sanofi, Novartis and CellCentric. S.L. is supported by the Prostate Cancer Foundation and the Edward Blank and Sharon Cosloy-Blank Family Foundation.

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Authors and Affiliations

Authors

Contributions

Introduction (R.J.R., C.O., R.G.B.); Epidemiology (R.J.R., C.O., T.V.d.K.); Mechanisms/pathophysiology (R.J.R., C.O., K.E.K., T.V.d.K.); Diagnosis, screening and prevention (R.J.R., C.O., S.L., R.E.R., T.V.d.K., R.G.B.); Management (R.J.R., C.O., S.G., T.V.d.K., R.G.B.); Quality of life (R.J.R., C.O., D.C.J., R.G.B.); Outlook (R.J.R., C.O., R.G.B.); Overview of the Primer (R.J.R., C.O., R.G.B.).

Corresponding author

Correspondence to Robert G. Bristow.

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Competing interests

R.J.R.: No competing interests. C.O.: Travel reimbursement from Ipsen, PharmaMar and Medac; research funding from Roche and PharmaMar. Speakers honoraria from Ipsen, Roche and Medac. K.E.K.: Consultant/advisor to Cell Centric, Sanofi, Celgene, Atrin and Genentech. S.L.: Reimbursed travel to the Prostate Cancer Foundation Retreat from Sanofi; consulting fees from Lumenis and Bayer; equity in Gilead. D.C.J.: No competing interests. R.E.R.: Speakers bureau for Janssen and Genomic Health; consultant/advisor to Progenics, Pfizer, Janssen, Exact Biosciences and Bayer. S.G.: Consultant/advisor to Janssen, Astellas Pharma (Inst.), Curevac (Inst.), Novartis (Inst.), Active Biotech (Inst.), Bristol-Myers Squibb (Inst.), Ferring (Inst.), MaxiVax, Advanced Accelerator Applications, Roche, Janssen (Inst.), Innocrin Pharma (Inst.), Sanofi, Bayer (Inst.), Orion Pharma GmbH, Clovis Oncology (Inst.) and Menarini Silicon Biosystems (Inst.); patents, royalties or other intellectual property in Method for biomarker (WO 3752009138392 A1); other relationships with Nektar and ProteoMediX. T.V.d.K.: Consultant/advisor to Janssen. R.G.B.: Advisory board to AstraZeneca and Astellas; grant from GenomeDX.

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Nature Reviews Disease Primers thanks S. Freedland, F. Saad, D. Murphy, W. Isaacs and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Acini

A cluster of cells which form the rounded termination of an exocrine gland where secretions are produced.

Western diet

A diet that is generally characterized by high-fat, high-sugar foods and processed or pre-packaged meat, eggs and grains along with low consumption of fruits, vegetables, unprocessed meat and whole grains.

Germline mutations

Any detectable mutation in germ cells (carried in oocyte or sperm) that are heritable and become expressed in every somatic and germline cell within an organism.

Oncogene

A gene that controls normal cell growth for which mutation results in gain of function and promotes malignant transformation.

Tumour suppressor genes

Genes that control normal cell growth for which mutation results in loss of function and promotes malignant transformation.

Genetic instability

High frequency of mutations within the genome of a cell that can result in chromosomal rearrangements or aneuploidy.

Hotspot mutations

A phenomenon in which the same amino acid position is mutated in many tumours, often occurring as activating mutations in oncogenes.

Kataegis

Regions of localized gene hypermutations within a small region of DNA.

Chromothripsis

Regions of chromosome shattering and reinsertions of minute DNA fragments within a single event and often confined to one or two chromosomes.

Chromoplexy

Highly complex and high-frequency genome-wide, gene structural rearrangements which create gene fusions and/or disrupt several genes.

Biochemical failure

An increase in blood PSA levels despite sufficient treatment.

Overdiagnosis and overtreatment

Detection and treatment of cancer in men whose disease would not have become symptomatic during their lifetime; treatment results in harm rather than benefit.

Eastern Cooperative Oncology Group (ECOG) performance status

A measure ranging from 0 (no effect on daily functioning) to 4 (100% bed-bound) to estimate a patient’s ability to perform certain activities of daily living.

Microsatellite instability

The condition of genetic hypermutability caused by a predisposition to mutation, resulting from DNA mismatch repair deficiency.

Multiparametric MRI

A detailed high-resolution technique to image the physiology of an organ using strong magnetic fields, field gradients and radio waves combined with a contrast agent.

Transdifferentiation

A process in which a mature somatic cell is transformed into another without first undergoing dedifferentiation into a pluripotent or multipotent cell type.

Tumour flare

Acutely accelerated tumour growth and exacerbation of symptoms due to a transient surge in luteinizing hormone and testosterone after luteinizing hormone-releasing hormone agonist introduction.

Abiraterone-induced mineralocorticoid excess

An adverse effect of abiraterone use defined by hypertension, fluid retention and low serum levels of potassium.

Occult metastasis

The presence of metastases that are not detected with routine imaging or clinical examination.

Prostate Imaging–Reporting and Data System

(PI-RADS). A reporting tool that defines standards for the image creation and reporting of multiparametric MRI data.

PSA doubling time

The number of months it would take for the PSA to increase by twofold.

Skeletal-related events

(SRE). Complications associated with metastasis that usually manifest as fractures, spinal cord compression, bone pain and high blood calcium levels.

Health-related quality of life

(HRQOL). An individual’s or group’s perceived physical and mental health after considering factors that affect health status.

Obstructive voiding symptoms

Lower urinary tract symptoms that include hesitancy, poor or intermittent urinary stream, straining, incomplete bladder emptying, dribbling and or urine storage symptoms.

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Rebello, R.J., Oing, C., Knudsen, K.E. et al. Prostate cancer. Nat Rev Dis Primers 7, 9 (2021). https://doi.org/10.1038/s41572-020-00243-0

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