Cancer Dictionary · Genitourinary

Prostate Cancer

Much prostate cancer is indolent and managed with surveillance. In advanced and castration-resistant disease the discussion changes substantially: DNA repair status, mismatch repair status and inherited risk all become relevant, and germline testing is discussed for all men with metastatic disease.

Also called Prostate adenocarcinoma, Castration-resistant prostate cancer.

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The governing idea

Prostate cancer covers an unusually wide spectrum, and the molecular discussion applies almost entirely to its advanced end, where DNA repair status and inherited risk both become prominent.

01Before any molecular question

How it usually presents

Usually established first: Gleason grade group, PSA level and its trajectory, stage, and whether disease is localised, biochemically recurrent, hormone-sensitive metastatic or castration-resistant. These states are not interchangeable and the molecular discussion differs across them.

Usually already established

Gleason grade group from biopsy or surgery
PSA level and trajectory
Disease state: localised, recurrent, hormone-sensitive metastatic, or castration-resistant
Whether germline testing has been offered

Major disease categories

The divisions below are not labels. Each one changes what the treatment discussion is actually about.

Localised, low risk

Often managed with active surveillance. Molecular profiling of the kind discussed here is not usually part of the conversation.

Localised, intermediate or high risk

Definitive local treatment organises the discussion. Tissue-based prognostic assays are sometimes used, which are a different category from genomic profiling.

Biochemically recurrent

Rising PSA after local treatment without visible disease. Imaging and timing dominate.

Metastatic hormone-sensitive

Where germline and tumour DNA repair testing enter the discussion.

Castration-resistant

The setting where molecular profiling most changes treatment options.

Neuroendocrine or aggressive variant

A distinct biology that can emerge under treatment pressure, and behaves differently.

03What is discussed

Molecular considerations

BRCA2 is the most consequential single finding, with BRCA1, ATM, PALB2 and other homologous recombination genes also relevant. Mismatch repair deficiency and high microsatellite instability occur in a small proportion and change the discussion where present. AR amplification and AR alterations emerge under treatment pressure and are a recognised resistance mechanism. PTEN loss and TP53 and RB1 co-loss are associated with more aggressive behaviour, including neuroendocrine transformation. SPOP alterations define a distinct subgroup.

Biomarkers commonly discussed

BRCA2

The most consequential single finding, relevant both as tumour and as inherited risk.

BRCA1, ATM, PALB2

Other homologous recombination genes, with varying degrees of evidence.

MMR / MSI

Uncommon, but changes the discussion where present.

Amplification and alterations emerge under treatment. A resistance mechanism rather than a baseline finding.

PTEN

Loss is associated with more aggressive behaviour.

TP53 and RB1

Co-loss is associated with neuroendocrine transformation.

PSMA

An imaging and therapeutic target, assessed by scan rather than by sequencing.

This is not an exhaustive list, and which markers are relevant depends on the individual case. Not every marker listed is assessed in every patient.

04What is tested, and from what

Testing, inherited risk and blood-based monitoring

Genomic testing considerations

Germline and tumour testing are both discussed in metastatic disease, and they answer different questions. Tumour tissue is often archival and can be a prostate biopsy from years earlier, which may not represent current disease; bone metastases, the most common site, yield poor-quality DNA. Plasma testing is therefore particularly useful in this disease. The practical sequence often discussed is germline testing plus plasma or tissue profiling at the point disease becomes metastatic, rather than waiting for castration resistance.

Germline considerations

Germline testing is discussed for all men with metastatic prostate cancer regardless of family history, and for selected men with high-risk localised disease. BRCA2, BRCA1, ATM, PALB2, CHEK2 and the Lynch syndrome genes are relevant. A finding affects the patient’s own treatment discussion and opens a cascade pathway for relatives, including female relatives for whom breast and ovarian risk is the more immediate implication. This is a good example of a germline finding in one person mattering most to someone else in the family.

Cancer genetics and hereditary risk

ctDNA and liquid biopsy considerations

Plasma testing is well suited to advanced prostate cancer because tissue is frequently archival or from bone. ctDNA levels correlate with disease burden, so plasma testing is more informative in higher-volume disease and less reliable when disease burden is low. AR alterations detected on plasma are a recognised resistance signal.

When molecular information matters

Testing that arrives after the decision it was meant to inform has already been made is a common and avoidable problem. This is the sequence in which molecular information tends to become relevant.

Localised diseaseGrade group, PSA and stage lead. Genomic profiling is not usually part of this discussion.
At the point disease becomes metastaticGermline testing is discussed for all men here. This is the moment it is most often missed.
Metastatic hormone-sensitive diseaseTumour DNA repair status is worth establishing before castration resistance develops, rather than after.
Castration-resistant diseaseProfiling most directly changes options here, and plasma is often the practical sample.
Where behaviour changes abruptlyRapid progression with low PSA raises the question of neuroendocrine transformation, which may warrant a biopsy.
For relativesA germline finding has implications for both male and female relatives.

06Take these to your team

Questions worth raising

When a decision is being made

Questions worth raising with a treating team.

Has germline testing been offered, given that it is discussed for all men with metastatic disease?
Has tumour DNA repair status been assessed, and on what sample: archival prostate tissue, a metastasis, or plasma?
If archival tissue is being used, how old is it and does it represent current disease?
Has mismatch repair status been checked?
Has the specific disease state been named precisely, since hormone-sensitive and castration-resistant disease are different discussions?

At progression, recurrence or resistance

The molecular picture at diagnosis is not always the molecular picture later.

Has AR status been considered as a resistance mechanism, and has plasma testing been used to look for it?
Where progression is rapid or PSA is disproportionately low, has neuroendocrine transformation been considered and a biopsy discussed?
Has profiling been repeated, rather than relying on a result from an earlier disease state?

07What shapes eligibility

Clinical trial considerations

Eligibility is usually written in terms of disease state, prior therapy and specific DNA repair alterations. Because the disease states are so precisely defined in this cancer, stating the state accurately is essential to matching.

Ask about trial matching

Plain-language glossary for this entry (5 terms)

Term	What it means
Gleason grade group	A grading system describing how abnormal prostate cancer cells look. A central part of risk assessment.
Castration-resistant	Disease progressing despite testosterone being suppressed to very low levels.
Biochemical recurrence	A rising PSA after treatment, without disease visible on scans.
Homologous recombination	A high-fidelity DNA repair mechanism. Its failure is the basis of a specific treatment class.
Neuroendocrine transformation	A change in cancer cell type under treatment pressure, associated with different behaviour.

Where OnKommon fits

These are the services most often relevant to this cancer. Which of them applies is a clinical question, not an automatic one.

HeritageInherited-risk testing, and a tested pathway for relatives.See how it works Signature STb O+The 523-gene comprehensive panel, with TMB and MSI.See how it works SentinelSerial monitoring during active treatment.See how it works DecipherReinterprets sequencing already done elsewhere, without repeating it.See how it works

This entry is educational. It describes what is commonly discussed in this cancer, not what should happen for any individual. Which of it applies depends on the specific diagnosis, stage, prior treatment and the person themselves. Nothing here is a recommendation, and no list of biomarkers here is exhaustive. Decisions belong with a treating team who know the whole case.

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