Diagnostic and Therapeutic Landscapes of Prostate Cancer

The Prostate

• Small, important gland in male reproductive system

• Produces a milky fluid that mixes with sperm to create semen

Incidence

• 2nd most common cancer in men, 5th leading cancer cause of death globally

• Lower in many Asian countries, higher rates in black people

• Higher in populations after they move into Western countries

• A mix of genetic and environmental factors

Symptoms of Prostate Cancer

• Inc in urination frequency

• Nocturne

• Urgency to urinate

• Hesitancy in starting urination

• Weak urinary stream

• Prolonged urination

• Incomplete bladder emptying

• Haematuria or haematospermia

• Symptoms also common to benign prostatic hyperplasia (BPH) - not specific to cancer

• Systematic signs e.g. weight lost, bone pain, fatigue, suggest advanced disease

Diagnostic Evaluation

• Family history of prostate, breast, ovarian and Lynch-associated cancers

• Consider genetic risk, germline mutations e.g. BRCA1/2

• Abnormal findings on digital rectal exam (DRE) = urgent referral

• Prostate-specific antigen (PSA) testing

• Pre-biopsy multiparametric MRI (mpMRI)

• Biopsy when indicated

Prostate Physical Exam

• Dr assesses size of prostate, looking for symmetry + consistency of tissue

• Asymmetry from L/R lobe or nodules raise malignancy suspicions - prompts further investigation

• DRE used to identify abnormalities in pts w elevated PSA

Risk Factors

• Diet: Asian immigrants in US show higher PC rates, hinting at a high-fat diet link (evidence is mixed)

• Family history: having a first -degree family member w PC inc chances by 2.5%

• Genetics: Not fully understood, but mutations e.g. HOXB13 and those linked to similar cancers raise risk (e.g. BRCA1/2, ATM, CHEK2, etc)

PTEN-Pl2K-AKT Pathway

• PC’s rely on hormones (androgens) for growth (hormones that bind to receptor, interact with different regulators to form a protein complex, turns on proteins responsible for male characteristics)

• Androgen-receptor (AR) activated MAPK, AKT pathways via SRC and Pl3K, promoting cell growth and immortality

• AKT pathway linked to cancer development bc of its role in tumorigenesis

• Pl3K binding to oncogenic RAS crucial for cell-transforming capabilities

TP53 Pathway

• TP53 is the most mutated gene in cancers, encodes p53 which regulates cell cycle

• Triggers apopotosis or pauses cell cycle for DNA repair and damage

• Mutations caused by TP53’s half-life, leads to abnormal nuclear build up detectable by IHC

• Mutations in prostate cancer occur in 20-40% of advanced cases

• Nuclear p53 accumulation linked to poor PC outcomes

UK Screening

• No national, population-level programme yet

• PSA testing is available by informed choice within primary care

• Limitations

  • False-positives - remedies by MRI scans first to verify any abnormalities before biopsy

  • False-negatives - misses 1 in 7 cases, aggressive cancers may be detected and treated promptly by slow growing ones which don’t always cause harm can also be identifies

  • Other treatments can be beneficial, but can also have bad side effects - some may leave treatment until it becomes absolutely unnecessary

  • Overdiagnosis = over treatment

PSA

• Protease produced by prostate epithelial cells, secreted into the seminal fluid where it is involved w liquefaction of the seminal coagulum

• Found circulating in blood either in free form or bound to plasma proteins

• Rises with age, must be interpreted w age-specific thresholds

• Racial differences mean it can vary

• Higher PSA density, shorter doubling time or rapid velocity increase suspicion (how rapidly the PSA level rises) (can also help guide post treatment effects)

• Can also vary w inflammation, ejaculation and prostate volume

What’s Changing (2025-2026)

• UK National Screening Committee proposes targeted screening

• For men aged 45-61 w confirmed BRCA1/2 mutations

• Every 2 years

• Population screening and screening based solely on ethnicity or family history not recomended (awaiting new tests accuracy & TRANSFORM trial - individuals can enter and data is added)

mpMRI

• First-line investigation for suspected PC

• Improves id of cancers missed by random biopsies

• Decreases procedures performed on benign conditions

• Precise localisation and improved diagnostic accuracy

• Pts w prior negative biopsy may not benefit from routine repeat MRI

• Active surveillance patients require tailored scan frequency

Prostate Biopsy

• Individualised, based on age, PSA, history, comorbidities and other risk calculators

• Preferred route is transperineal rather than transrectal due to lower infection risk - ultrasound guides needle, and then cores are taken for lesion visualisation

• MRI-targeted biopsy helps improves ID of clinically significant cancers, reduces ID of low-risk

• But negative biopsies don’t always mean no cancer - if concerning features then monitoring is needed

Histopathology

• Limited sample challenges: only provide small amount of tissue, benign glands can mimic malignant ones

• Normale prostate glands contient basal cells, absent in cancerous glands

• Perineural invasion strongly suggests cancer

• Immunostaining w markers e.g. CK5/CK6, p63 and ACMR help resolve ambiguous cases

• Very expensive - could mean 20 slides, a single vial of 500 microlitre antibodies can cause £300

• IHC only done selectively, only on glands where the morphology is unclear - H&E stains important for diagnosis

AI and Digital Pathology

• AI systems pre-analyse biopsies, offer diagnostic insights before pathologic review

• AI generates Gleason scores, assesses tumour sizes, morphological details, enhances support for decision making

• BCUHB is UK’s first health board to use AI for PC diagnosis in 2021

Grading - Gleason score

• Low grade <6 = well-differentiated tumour

• Intermediate 7 = moderately differentiated

• High grade 8-10 = poorly differentiated or undifferentiated aggressive cancers

• IHC confirms challenging diagnosis - key markers e.g. cytokeratin (AE1/3) and CD68

Cambridge Prognostic Calculator

• Decision-making in non-metastatic PC treatment planning

• Data inputs

  • Grade group or Gleason score assesses aggressiveness of cancer

  • PSA - not great when cancer has spread beyond prostate or if disease is aggressive

  • Tumour stage uses the T category for TNM staging to determine extent or primary tumour

Hormonal Treatment Strats

• Orchidectomy - gold-standard for reducing androgen levels but invasive

• GnRH agonists - non-surgical, causes surge in hormone levels and managed w anti-androgens

• Androgen Receptor Blockers - inhibit testosterone’s effect on cancer cells

• Androgen Synthesis Inhibitors - decreases androgen production by targeting enzymes e.g. CYP17

Non-hormonal strategies

• Early chemotherapy - docetaxel improves survival when used early, timing w hormonal therapy remains debated

• Radioligand therapy (PSMA postive cancers) - delivered through blood stream directly to tumour cells, PSMA is found on surface of prostate cancer cells. PSMA presence is confirmed via PET scan, and then Pluto is attached to deliver focused radiation. However not present on benign tissues

• PARP inihibors e.g. olaprib can help pts w DNA repair deficient tumours (BRCA2 predominant) - can cause cancer cell death and spare healthy cells

• Bone targeted treatments e.g. alpharadin alleviates bone mestastess bc PC spreads to bone. Combined w palliative radiotherapy bc it relieves pain

Brachytherapy

• Internal radiation therapy - delivers radiation directly from within body

• Smal radioactive seeds implanted into prostate under general anaesthesia

• Release radiation over several months targeting caner cells

• Maximises radiation, minimises exposure to surrounding tissues and organs

Pembrolizumab

• Immunotherapy, blocks PD-1

• Works best in cancers visible to immune system

• In most mCRPC (Metastatic castration-resistant prostate cancer) large Phase 3 trials did not show overall benefit when added to standard treatments

• In some in showed more toxicity

• Good for MSI-H/dMMR prostate cancers

• FDA tumour-agnostic approval for MSI-H/dMMR tumours

• Generally not routine, can be accessed by clinical trials

Provenge (Sipuleuce-T)

• Personalised cancer vaccine/immunotherapy

• Uses pt’s own immune cells activated ex vivo w fusion protein (PAP-GM-CSF) yo teach immune system to target and destroy immune cells

• Proven survival benefit

• New option for pts w mCRPC

• USA FDA approved by EU authorisation withdrawn

TMPRSS2:ERG gene fusions

• Most common gene fusions in PC

• Fusion links androgen-regulated TMPRSS2 to ERG, driving over expression of ERG and defines molecular subtype

• Best current use is risk stratifications before biopsy, not population screening

• Detectable in post-DRE urine as T2:ERG can be combined with PCA3 to improve predictions

• Therapeutic value still inconsistent, not yet fusion targeted therapy like Philadelphia chromosome in CML

Survival Stats

• Over 96% of pts drive after one year

• 84% survive five years or more

• Metastatic = only 30% survive five years or more

• Stable mortality rates are vulnerable without improvements to early detections strats