About the disease

Briefly about the disease and its targeted therapies

Prostate cancer is the second most common cancer in men worldwide, and it mostly affects older men.  The most common type is acinar adenocarcinoma, accounting for approximately 90% of the cases, which develops in the outer gland cells of the prostate. The early cancer typically has no symptoms; however, in some cases the urethra is pressed by the tumour, resulting in difficulty, increased frequency and urgency of urination.  Malignant transformation of the prostate follows a multistep process, initiated as prostatic intraepithelial neoplasia (PIN) followed by localized prostate cancer and then advanced disease with local invasion, culminating in metastatic cancer. This last phase is the leading cause of deaths. A diagnosis of prostate cancer is based on clinical examination including digital rectal examination, ultrasonography, blood test to check the level of prostate-specific antigen (PSA), and histology from biopsy.

Treatment approaches for prostate cancer include active surveillance, surgery, radiotherapy, hormone therapy (e.g., androgen deprivation therapy, anti-androgens or testosterone synthesis blocker), and chemotherapy. Cataloguing the genetic drivers of prostate cancer has been foundational in defining disease subtypes and associated therapeutic strategies. It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology and acquired (somatic) mutations that occur in prostate cancer cells.

In the advanced disease setting, mutations in homologous recombination repair genes (e.g., BRCA1, BRCA2, ATM, CHEK2, and PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumour-directed somatic sequencing may guide treatment decision-making. Additional genes are also recommended to be included in specific research or clinical contexts. For instance, HOXB13 does not have a clear therapeutic implication, but it is important for hereditary family risk assessment. Somatic next-generation sequencing (NGS) assays also report alterations that, although investigational, may provide information about clinical trial candidacy: androgen receptor amplifications, PTEN deletions, PI3K/Akt/mTOR pathway alterations, and TMPRSS2-ERG gene fusions.