Pharmacogenomics: A pathway to personalized treatment in prostate cancer

Prostate cancer (PC) stands as the second leading cause of death among American men, with about 1 in 8 men diagnosed during their lifetime. PC is categorized into four main types based on disease progression and treatment response: localized PC, nonmetastatic castration-resistant PC, metastatic castration-resistant PC, and metastatic castration-sensitive PC. While localized PC has a high 5-year survival rate of over 99%, metastatic cases see this rate plummet to 34.1%, highlighting the need for optimized treatments for metastatic PC. Precision medicine, which includes pharmacogenomics (PGx), offers a promising avenue for improving treatment outcomes by tailoring therapies based on genetic profiles.

Pharmacogenomics (PGx) involves studying how genetic variations affect an individual's response to drugs, enabling more precise and effective treatment plans. In prostate cancer, PGx testing can predict how patients will respond to systemic therapies, thereby personalizing treatment, optimizing medication dosages, and avoiding adverse drug reactions. PGx-related genes encode proteins involved in drug metabolism, and understanding these genetic variants can significantly impact treatment efficacy.

One critical gene in PGx testing for prostate cancer is HSD3B1, which encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1). This enzyme is crucial in converting adrenal androgen precursors into dihydrotestosterone (DHT), a potent androgen involved in prostate cancer progression. A single nucleotide variant (SNV) in the HSD3B1 gene (rs1047303) can lead to an amino acid change (p.367T>N), causing the enzyme to resist degradation and increasing DHT production. This genetic variant has been linked to the development of castration-resistant prostate cancer (CRPC), as increased DHT levels promote cancer cell growth despite androgen deprivation therapy (ADT).

Research has shown that patients with the HSD3B1 (1245C) allele and 367T variant exhibit higher levels of 3βHSD1 enzyme, resulting in elevated DHT levels. A 2016 study by Hearn et al. demonstrated a significant association between inheriting the HSD3B1 (1245C) allele and progression-free survival (PFS), distant metastasis-free survival, and overall survival (OS) in prostate cancer patients. This finding underscores the importance of PGx testing in identifying genetic variants that can influence treatment outcomes and guide clinical decisions.

Despite the benefits, PGx testing is underutilized in clinical settings compared to genetic testing. To bridge this gap, a four-step approach has been proposed: patient identification, PGx test ordering, application of PGx test results, and patient education. Identifying the right patients for PGx testing involves considering family history, disease risk, and specific genetic markers. Clinicians must be knowledgeable about PGx testing processes and interpretation to integrate these insights effectively into patient care.

The integration of PGx testing into routine clinical practice faces several challenges, including a lack of awareness, limited clinical guidelines, and the need for standardized testing protocols. Addressing these issues through education, research, and policy development is crucial for the widespread adoption of PGx in prostate cancer treatment. As precision medicine continues to evolve, PGx testing holds the potential to revolutionize prostate cancer care by enabling highly individualized treatment strategies.

The application of pharmacogenomics in prostate cancer represents a significant advancement in precision medicine. By understanding genetic variants that influence drug metabolism and response, healthcare providers can tailor treatments to individual patients, improving outcomes and reducing adverse effects. Continued research, education, and policy support are essential to fully realize the potential of PGx in transforming prostate cancer care.