Clinical implications of PTEN loss in prostate cancer

Abstract

Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer. Inactivation of the PTEN gene by deletion or mutation is identified in ~20% of primary prostate tumour samples at radical prostatectomy and as many as 50% of castration resistant tumours. Loss of PTEN function leads to activation of the PI3K–AKT pathway and is strongly associated with adverse oncological outcomes, making PTEN a potentially useful genomic marker to distinguish indolent from aggressive disease in patients with clinically localized tumours. At the other end of the disease spectrum, therapeutic compounds targeting nodes in the PI3K/AKT/mTOR signalling pathway are being tested in clinical trials for patients with metastatic castration-resistant prostate cancer (CRPC). Knowledge of PTEN status might be helpful to identify patients who are more likely to benefit from these therapies. To enable the use of PTEN status as a prognostic and predictive biomarker, analytically validated assays have been developed for reliable and reproducible detection of PTEN loss in tumour tissue and in blood liquid biopsies. Use of clinical-grade assays in tumour tissue have shown a robust correlation between loss of PTEN and of its protein as well as a strong association between PTEN loss and adverse pathological features and oncological outcomes. In advanced disease, assessing PTEN status in liquid biopsies shows promise in predicting response to targeted therapy. Finally, studies have shown that PTEN might have additional functions that are independent of the PI3K/AKT pathway, including those affecting tumour growth through modulation of the immune response and tumour microenvironment.