Clinical implications of PTEN loss in prostate cancer

Key Points

  • Large-scale next-generation genetic analyses of prostate cancer emphasize the frequent occurrence and importance of focal genomic deletions inactivating PTEN

  • Phosphatase and tensin homologue (PTEN) loss in radical prostatectomy samples is often concurrent with genomic rearrangements involving the ETS family transcription factors

  • PTEN loss is reproducibly associated with adverse oncological outcomes by itself or in combination with other biomarkers and helps distinguish indolent tumours from those likely to progress

  • PTEN might be a useful prognostic biomarker to distinguish potentially aggressive Grade Group 1 or 2 tumours, which might make patients poor candidates for active surveillance programmes

  • Robust clinical assays using immunohistochemistry and fluorescence in situ hybridization (FISH) have been developed to reproducibly measure PTEN protein and gene loss using diagnostic tissue biopsies and circulating tumour cells from plasma

  • PTEN loss is associated with suppression of androgen receptor (AR) transcriptional output, and phosphoinositide 3-kinase (PI3K) inhibitors activate AR signalling, suggesting potential efficacy of combination therapies targeting the PI3K and AR signalling pathways

  • Emerging studies indicate that PTEN loss is associated with alterations to cellular interferon responses in the tumour microenvironment — tumours with loss of PTEN are more likely to have an immunosuppressive microenvironment, suggesting that advanced prostate cancers with PTEN loss might be amenable to immune-based therapies

Abstract

Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer. Inactivation of PTEN by deletion or mutation is identified in 20% of primary prostate tumour samples at radical prostatectomy and in as many as 50% of castration-resistant tumours. Loss of phosphatase and tensin homologue (PTEN) function leads to activation of the PI3K–AKT (phosphoinositide 3-kinase–RAC-alpha serine/threonine-protein kinase) 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 (mechanistic target of rapamycin) signalling pathway are being tested in clinical trials for patients with metastatic castration-resistant prostate cancer. 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. The use of clinical-grade assays in tumour tissue has shown a robust correlation between loss of PTEN and 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.

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Figure 1: The diverse cellular roles of PTEN.
Figure 2: Prostate cancer samples with variable PTEN protein expression by IHC and corresponding PTEN FISH.
Figure 3: Heterogeneous immunohistochemical expression of ERG and PTEN in prostate tumours.
Figure 4: Algorithm for when to determine PTEN status on diagnostic biopsy material using IHC and FISH.
Figure 5: Proposed management options using clinicopathological variables at biopsy and PTEN status.
Figure 6: Selected drugs in clinical trials targeting the PI3K–AKT pathway that have been used in combination with androgen deprivation therapy.

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Acknowledgements

Funding for this research was provided in part by a Transformative Impact Award from the Congressionally Directed Medical Research Program–Prostate Cancer Research Program (CDMRP-PCRP) (W81XWH-13-2-0070, H.I.S. and T.L.L.). T.L.L. was additionally supported by the NIH and National Cancer Institute (NCI) P30 Cancer Center Support Grant CA006973 and the Patrick Walsh Prostate Cancer Research Fund. H.I.S. was additionally supported by NIH and NCI Prostate SPORE Grant P50-CA92629, NIH and NCI P30 Cancer Center Support Grant CA008748, and the Prostate Cancer Foundation. T.J. and D.M.B. were funded by Prostate Cancer Canada and the Movember Foundation (Grant #T2014-01-PRONTO). T.J. was supported by a Transformative Pathology Fellowship funded by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.

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All authors researched data for the article, took part in discussions of the content, and wrote the manuscript. T.J., D.M.B., H.I.S., A.M.D.M., J.A.S., and T.L.L. reviewed and edited the manuscript before submission.

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Correspondence to Tamara L. Lotan.

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T.L.L. has received research support from Ventana Medical Systems. D.M.B. has received financial support from Myriad Genetics and Metamark Genetics.

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Jamaspishvili, T., Berman, D., Ross, A. et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 15, 222–234 (2018). https://doi.org/10.1038/nrurol.2018.9

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