PTEN Deficiency in Metastatic Prostate Cancer

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Prostate Cancer
PTEN

PTEN

Jump to:

Clinical Relevance
Prevalence
Testing Recommendations
Interpreting and Reporting
Considerations for Your Practice
Helpful Resources

PTEN Is a Prognostic Biomarker With OS and PFS Implications^1,2

Early testing for PTEN deficiency is critical^1,2

PTEN deficiency is an independent predictor for shorter OS and PFS
(compared with PTEN proficiency in patients with de novo mHSPC)

PTEN Deficiency Leads to Shorter OS³
Median OS: 43.8 vs 80.2 months (P<0.001)

43.8 mo

80.2 mo

Adjusted HR: 1.67
(1.14–2.43, P=0.008)

PTEN altered

PTEN non-altered

PTEN alterations were associated with a 36.4-month difference in OS, a significantly shorter span vs non-altered PTEN.

HR, hazard ratio; mHSPC, metastatic hormone-sensitive prostate cancer; OS, overall survival.

PTEN deficiency is an independent prognostic factor for worse progression-free survival^2,3

A real-world study found that PFS was shorter in PTEN-deficient mPC patients²
Patients with non-altered PTEN experienced 6.5 months longer PFS²

mPFS in mPC by PTEN status²
mPFS: 31.0 vs 37.5 months (P=0.019)

PTEN
alterations

31.0

PTEN
non-altered

37.5

Months

HR: 0.80 (0.66 - 0.96)

HR, hazard ratio; mPC, metastatic prostate cancer; mPFS, median progression-free survival; PFS, progression-free survival.

PTEN deficiency negatively impacts outcomes in patients with prostate cancer and is emerging as an important biomarker in de novo mHSPC^1,2

PTEN regulates cell growth and suppression of tumors⁴

Proficient PTEN and Normal AKT Signaling Pathway Diagram

PTEN Deficiency and Aberrant AKT Signaling Pathway Diagram

AKT, AKR strain transforming; FOX01, Forkhead box 01; GSK3, glycogen synthase kinase-3; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog.

PTEN is a tumor suppressor that negatively regulates the PI3K–AKT pathway; intact PTEN maintains controlled cell growth, while PTEN loss leads to unchecked AKT signaling and tumor progression.^4-7

PTEN Prevalence:
Nearly 25% of mHSPC Patients Are PTEN Deficient⁸

24%

PTEN deficient

(258/1095)

76%

PTEN proficient

(837/1095)

IHC, in Addition to NGS, Enhances Identification of All PTEN-Deficient Patients^1,9

Why IHC biomarker testing should be routine at mPC diagnosis^1,2

PTEN deficiency can lead to significantly faster time to progression and worse outcomes; therefore, it is critical to ensure all patients with PTEN deficiency are identified.

Homozygous deletions, followed by truncations, are the most common PTEN alterations in prostate cancer¹⁰

Fusion

Missense

Splice

Homozygous deletion

mHSPC

Truncating mutation

~90% of PC PTEN alterations⁸

Genomic PTEN deletions and truncating mutations may result in loss of detectable protein that can be
assessed by IHC¹¹

IHC is another testing method for PTEN deficiency in mPC due to the potential that NGS alone may fail to identify nearly 1 in 5^1,9,12

PTEN loss can occur via various nongenetic mechanisms¹³

NGS (next-generation sequencing) is a well-validated and convenient assay for identification of genomic alterations in a large panel of biomarkers.¹²

While NGS can detect genomic PTEN alterations, IHC (immunohistochemistry) should be used to detect PTEN protein deficiency^14,15
Pre- and post-transcriptional factors also influence PTEN expression and would not be revealed through NGS alone^13,15,16
IHC requires less tumor tissue vs NGS¹⁵

NGS limitations underscore the importance of IHC testing^1,9

PTEN-deficient PC detected by NGS

PTEN-deficient PC missed by NGS but detectable with IHC

Nearly 1 in 5 PTEN-deficient patients are missed by NGS alone^1,9

PTEN loss status was defined as a minimum of 50% of the specimen's tumor area with no detectable PTEN staining.

Relying solely on NGS may overlook PTEN-deficient tumors in mPC^1,9

IHC Testing Identifies PTEN Deficiency Caused by Genomic Alterations and Factors Beyond the Genome^11,13,15,17

IHC testing utilizes antibodies specific for an antigen of interest to evaluate the presence of that antigen in a tissue sample.

IHC is commonly used to assess patient samples for changes in PTEN protein concentrations¹⁵

Advantages of IHC for PTEN testing

Monitoring of biomarker without disrupting the architecture of the tissue—especially relevant in tumors with high intratumoral heterogeneity¹²

Simple yet sensitive and specific approach that avoids many of the technical limitations of NGS^15,18

IHC detects PTEN protein levels instead of relying on DNA sequencing, revealing PTEN loss that may be undetectable by FISH/NGS/ctDNA^14,16

Less expensive and less time-consuming than FISH and NGS for the routine screening of prostate tumor specimens^14,15

Requires less tumor tissue than NGS, which is appropriate in PC due to the limited size of biopsies¹⁵

Systemic PTEN IHC analysis could be easily and cost-effectively implemented in the diagnostic workup of patients with mPC¹²

ctDNA, circulating tumor DNA; FISH, fluorescence in situ hybridization.

IHC-based analyses are best to determine the level of PTEN expression in histological samples.¹⁷

IHC is the only prospectively validated test and is considered the gold standard for testing PTEN deficiency.¹²

Interpreting and Reporting PTEN IHC

PTEN status evaluated by IHC and NGS has different clinical implications. IHC allows for easy visualization of PTEN protein expression levels and evaluation for PTEN deficiency. NGS can provide insight into genomic alterations.¹⁵

To dive deeper into PTEN IHC interpretation and view clinical slides, click here: pioneerhubprostate.com

Visually Accessible Analysis
With IHC²⁰

PTEN proficient

Presence of PTEN-specific
antibody staining

Stained

PTEN deficient

Presence of PTEN-specific
antibody staining

Absence of PTEN-specific
antibody staining

Unstained

Simple and Sensitive Clinical Interpretation

PTEN deficiency has been defined in literature as ≥90% of viable malignant cells with no specific cytoplasmic staining.^19-21

Accurate reporting should clearly state PTEN deficiency and percentage of staining loss

A PTEN IHC Assay Scoring Algorithm^19-21

Clinical interpretation:
PTEN status

Staining pattern

Deficient^a

≥90% viable malignant cells with no specific cytoplasmic
staining

Proficient^a

>10% viable malignant cells with any specific cytoplasmic stain intensity

^aProstatic adenocarcinoma tissue samples are assessed for PTEN deficiency in the presence of acceptable controls. Nuclear staining of viable malignant cells must be disregarded.

PTEN NGS testing quantifies mutations, copy-number losses, and loss of heterozygosity across the gene. Pathogenic variants, single-copy deletions, or deep (biallelic) losses indicate disrupted PTEN function. This provides a comprehensive view of how the PI3K/AKT pathway is genomically activated.^4,19,22

Considerations for Your Practice

Key Takeaways for PTEN Testing in Prostate Cancer

Patients who are PTEN deficient have worse OS, PFS, and general outcomes of standard of care treatment than patients who are PTEN proficient^1,2
PTEN plays an important role in cell growth by regulating the AKT pathway and ensuring normal cell division²³
IHC testing may identify patients with PTEN deficiency who are missed with NGS testing alone. Testing should be conducted with IHC to confirm PTEN status^1,9
PTEN deficiency is defined as ≥90% of viable malignant cells with no specific cytoplasmic staining^19-21

OS, overall survival; PFS, progression-free survival.

Pathologist Reviewing Lab Sample for PTEN Testing Image

Ensure PTEN deficiency is clearly reported with the percentage of protein loss. Collaboration between pathologists, labs, and MDT (multidisciplinary team) on PTEN testing, ordering, and reporting may help improve patient care.

View educational resources that can help facilitate conversations between you and your MDT colleagues treating metastatic prostate cancer at pioneerhubprostate.com

Helpful Resources

Check out these featured resources on PTEN biomarker testing in metastatic prostate cancer.

de Bono J, et al. 2021. Presented at ASCO-GU Cancers Symposium 2021. Abstract #13.
Thapa B, et al. Ann Oncol. 2024;35:S991.
Zhang J-Y, et al. Asian J Androl. 2022;24:50–55.
Jamaspishvili T, et al. Nat Rev Urol. 2018;15:222–234.
Brown JS, Banerji U. Pharmacol Ther. 2017;172:101–115.
Marques RB, et al. Eur Urol. 2015;67(6):1177–1185.
Ferraldeschi R, et al. Eur Urol. 2015;67(4):795–802.
Stopsack KH et al. Clin Oncol Res. 2020;26:3230-3238.
Sweeney C, et al. Lancet. 2021;398:131–142.
Gilson C, et al. JCO Precis Oncol. 2020;4:882–897.
Pulido R, et al. Cold Spring Harb Perspect Med. 2019;9:a036293.
Giunta EF, et al. Cancers (Basel). 2021;13(19):4771.
Leslie NR, et al. Trends Pharmacol Sci. 2011;32(3):131–140.
Lotan TL, et al. Mod Pathol. 2016;29(8):904-914.
Tsao MS, Yatabe Y. J Thorac Oncol. 2019;14:2035–2038.
Wise HM, et al. Clin Sci (Lond). 2017;131:197–210.
Castillo-Martin M, et al. Methods Mol Biol. 2016;1388:23–37.
Shah RB, et al. Prostate. 2019;79:1267–1273.
Lotan TL, et al. Clin Cancer Res. 2011;17(20):6563–6573.
Lotan TL, et al. Oncotarget. 2017;8(39):65566–65576.
Fizazi K, et al. Ann Oncol. 2026;37(1):53-68.
Turnham, DJ et al. Cells. 2020;9:2342.
Tortorella E, et al. Int J Mol Sci. 2023;24:2046.

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PTEN Deficiency in Prostate Cancer

PTEN Is a Prognostic Biomarker With OS and PFS Implications1,2

PTEN deficiency is an independent prognostic factor for worse progression-free survival2,3

PTEN regulates cell growth and suppression of tumors4

PTEN Prevalence: Nearly 25% of mHSPC Patients Are PTEN Deficient8

IHC, in Addition to NGS, Enhances Identification of All PTEN-Deficient Patients1,9

IHC is another testing method for PTEN deficiency in mPC due to the potential that NGS alone may fail to identify nearly 1 in 51,9,12

IHC Testing Identifies PTEN Deficiency Caused by Genomic Alterations and Factors Beyond the Genome11,13,15,17

Interpreting and Reporting PTEN IHC

Simple and Sensitive Clinical Interpretation

Considerations for Your Practice

Helpful Resources

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