Thrombospondin 1 and cathepsin D improve prostate cancer diagnosis by avoiding potentially unnecessary prostate biopsies

Steuber, Thomas; Tennstedt, Pierre; Macagno, Annalisa; Athanasiou, Alcibiade; Wittig, A.; Huber, Ramy; Golding, Bruno; Schiess, Ralph; Gillessen, Silke

doi:10.1111/bju.14540

Cited by 28 publications

(37 citation statements)

References 32 publications

(36 reference statements)

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“…The clinical utility of PGI was compared to biomarkers applied to second opinion tests (i.e., fPSA% and PHI) by determining which men should be biopsied at 90% sensitivity, as previously proposed [ 7 , 17 ] ( Figure 2 A,B). The biomarker fPSA% avoided 11 out of 63 negative biopsies (17.5%), PHI avoided 21 biopsies (33.3%), and PGI avoided 40 out of 63 negative biopsies (63.5%).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, new biomarkers such as prostate cancer antigen 3 (PCA3) or marker combinations such as the prostate health index (PHI) or the analysis of four kallikreins (4K) (intact PSA, human kallikrein 2, tPSA and fPSA) score, as well as multiparametric magnetic resonance imaging (mpMRI), have been introduced to improve the accuracy of detecting clinically significant PCa and to help in deciding whether a biopsy is needed [ 6 , 7 , 8 ]. A widely accepted standardized regimen for screening and early detection of PCa is yet to be established, and a need for further improvement using multi-analyte blood tests has been recognized [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Validating fPSA Glycoprofile as a Prostate Cancer Biomarker to Avoid Unnecessary Biopsies and Re-Biopsies

Bertók

Jáné

Bertóková

et al. 2020

Cancers

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Background: To compare the clinical performance of a new PCa serum biomarker based on fPSA glycoprofiling to fPSA% and PHI. Methods: Serum samples from men who underwent prostate biopsy due to increased PSA were used. A comparison between two equal groups (with histologically confirmed PCa or benign, non-cancer condition) was used for the clinical validation of a new glycan-based PCa oncomarker. SPSS and R software packages were used for the multiparametric analyses of the receiver operating curve (ROC) and for genetic algorithm metaheuristics. Results: When comparing the non-cancer and PCa cohorts, the combination of four fPSA glycoforms with two clinical parameters (PGI, prostate glycan index (PGI)) showed an area under receiver operating curve (AUC) value of 0.821 (95% CI 0.754–0.890). AUC values were 0.517 for PSA, 0.683 for fPSA%, and 0.737 for PHI. A glycan analysis was also applied to discriminate low-grade tumors (GS = 6) from significant tumors (GS ≥ 7). Conclusions: Compared to PSA on its own, or fPSA% and the PHI, PGI showed improved discrimination between presence and absence of PCa and in predicting clinically significant PCa. In addition, the use of PGI would help practitioners avoid 63.5% of unnecessary biopsies, while the use of fPSA% and PHI would help avoid 17.5% and 33.3% of biopsies, respectively, while missing four significant tumors (9.5%).

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Validating fPSA Glycoprofile as a Prostate Cancer Biomarker to Avoid Unnecessary Biopsies and Re-Biopsies

Bertók

Jáné

Bertóková

et al. 2020

Cancers

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“…Accordingly, circulating TSP-1 levels were higher in women with metastatic breast cancer compared to those with localized disease, while tumoral expression of TSP-1 was increased in patients with early breast cancer [20]. TSP-1 platelet concentration when combined with free PSA to total PSA ratio and serum Cathepsin D concentrations was able to diagnose CaP [59]. Our data demonstrates that TSP-1 in platelets is increased in tumor-bearing mice and this is associated with an increase in platelet concentrations of TGF-β1.…”

Section: Discussionmentioning

confidence: 99%

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

Kerr

Harris

Shi

et al. 2020

Preprint

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The development of distant metastasis is the main cause of prostate cancer (CaP)related death with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induce bone formation and bone marrow-derived cell mobilization to cancers supporting angiogenesis. We hypothesized that proteins released by the platelet α granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically antiangiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice bearing tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche formation. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis but reduced bone marrow-derived cell mobilization and tumor-induced bone formation with enhanced osteoclast formation. We hypothesized that these changes in the pre-metastatic niche were due to the retention of TGF-β1 in the platelets of mice with TSP-1 deleted. To assess the importance of platelet-derived TGF-β1, we implanted CaP tumors in mice with platelet-specific deletion of TGF-β1. Similar to TSP-1 deletion, loss of platelet TGF-β1 resulted in increased angiogenesis with a milder effect on tumor size and BMDC release.Within the bone microenvironment, platelet TGF-β1 deletion prevented tumor-induced bone formation due to increased osteoclastogenesis. Thus, we demonstrate that the TSP-1/TGF-β1 axis regulates pre-metastatic niche formation and tumor-induced bone Kerr 3 turnover. Targeting the platelet release of TSP-1 or TGF-β1 represents a potential method to interfere with the process of CaP metastasis to bone. Abbreviations: CaP: prostate cancer; MMP: matrix metalloproteinase; RANKL: receptor activator of NF-κB ligand; SMA: smooth muscle actin; TGF-β1: transforming growth factor beta-1 TRAP: tartrate-resistant acid phosphatase; TSP: thrombospondin, VEGF: vascular endothelial growth factor Kerr 4 INTRODUCTION An estimated 191,930 men will be diagnosed with prostate cancer (CaP) in 2020, surpassing even lung cancer in incidence [1]. Early detection has improved survival rates to 100 percent with a local diagnosis. However, men diagnosed with distant CaP metastases face a 30 percent chance of survival at five years, with bone being the most common site of CaP metastasis [1]. In fact, 90% of CaP patients display skeletal metastases at autopsy regardless of prior bone symptom reporting. Bone metastases are responsible for severe bone pain, decreased mobility, fractures, spinal cord compression, and hypercalcemia resulting in patient morbidity. Metastatic skeletal CaP lesions can produce many growth factors and cytokines which alter the bone struc...

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“…We have previously shown in one of the most challenging subsets of subjects presenting with a tPSA of 2‐10 ng/mL, prostate volume ≥35 mL, no prior history of PCa and a normal DRE, that the combined measurement of two novel glycoproteins thrombospondin‐1 (THBS1) and cathepsin D (CTSD) can improve the identification of clinically significant PCa . Based on these results we have developed a new test named Proclarix.…”

Section: Introductionmentioning

confidence: 99%

“…13,14 We have previously shown in one of the most challenging subsets of subjects presenting with a tPSA of 2-10 ng/mL, prostate volume ≥35 mL, no prior history of PCa and a normal DRE, that the combined measurement of two novel glycoproteins thrombospondin-1 (THBS1) and cathepsin D (CTSD) can improve the identification of clinically significant PCa. 15 Based on these results we have developed a new test named Proclarix. This test incorporates THBS1 and CTSD with patient age, tPSA and %fPSA values into a dedicated algorithm and provides a risk score that corresponds to the probability of detecting clinically significant PCa on biopsy.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a novel multivariate risk score to guide biopsy decision for the diagnosis of clinically significant prostate cancer

Klocker

Golding²,

Weber³

et al. 2020

BJUI Compass

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Objectives Selecting patients suspected of having prostate cancer (PCa) for a prostate biopsy remains a challenge. Prostate‐specific antigen (PSA)‐based testing is hampered by its low specificity that often leads to negative biopsy results or detection of clinically insignificant cancers, especially in the 2‐10 ng/mL range. The objective was to evaluate a novel diagnostic test called Proclarix incorporating thrombospondin‐1 and cathepsin D alongside total and free PSA as well as age for predicting clinically significant PCa. Patients and methods The test was developed following a retrospective study design using biobanked samples of 955 men from two reference centres. A multivariate approach was used for model development followed by validation to discriminate significant (grade group ≥2) from insignificant or no cancer at biopsy. The test specificity, positive predictive value (PPV) and negative predictive value (NPV) at a fixed sensitivity of 90% were compared to percent free PSA (%fPSA) alone. The number of avoidable prostate biopsies deemed to be representative of clinical utility was also assessed. Results In the targeted patient population, the test displayed increased diagnostic accuracy compared to %fPSA alone. Application of the established model on 955 patients at a fixed sensitivity of 90% for significant disease resulted in a specificity of 43%, NPV of 95% and a PPV of 25%. This is in comparison to a specificity of 17%, NPV of 89% and PPV of 19% for %fPSA alone and had the potential to reduce the total number of biopsies needed to identify clinically significant cancer. Further, the test score correlated with significance of cancer assessed on prostate biopsy. Conclusions The Proclarix test can be used as an aid in the decision‐making process if to biopsy men in this challenging patient population. The use of the test could reduce the number of biopsies performed avoiding invasive procedures, anxiety, discomfort, pain and complications.

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Thrombospondin 1 and cathepsin D improve prostate cancer diagnosis by avoiding potentially unnecessary prostate biopsies

Abstract: A model combining two cancer-related glycoproteins (THBS1 and CTSD) and %fPSA can improve PCa diagnosis and may reduce the number of unnecessary prostate biopsies because of its improved specificity for PCa when compared to %fPSA alone.

Cited by 28 publications

References 32 publications

Validating fPSA Glycoprofile as a Prostate Cancer Biomarker to Avoid Unnecessary Biopsies and Re-Biopsies

Validating fPSA Glycoprofile as a Prostate Cancer Biomarker to Avoid Unnecessary Biopsies and Re-Biopsies

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

Development and validation of a novel multivariate risk score to guide biopsy decision for the diagnosis of clinically significant prostate cancer

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