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Published in: World Journal of Urology 12/2019

01-12-2019 | Topic Paper

Discovery and validation of a serum microRNA signature to characterize oligo- and polymetastatic prostate cancer: not ready for prime time

Authors: Bert Dhondt, Elise De Bleser, Tom Claeys, Sarah Buelens, Nicolaas Lumen, Jo Vandesompele, Anneleen Beckers, Valerie Fonteyne, Kim Van der Eecken, Aurélie De Bruycker, Jérôme Paul, Pierre Gramme, Piet Ost

Published in: World Journal of Urology | Issue 12/2019

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Abstract

Purpose

Patients with oligometastatic prostate cancer (PC) may benefit from metastasis-directed therapy (MDT), delaying disease progression and the start of palliative systemic treatment. However, a significant proportion of oligometastatic PC patients progress to polymetastatic PC within a year following MDT, suggesting an underestimation of the metastatic load by current staging modalities. Molecular markers could help to identify true oligometastatic patients eligible for MDT.

Methods

Patients with asymptomatic biochemical recurrence following primary PC treatment were classified as oligo- or polymetastatic based on 18F-choline PET/CT imaging. Oligometastatic patients had up to three metastases at baseline and did not progress to more than three lesions following MDT or surveillance within 1 year of diagnosis of metastases. Polymetastatic patients had > 3 metastases at baseline or developed > 3 metastases within 1 year following imaging. A model aiming to prospectively distinguish oligo- and polymetastatic PC patients was trained using clinicopathological parameters and serum-derived microRNA expression profiles from a discovery cohort of 20 oligometastatic and 20 polymetastatic PC patients. To confirm the models predictive performance, it was applied on biomarker data obtained from an independent validation cohort of 44 patients with oligometastatic and 39 patients with polymetastatic disease.

Results

Oligometastatic PC patients had a more favorable prognosis compared to polymetastatic ones, as defined by a significantly longer median CRPC-free survival (not reached versus 38 months; 95% confidence interval 31–45 months with P < 0.001). Despite the good performance of a predictive model trained on the discovery cohort, with an AUC of 0.833 (0.693–0.973; 95% CI) and a sensitivity of 0.894 (0.714–1.000; 95% CI) for oligometastatic disease, none of the miRNA targets were found to be differentially expressed between oligo- and polymetastatic PC patients in the signature validation cohort. The multivariate model had an AUC of 0.393 (0.534 after cross-validation) and therefore, no predictive ability.

Conclusions

Although PC patients with oligometastatic disease had a more favorable prognosis, no serum-derived biomarkers allowing for prospective discrimination of oligo- and polymetastatic prostate cancer patients could be identified.
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Literature
1.
go back to reference Hellman S, Weichselbaum RR (1995) Oligometastases. J Clin Oncol 13(1):8–10CrossRef Hellman S, Weichselbaum RR (1995) Oligometastases. J Clin Oncol 13(1):8–10CrossRef
2.
go back to reference De Bleser E, Tran PT, Ost P (2017) Radiotherapy as metastasis-directed therapy for oligometastatic prostate cancer. Curr Opin Urol 27(6):587–595CrossRef De Bleser E, Tran PT, Ost P (2017) Radiotherapy as metastasis-directed therapy for oligometastatic prostate cancer. Curr Opin Urol 27(6):587–595CrossRef
3.
go back to reference Schweizer MT, Zhou XC, Wang H, Yang T, Shaukat F, Partin AW et al (2013) Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol 24(11):2881–2886CrossRef Schweizer MT, Zhou XC, Wang H, Yang T, Shaukat F, Partin AW et al (2013) Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol 24(11):2881–2886CrossRef
4.
go back to reference Ost P, Decaestecker K, Lambert B, Fonteyne V, Delrue L, Lumen N et al (2014) Prognostic factors influencing prostate cancer-specific survival in non-castrate patients with metastatic prostate cancer. Prostate 74(3):297–305CrossRef Ost P, Decaestecker K, Lambert B, Fonteyne V, Delrue L, Lumen N et al (2014) Prognostic factors influencing prostate cancer-specific survival in non-castrate patients with metastatic prostate cancer. Prostate 74(3):297–305CrossRef
5.
go back to reference Sridharan S, Steigler A, Spry NA, Joseph D, Lamb DS, Matthews JH et al (2016) Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial. Radiother Oncol J Eur Soc Ther Radiol Oncol 121(1):98–102CrossRef Sridharan S, Steigler A, Spry NA, Joseph D, Lamb DS, Matthews JH et al (2016) Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial. Radiother Oncol J Eur Soc Ther Radiol Oncol 121(1):98–102CrossRef
6.
go back to reference Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M et al (2015) Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373(8):737–746CrossRef Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M et al (2015) Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373(8):737–746CrossRef
7.
go back to reference De Bruycker A, Lambert B, Claeys T, Delrue L, Mbah C, De Meerleer G et al (2017) Prevalence and prognosis of low-volume, oligorecurrent, hormone-sensitive prostate cancer amenable to lesion ablative therapy. BJU Int 120(6):815–821CrossRef De Bruycker A, Lambert B, Claeys T, Delrue L, Mbah C, De Meerleer G et al (2017) Prevalence and prognosis of low-volume, oligorecurrent, hormone-sensitive prostate cancer amenable to lesion ablative therapy. BJU Int 120(6):815–821CrossRef
8.
go back to reference Hong MK, Macintyre G, Wedge DC, Van Loo P, Patel K, Lunke S et al (2015) Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat Commun 6:6605CrossRef Hong MK, Macintyre G, Wedge DC, Van Loo P, Patel K, Lunke S et al (2015) Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat Commun 6:6605CrossRef
9.
go back to reference Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E et al (2015) The evolutionary history of lethal metastatic prostate cancer. Nature 520(7547):353–357CrossRef Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E et al (2015) The evolutionary history of lethal metastatic prostate cancer. Nature 520(7547):353–357CrossRef
10.
go back to reference Weichselbaum RR, Hellman S (2011) Oligometastases revisited. Nat Rev Clin Oncol 8(6):378–382CrossRef Weichselbaum RR, Hellman S (2011) Oligometastases revisited. Nat Rev Clin Oncol 8(6):378–382CrossRef
11.
go back to reference Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ et al (2015) Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol 67(5):852–863CrossRef Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ et al (2015) Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol 67(5):852–863CrossRef
12.
go back to reference Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A et al (2018) Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol 36(5):446–453CrossRef Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A et al (2018) Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol 36(5):446–453CrossRef
13.
go back to reference Wei J, Zhu H, Liao X (2018) Trigger pSA predicting recurrence from positive choline PET/CT with prostate cancer after initial treatment. Oncotarget 9(18):14630–14641CrossRef Wei J, Zhu H, Liao X (2018) Trigger pSA predicting recurrence from positive choline PET/CT with prostate cancer after initial treatment. Oncotarget 9(18):14630–14641CrossRef
14.
go back to reference Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG et al (2016) Sensitivity, specificity, and predictors of positive (68)Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol 70(6):926–937CrossRef Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG et al (2016) Sensitivity, specificity, and predictors of positive (68)Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol 70(6):926–937CrossRef
15.
go back to reference van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B et al (2016) (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int 117(5):732–739CrossRef van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B et al (2016) (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int 117(5):732–739CrossRef
16.
go back to reference Murphy DG, Sweeney CJ, Tombal B (2017) “Gotta Catch ‘em All”, or Do We? Pokemet approach to metastatic prostate cancer. Eur Urol 72(1):1–3CrossRef Murphy DG, Sweeney CJ, Tombal B (2017) “Gotta Catch ‘em All”, or Do We? Pokemet approach to metastatic prostate cancer. Eur Urol 72(1):1–3CrossRef
17.
go back to reference Joice GA, Rowe SP, Pienta KJ, Gorin MA (2017) Oligometastatic prostate cancer: shaping the definition with molecular imaging and an improved understanding of tumor biology. Curr Opin Urol 27(6):533–541CrossRef Joice GA, Rowe SP, Pienta KJ, Gorin MA (2017) Oligometastatic prostate cancer: shaping the definition with molecular imaging and an improved understanding of tumor biology. Curr Opin Urol 27(6):533–541CrossRef
18.
go back to reference Dhondt B, Rousseau Q, De Wever O, Hendrix A (2016) Function of extracellular vesicle-associated miRNAs in metastasis. Cell Tissue Res 365:621–641CrossRef Dhondt B, Rousseau Q, De Wever O, Hendrix A (2016) Function of extracellular vesicle-associated miRNAs in metastasis. Cell Tissue Res 365:621–641CrossRef
19.
go back to reference Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T et al (2017) EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 71(4):630–642CrossRef Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T et al (2017) EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 71(4):630–642CrossRef
20.
go back to reference Moore HM, Kelly AB, Jewell SD, McShane LM, Clark DP, Greenspan R et al (2011) Biospecimen reporting for improved study quality (BRISQ). Cancer Cytopathol 119(2):92–102CrossRef Moore HM, Kelly AB, Jewell SD, McShane LM, Clark DP, Greenspan R et al (2011) Biospecimen reporting for improved study quality (BRISQ). Cancer Cytopathol 119(2):92–102CrossRef
21.
go back to reference Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y, Zhang Q et al (2011) MicroRNA expression characterizes oligometastasis(es). PLoS One 6(12):e28650CrossRef Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y, Zhang Q et al (2011) MicroRNA expression characterizes oligometastasis(es). PLoS One 6(12):e28650CrossRef
22.
go back to reference Lussier YA, Khodarev NN, Regan K, Corbin K, Li H, Ganai S et al (2012) Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS One 7(12):e50141CrossRef Lussier YA, Khodarev NN, Regan K, Corbin K, Li H, Ganai S et al (2012) Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS One 7(12):e50141CrossRef
23.
go back to reference Pitroda SP, Khodarev NN, Huang L, Uppal A, Wightman SC, Ganai S et al (2018) Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nat Commun 9(1):1793CrossRef Pitroda SP, Khodarev NN, Huang L, Uppal A, Wightman SC, Ganai S et al (2018) Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nat Commun 9(1):1793CrossRef
24.
go back to reference Banks RE, Stanley AJ, Cairns DA, Barrett JH, Clarke P, Thompson D et al (2005) Influences of blood sample processing on low-molecular-weight proteome identified by surface-enhanced laser desorption/ionization mass spectrometry. Clin Chem 51(9):1637–1649CrossRef Banks RE, Stanley AJ, Cairns DA, Barrett JH, Clarke P, Thompson D et al (2005) Influences of blood sample processing on low-molecular-weight proteome identified by surface-enhanced laser desorption/ionization mass spectrometry. Clin Chem 51(9):1637–1649CrossRef
25.
go back to reference McLerran D, Grizzle WE, Feng Z, Bigbee WL, Banez LL, Cazares LH et al (2008) Analytical validation of serum proteomic profiling for diagnosis of prostate cancer: sources of sample bias. Clin Chem 54(1):44–52CrossRef McLerran D, Grizzle WE, Feng Z, Bigbee WL, Banez LL, Cazares LH et al (2008) Analytical validation of serum proteomic profiling for diagnosis of prostate cancer: sources of sample bias. Clin Chem 54(1):44–52CrossRef
26.
go back to reference Wang K, Yuan Y, Cho J-H, McClarty S, Baxter D, Galas DJ (2012) Comparing the MicroRNA spectrum between serum and plasma. PLoS One 7(7):e41561 (Ahuja SK, editor) CrossRef Wang K, Yuan Y, Cho J-H, McClarty S, Baxter D, Galas DJ (2012) Comparing the MicroRNA spectrum between serum and plasma. PLoS One 7(7):e41561 (Ahuja SK, editor) CrossRef
27.
go back to reference Radwan N, Phillips R, Ross A, Rowe SP, Gorin MA, Antonarakis ES et al (2017) A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE). BMC Cancer 17(1):453CrossRef Radwan N, Phillips R, Ross A, Rowe SP, Gorin MA, Antonarakis ES et al (2017) A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE). BMC Cancer 17(1):453CrossRef
Metadata
Title
Discovery and validation of a serum microRNA signature to characterize oligo- and polymetastatic prostate cancer: not ready for prime time
Authors
Bert Dhondt
Elise De Bleser
Tom Claeys
Sarah Buelens
Nicolaas Lumen
Jo Vandesompele
Anneleen Beckers
Valerie Fonteyne
Kim Van der Eecken
Aurélie De Bruycker
Jérôme Paul
Pierre Gramme
Piet Ost
Publication date
01-12-2019
Publisher
Springer Berlin Heidelberg
Published in
World Journal of Urology / Issue 12/2019
Print ISSN: 0724-4983
Electronic ISSN: 1433-8726
DOI
https://doi.org/10.1007/s00345-018-2609-8

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