Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer

Adam Sharp; Jon C. Welti; Maryou B.K. Lambros; David Dolling; Daniel Nava Rodrigues; Lorna Pope; Caterina Aversa; Ines Figueiredo; Jennifer Fraser; Zai Ahmad; Changxue Lu; Pasquale Rescigno; Michael Kolinsky; Claudia Bertan; George Seed; Ruth Riisnaes; Susana Miranda; Mateus Crespo; Rita Pereira; Ana Ferreira; Gemma Fowler; Berni Ebbs; Penny Flohr; Antje Neeb; Diletta Bianchini; Antonella Petremolo; Semini Sumanasuriya; Alec Paschalis; Joaquin Mateo; Nina Tunariu; Wei Yuan; Suzanne Carreira; Stephen R. Plymate; Jun Luo; Johann S. de Bono

doi:10.1016/j.eururo.2019.04.006

Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer

Adam Sharp, Jon C. Welti, Maryou B.K. Lambros, David Dolling, Daniel Nava Rodrigues, Lorna Pope, Caterina Aversa, Ines Figueiredo, Jennifer Fraser, Zai Ahmad, Changxue Lu, Pasquale Rescigno, Michael Kolinsky, Claudia Bertan, George Seed, Ruth Riisnaes, Susana Miranda, Mateus Crespo, Rita Pereira, Ana FerreiraGemma Fowler, Berni Ebbs, Penny Flohr, Antje Neeb, Diletta Bianchini, Antonella Petremolo, Semini Sumanasuriya, Alec Paschalis, Joaquin Mateo, Nina Tunariu, Wei Yuan, Suzanne Carreira, Stephen R. Plymate, Jun Luo, Johann S. de Bono

School of Medicine

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Background: Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression. Objective: To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS). Design, setting, and participants: CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients). Outcome measurements and statistical analysis: CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined. Results and limitations: Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range [IQR]: 60, 19–184 vs 9, 2–64; Mann-Whitney test p < 0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63–148 vs 15, 0–113; Mann-Whitney test p = 0.004) than CTC+/AR-V7− samples. However, both CTC− (63%) and CTC+/AR-V7− (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC− patients (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.23–3.71; p = 0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7− patients (HR 1.26; 95% CI 0.73–2.17; p = 0.4). A limitation of this study was the heterogeneity of treatment received. Conclusions: Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported. Patient summary: Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use.

Original language	English (US)
Pages (from-to)	676-685
Number of pages	10
Journal	European Urology
Volume	76
Issue number	5
DOIs	https://doi.org/10.1016/j.eururo.2019.04.006
State	Published - Nov 2019

Keywords

Androgen receptor
Androgen receptor splice variant-7
Biomarker
Liquid biopsy
Metastatic castration-resistant prostate cancer
Prognostic

ASJC Scopus subject areas

Urology

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10.1016/j.eururo.2019.04.006

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Sharp, A., Welti, J. C., Lambros, M. B. K., Dolling, D., Rodrigues, D. N., Pope, L., Aversa, C., Figueiredo, I., Fraser, J., Ahmad, Z., Lu, C., Rescigno, P., Kolinsky, M., Bertan, C., Seed, G., Riisnaes, R., Miranda, S., Crespo, M., Pereira, R., ... de Bono, J. S. (2019). Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer. European Urology, 76(5), 676-685. https://doi.org/10.1016/j.eururo.2019.04.006

Sharp, A, Welti, JC, Lambros, MBK, Dolling, D, Rodrigues, DN, Pope, L, Aversa, C, Figueiredo, I, Fraser, J, Ahmad, Z, Lu, C, Rescigno, P, Kolinsky, M, Bertan, C, Seed, G, Riisnaes, R, Miranda, S, Crespo, M, Pereira, R, Ferreira, A, Fowler, G, Ebbs, B, Flohr, P, Neeb, A, Bianchini, D, Petremolo, A, Sumanasuriya, S, Paschalis, A, Mateo, J, Tunariu, N, Yuan, W, Carreira, S, Plymate, SR, Luo, J & de Bono, JS 2019, 'Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer', European Urology, vol. 76, no. 5, pp. 676-685. https://doi.org/10.1016/j.eururo.2019.04.006

@article{263e9f0a59094545b6f1035ae23e0c7c,

title = "Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer",

abstract = "Background: Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression. Objective: To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS). Design, setting, and participants: CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients). Outcome measurements and statistical analysis: CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined. Results and limitations: Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range [IQR]: 60, 19–184 vs 9, 2–64; Mann-Whitney test p < 0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63–148 vs 15, 0–113; Mann-Whitney test p = 0.004) than CTC+/AR-V7− samples. However, both CTC− (63%) and CTC+/AR-V7− (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC− patients (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.23–3.71; p = 0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7− patients (HR 1.26; 95% CI 0.73–2.17; p = 0.4). A limitation of this study was the heterogeneity of treatment received. Conclusions: Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported. Patient summary: Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use.",

keywords = "Androgen receptor, Androgen receptor splice variant-7, Biomarker, Liquid biopsy, Metastatic castration-resistant prostate cancer, Prognostic",

author = "Adam Sharp and Welti, {Jon C.} and Lambros, {Maryou B.K.} and David Dolling and Rodrigues, {Daniel Nava} and Lorna Pope and Caterina Aversa and Ines Figueiredo and Jennifer Fraser and Zai Ahmad and Changxue Lu and Pasquale Rescigno and Michael Kolinsky and Claudia Bertan and George Seed and Ruth Riisnaes and Susana Miranda and Mateus Crespo and Rita Pereira and Ana Ferreira and Gemma Fowler and Berni Ebbs and Penny Flohr and Antje Neeb and Diletta Bianchini and Antonella Petremolo and Semini Sumanasuriya and Alec Paschalis and Joaquin Mateo and Nina Tunariu and Wei Yuan and Suzanne Carreira and Plymate, {Stephen R.} and Jun Luo and {de Bono}, {Johann S.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = nov,

doi = "10.1016/j.eururo.2019.04.006",

language = "English (US)",

volume = "76",

pages = "676--685",

journal = "European Urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "5",

}

TY - JOUR

T1 - Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer

AU - Sharp, Adam

AU - Welti, Jon C.

AU - Lambros, Maryou B.K.

AU - Dolling, David

AU - Rodrigues, Daniel Nava

AU - Pope, Lorna

AU - Aversa, Caterina

AU - Figueiredo, Ines

AU - Fraser, Jennifer

AU - Ahmad, Zai

AU - Lu, Changxue

AU - Rescigno, Pasquale

AU - Kolinsky, Michael

AU - Bertan, Claudia

AU - Seed, George

AU - Riisnaes, Ruth

AU - Miranda, Susana

AU - Crespo, Mateus

AU - Pereira, Rita

AU - Ferreira, Ana

AU - Fowler, Gemma

AU - Ebbs, Berni

AU - Flohr, Penny

AU - Neeb, Antje

AU - Bianchini, Diletta

AU - Petremolo, Antonella

AU - Sumanasuriya, Semini

AU - Paschalis, Alec

AU - Mateo, Joaquin

AU - Tunariu, Nina

AU - Yuan, Wei

AU - Carreira, Suzanne

AU - Plymate, Stephen R.

AU - Luo, Jun

AU - de Bono, Johann S.

PY - 2019/11

Y1 - 2019/11

N2 - Background: Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression. Objective: To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS). Design, setting, and participants: CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients). Outcome measurements and statistical analysis: CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined. Results and limitations: Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range [IQR]: 60, 19–184 vs 9, 2–64; Mann-Whitney test p < 0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63–148 vs 15, 0–113; Mann-Whitney test p = 0.004) than CTC+/AR-V7− samples. However, both CTC− (63%) and CTC+/AR-V7− (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC− patients (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.23–3.71; p = 0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7− patients (HR 1.26; 95% CI 0.73–2.17; p = 0.4). A limitation of this study was the heterogeneity of treatment received. Conclusions: Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported. Patient summary: Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use.

AB - Background: Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression. Objective: To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS). Design, setting, and participants: CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients). Outcome measurements and statistical analysis: CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined. Results and limitations: Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range [IQR]: 60, 19–184 vs 9, 2–64; Mann-Whitney test p < 0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63–148 vs 15, 0–113; Mann-Whitney test p = 0.004) than CTC+/AR-V7− samples. However, both CTC− (63%) and CTC+/AR-V7− (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC− patients (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.23–3.71; p = 0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7− patients (HR 1.26; 95% CI 0.73–2.17; p = 0.4). A limitation of this study was the heterogeneity of treatment received. Conclusions: Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported. Patient summary: Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use.

KW - Androgen receptor

KW - Androgen receptor splice variant-7

KW - Biomarker

KW - Liquid biopsy

KW - Metastatic castration-resistant prostate cancer

KW - Prognostic

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DO - 10.1016/j.eururo.2019.04.006

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SN - 0302-2838

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JO - European Urology

JF - European Urology

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ER -

Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer

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