AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel
The androgen receptor splice variant (AR‐V) 7 in circulating tumor cells (CTCs) is a predictor for resistance to anti‐AR‐targeted treatment, but not to taxane‐based chemotherapy in metastatic castration‐resistant prostate cancer (mCRPC). In this study, we investigated whether the presence of two con...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-08-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12529 |
| _version_ | 1818191834847903744 |
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| author | Anieta M. Sieuwerts Wendy Onstenk Jaco Kraan Corine M. Beaufort Mai Van Bram De Laere Luc Y. Dirix Paul Hamberg Aart Beeker Hielke J. Meulenbeld Geert‐Jan Creemers Wytske M. vanWeerden Guido W. Jenster Annemieke J. M. Nieuweboer Ron H. J. Mathijssen Ronald deWit John W. M. Martens Stefan Sleijfer |
| author_facet | Anieta M. Sieuwerts Wendy Onstenk Jaco Kraan Corine M. Beaufort Mai Van Bram De Laere Luc Y. Dirix Paul Hamberg Aart Beeker Hielke J. Meulenbeld Geert‐Jan Creemers Wytske M. vanWeerden Guido W. Jenster Annemieke J. M. Nieuweboer Ron H. J. Mathijssen Ronald deWit John W. M. Martens Stefan Sleijfer |
| author_sort | Anieta M. Sieuwerts |
| collection | DOAJ |
| description | The androgen receptor splice variant (AR‐V) 7 in circulating tumor cells (CTCs) is a predictor for resistance to anti‐AR‐targeted treatment, but not to taxane‐based chemotherapy in metastatic castration‐resistant prostate cancer (mCRPC). In this study, we investigated whether the presence of two constitutively active variants (AR‐V3, AR‐V7) and two other conditionally activated variants (AR‐V1, AR‐V9) vs full‐length androgen receptor (AR‐FL) measured in CTCs from patients with mCRPC were associated with outcome to therapy with the taxane cabazitaxel. Blood was collected at baseline and after two cycles of cabazitaxel from 118 mCRPC patients starting cabazitaxel in a prospective phase II trial. CellSearch‐enriched CTCs were enumerated and in parallel characterized for the presence of the AR‐Vs by reverse transcription quantitative polymerase chain reaction. Correlations with CTC and prostate‐specific antigen response to cabazitaxel as well as associations with overall survival (OS) were investigated. All AR‐Vs were frequently present and co‐expressed at frequencies of 31–48% at baseline and at 19–40% after two cycles of cabazitaxel. No specific directions of change in the measured variants were detected between the start of treatment and after two cycles of cabazitaxel. No associations between the presence of AR‐V3 and AR‐V7 and outcome to cabazitaxel were observed. While a reduction in CTCs to < 5 CTCs during treatment (CTC5‐response) was less often observed in patients with AR‐V9‐positive CTCs at baseline (P = 0.004), the CTC5‐adjusted detection of AR‐V1 after two cycles of cabazitaxel was an independent prognostic factor for OS [HR 2.4 (95% CI 1.1–5.1, P = 0.03)]. These novel findings are expected to contribute to more personalized treatment approaches in mCRPC patients. |
| first_indexed | 2024-12-12T00:20:55Z |
| format | Article |
| id | doaj.art-9ca2c96fafc6462f975ce13bf278760c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-12T00:20:55Z |
| publishDate | 2019-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-9ca2c96fafc6462f975ce13bf278760c2022-12-22T00:44:44ZengWileyMolecular Oncology1574-78911878-02612019-08-011381795180710.1002/1878-0261.12529AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxelAnieta M. Sieuwerts0Wendy Onstenk1Jaco Kraan2Corine M. Beaufort3Mai Van4Bram De Laere5Luc Y. Dirix6Paul Hamberg7Aart Beeker8Hielke J. Meulenbeld9Geert‐Jan Creemers10Wytske M. vanWeerden11Guido W. Jenster12Annemieke J. M. Nieuweboer13Ron H. J. Mathijssen14Ronald deWit15John W. M. Martens16Stefan Sleijfer17Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsGZA Hospitals Sint‐Augustinus Wilrijk BelgiumGZA Hospitals Sint‐Augustinus Wilrijk BelgiumDepartment of Internal Medicine Franciscus Gasthuis and Vlietland Rotterdam The NetherlandsDepartment of Internal Medicine Spaarne Gasthuis Hoofddorp The NetherlandsDepartment of Internal Medicine Gelre Ziekenhuizen Zutphen The NetherlandsDepartment of Internal Medicine Catharina Ziekenhuis Eindhoven The NetherlandsDepartment of Urology Erasmus MC Rotterdam The NetherlandsDepartment of Urology Erasmus MC Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsThe androgen receptor splice variant (AR‐V) 7 in circulating tumor cells (CTCs) is a predictor for resistance to anti‐AR‐targeted treatment, but not to taxane‐based chemotherapy in metastatic castration‐resistant prostate cancer (mCRPC). In this study, we investigated whether the presence of two constitutively active variants (AR‐V3, AR‐V7) and two other conditionally activated variants (AR‐V1, AR‐V9) vs full‐length androgen receptor (AR‐FL) measured in CTCs from patients with mCRPC were associated with outcome to therapy with the taxane cabazitaxel. Blood was collected at baseline and after two cycles of cabazitaxel from 118 mCRPC patients starting cabazitaxel in a prospective phase II trial. CellSearch‐enriched CTCs were enumerated and in parallel characterized for the presence of the AR‐Vs by reverse transcription quantitative polymerase chain reaction. Correlations with CTC and prostate‐specific antigen response to cabazitaxel as well as associations with overall survival (OS) were investigated. All AR‐Vs were frequently present and co‐expressed at frequencies of 31–48% at baseline and at 19–40% after two cycles of cabazitaxel. No specific directions of change in the measured variants were detected between the start of treatment and after two cycles of cabazitaxel. No associations between the presence of AR‐V3 and AR‐V7 and outcome to cabazitaxel were observed. While a reduction in CTCs to < 5 CTCs during treatment (CTC5‐response) was less often observed in patients with AR‐V9‐positive CTCs at baseline (P = 0.004), the CTC5‐adjusted detection of AR‐V1 after two cycles of cabazitaxel was an independent prognostic factor for OS [HR 2.4 (95% CI 1.1–5.1, P = 0.03)]. These novel findings are expected to contribute to more personalized treatment approaches in mCRPC patients.https://doi.org/10.1002/1878-0261.12529androgen receptorAR splice variantscabazitaxelcastration‐resistant prostate cancercirculating tumor cells |
| spellingShingle | Anieta M. Sieuwerts Wendy Onstenk Jaco Kraan Corine M. Beaufort Mai Van Bram De Laere Luc Y. Dirix Paul Hamberg Aart Beeker Hielke J. Meulenbeld Geert‐Jan Creemers Wytske M. vanWeerden Guido W. Jenster Annemieke J. M. Nieuweboer Ron H. J. Mathijssen Ronald deWit John W. M. Martens Stefan Sleijfer AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel Molecular Oncology androgen receptor AR splice variants cabazitaxel castration‐resistant prostate cancer circulating tumor cells |
| title | AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel |
| title_full | AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel |
| title_fullStr | AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel |
| title_full_unstemmed | AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel |
| title_short | AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel |
| title_sort | ar splice variants in circulating tumor cells of patients with castration resistant prostate cancer relation with outcome to cabazitaxel |
| topic | androgen receptor AR splice variants cabazitaxel castration‐resistant prostate cancer circulating tumor cells |
| url | https://doi.org/10.1002/1878-0261.12529 |
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