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  • American Association for Cancer Research (AACR)  (23)
  • 1
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    Correction: A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 13 ( 2022-07-01), p. 2969-2969
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 13 ( 2022-07-01), p. 2969-2969
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1792
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 23 ( 2021-12-01), p. 6366-6375
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 23 ( 2021-12-01), p. 6366-6375
    Abstract: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P & lt; 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-4185
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 3
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    Abstract 3919: Liquid biopsy derived organoids as a potential platform for personalized cancer therapy in metastatic prostate cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3919-3919
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3919-3919
    Abstract: Introduction Circulating tumor cells (CTCs) can serve as a source of metastatic tumor material, however their low numbers often limit downstream applications. Diagnostic leukapheresis (DLA) has been shown to substantially increase CTC yield. In this study we isolated CTCs from metastatic prostate cancer (mPCa) patients by DLA to propagate them in vitro as organoid cultures. Furthermore, tumor-derived organoids were used as a model for drug discovery and sensitivity-screening, thereby exploring potential treatment selection. Methods We included 44 mPCa patients into the study and 18 were selected for DLA, based on the presence of ≥5 CTCs/ 7.5 mL blood. We optimized the DLA procedure by comparing low versus high density settings and their impact on CTC isolation efficacy. As the DLA product contains a median of 8.6*10^9 white blood cells (WBC), stringent enrichment methods are needed. CTC enrichment from DLA product was performed by antibody-based WBC depletion alone, or combined with subsequent EpCAM based enrichment. Enriched CTC fractions were cultured in vitro under optimized conditions, to initiate organoid expansion. Results We show that DLA is a safe and efficient method to collect large amounts of CTCs from mPCa patients. With optimized DLA settings we were able to improve CTC enrichment and observed a non-significant increase in CTC yield from DLA (median CTC recovery 15339 vs 5796, P=0.125). WBC depletion alone was found to reduce WBCs by ~2000-fold while retaining & gt;50% of the CTCs, resulting in a WBC to CTC ratio of 545:1. We were able to culture and confirm CTC-derived organoids in 9/18 samples, including one organoid cell line, EMC-PCa-41. Whole Genome Sequencing (WGS) of EMC-PCa-41 revealed a triploid genome characterized by focal amplification of AR, a TMPRSS2-ERG fusion, a PTEN deletion and multiple inter-chromosomal rearrangements. Next we determined copy number profiles in single CTCs and matched organoids from two patients using shallow WGS. These data confirm prior data that CTCs represent the inherent intra-patient heterogeneity and organoids resemble CTCs from the original DLA product. Moreover, we performed an in vitro drug screen with the organoid cell line EMC-PCa-41, and found that it has a limited response to Enzalutamide, which correlated with the relatively short response to Enzalutamide that was observed in the patient. Conclusion Overall our study demonstrates that DLA provides a high CTC yield which enables short-term organoid cultures that preserve the genomic hallmarks of prostate cancer. Viable CTCs obtained by DLA may serve as a (personalized) drug screening system in metastatic prostate cancer. Citation Format: Lisanne Mout, Lisanne F. van Dessel, Jaco Kraan, Anouk C. de Jong, Rui P. Neves, Sigrun Erkens-Schulze, Anieta M. Siewerts, Job van Riet, Ronald de Wit, Stefan Sleijfer, Paul Hamberg, Yorick Sandberg, Peter A. te Boekhorst, Harmen J. van de Werken, John W. Martens, Nikolas H. Stoecklein, Wytske M. van Weerden, Martijn P. Lolkema. Liquid biopsy derived organoids as a potential platform for personalized cancer therapy in metastatic prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3919.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3919
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 7 ( 2022-04-01), p. 1402-1411
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 7 ( 2022-04-01), p. 1402-1411
    Abstract: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-3752
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    Abstract 2190: Integrative genomic and transcriptomic characterization of metastatic urothelial carcinoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2190-2190
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2190-2190
    Abstract: Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options available. To identify novel targets for therapy, large-scale sequencing efforts are needed. The Cancer Genome Atlas (TCGA) initiative substantially improved our knowledge on the genomic and transcriptomic characteristics of primary UC (Robertson et al. Cell 2017), however, the molecular landscape of mUC still remains largely unexplored. We performed whole genome sequencing (WGS) on 116 biopsies of UC metastases and matched mRNA sequencing (RNAseq) for 90 samples. We applied genomic alteration analysis on the WGS data and consensus clustering on the RNAseq data. We compared the molecular alterations of mUC with the data of the TCGA cohort and found that most affected driver genes were similar between primary UC and mUC. However, we identified CNTNAP5, RARG and MGP as exclusively mutated driver genes in the metastatic setting, and TP53 alterations were more prevalent in mUC than in primary UC. APOBEC induced mutation signatures in coding and non-coding regions were identified in 91% of the mUC samples and correlated with ploidy, mutational burden and copy number alterations. Based on the etiology of observed mutational signatures, five genomic subtypes were identified in mUC and validated in the TCGA cohort. APOBEC mutagenesis was the main mutational process in genomic subtype 1, which was the most common subtype (67%, N = 78). Moreover, APOBEC deamination mutations were found to be increased over time in paired biopsies from eight patients, indicating that APOBEC enzyme activity is ongoing in the metastatic setting. Unsupervised clustering and comparing phenotypic markers between the groups revealed five clinically-relevant transcriptomic subtypes: luminal-a (20%), luminal-b (20%), stroma-rich (24%), basal/squamous (23%) and a non-specified phenotype (12%). The basal/squamous and stroma-rich subtypes showed highly similar molecular characteristics as the TCGA subtypes, but with enrichment of the stroma-rich and reduction of the basal/squamous subtype. Based on genomic alterations, potential therapeutic targets were identified in 111/116 mUC patients, of which FGFR3 alterations (18%) and fusions (6%), and CDKN2A (44%), ERBB2 (20%), and TSC1 (14%) alterations were most common. By integrating the genomic and transcriptomic data, we propose potential novel therapeutic options per transcriptomic subtype, like addition of a TGF-β inhibitor to immune checkpoint inhibition for the stroma-rich and basal/squamous subtypes that showed the highest TGF-β pathway activity. Using WGS and RNAseq analyses, we provide a comprehensive overview of the molecular landscape of mUC that may serve as a reference for more subgroup-oriented and patient-specific research on the etiology of mUC and future drug development. Citation Format: Maud Rijnders, J Alberto Nakauma-González, Job van Riet, Michiel S. van der Heijden, Jens Voortman, Edwin P. J. G Cuppen, Niven Mehra, Sandra van Wilpe, Sjoukje F. Oosting, L Lucia Rijstenberg, Ellen C. Zwarthoff, Ronald de Wit, Astrid A. van der Veldt, Harmen J. van de Werken, Martijn P. Lolkema, Joost L. Boormans. Integrative genomic and transcriptomic characterization of metastatic urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2190.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2190
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract 5673: In-depth analysis of the genomic landscape of 91 metastatic neuroendocrine tumors reveals subtype-heterogeneity and potential therapeutic targets
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5673-5673
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5673-5673
    Abstract: Background: Metastatic neuroendocrine tumors (mNET) form a clinically and genetically heterogeneous malignancy, characterized by distinct prognosis based upon primary tumor localization, functionality, grade and proliferation index, and a wide variation in treatment outcome. To get a better insight into this heterogeneity in prognosis and outcome, and also to reveal putative novel treatment targets, we here analyzed the mutational landscape of 91 metastatic mNET biopsies derived from whole-genome sequencing (WGS). Material and Methods: Between May 2016 and July 2018, 91 mNET patients from 14 Dutch hospitals were included in the study protocol (NCT01855477) of the Center for Personalized Cancer Treatment (CPCT). Patients with mNET were categorized by primary location into midgut (N = 44), pancreas (N = 26), lung (N = 5), unknown (N = 12) and other (N = 4). The WGS of matched peripheral blood and tumor tissues was performed on a HiSeq X Ten system to sequencing depths of 38x and 105x, respectively, and subsequently aligned to the human reference genome (GRCh37) and analyzed for somatic mutations, mutational signatures, copy-number alterations and structural variants with the GRIDSS, PURPLE, LINX suite, GISTIC2 and in-house algorithms. Results: The overall mutational landscape of mNET is hallmarked by a relative stable diploid tumor genome and low median tumor mutational burden (TMB) of 1.32 (IQR: 0.91 - 2.1) mutations per genomic Mb. Differences in median TMB relating to primary location were observed; ranging from 1.1 (midgut), 1.49 (pancreas), 2.87 (lung) to 4.18 (unknown); six mNET had high tumor mutational burden (TMB ≥ 10), but without microsatellite-instability signatures. In addition, we observed striking evidence of somatic aberrations due to alkylating agents (sig. 11), combined with the highest cohort-wide TMB (39.6) for a single patient treated with streptozocin prior to biopsy. Three mNETs revealed MUTYH-related alterations (sig. 18) and furthermore, we detected chromothripsis (n = 6) and APOBEC-related regional hypermutation (kataegis; n = 11). Midgut-derived mNET (n = 44) predominantly harbored somatic alterations in CDKN1B (n = 11) and CDKN2A/B (n = 7). Strikingly, no somatic driver mutation was seen in almost half of these midgut-derived mNET (n = 21). Pancreatic mNET (n = 26) predominantly harbored alterations in MEN1 (n = 8), TP53 (n = 8), ATRX (n = 6), CDKN2A/B (n = 6) and DAXX (n = 5). In total, 39 mNET (43%) showed clinically-actionable somatic alterations for current on- and off-label NET therapies. Conclusion: This study comprises the largest WGS repository of mNET to date, and demonstrates the genetic heterogeneity of mNET linked to primary localization. Several potential therapeutic targets were identified which are worthwhile to explore for their clinical value in the treatment of mNET patients. Citation Format: Job van Riet, Harmen J. van de Werken, Edwin Cuppen, Ferry A. L. M. Eskens, Margot E. Tesselaar, Linde M. van Veenendaal, Heinz-Josef Klümpen, Wouter Dercksen, Gerlof D. Valk, Martijn P. J. K. Lolkema, Stefan Sleijfer, Bianca Mostert. In-depth analysis of the genomic landscape of 91 metastatic neuroendocrine tumors reveals subtype-heterogeneity and potential therapeutic targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5673.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5673
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
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    Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug–Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 3 ( 2018-02-01), p. 541-546
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 3 ( 2018-02-01), p. 541-546
    Abstract: Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug–drug interaction needs to be investigated. Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added. Results: A potential clinically relevant 22% (95% CI, 9%–34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0–24h of cabazitaxel was 181 ng*h/mL (95% CI, 150–219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209–261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising. Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug–drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541–6. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-2336
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
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  • 8
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    Abstract 1099: Testosterone abolishes cabazitaxel efficacy in an in vivo model of prostate cancer and affects intratumoral concentrations
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1099-1099
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1099-1099
    Abstract: Introduction Docetaxel combined with castration provides a major survival benefit in newly diagnosed metastatic PCa. Conversely, docetaxel without castration in high-risk localized PCa is not active. Cabazitaxel is a new taxane retaining its activity in tumors resistant to docetaxel and new hormonal therapies. We aimed at better characterizing in vivo the relationship between cabazitaxel and circulating androgens in a preclinical human-derived xenograft model of castration-resistant prostate cancer (CRPC). Material and methods Athymic nude mice were inoculated with the androgen receptor wt, PSA secreting CRPC cell line PC346C-DCC-K. Mice were surgically castrated when tumors were established (tumor volume (TV) of 150 mm3). After 7 days, mice were randomized to receive testosterone (40 mg) or empty pellet. The following day mice were injected with one bolus injection of cabazitaxel (33 mg/kg) or NaCl intraperitoneally. Mice were sacrificed when tumors exceeded a volume of 1,500 mm3 or the maximum follow-up of 90 days after cabazitaxel treatment. Blood was sampled biweekly for PSA and testosterone and analyzed by an immunoassay. In a second in vivo experiment intratumoral uptake of cabazitaxel was determined in the presence and absence of testosterone using a similar experimental set-up, with the exception that mice were sacrificed 7 days after cabazitaxel treatment. Here, intratumoral cabazitaxel concentrations were determined in snap frozen tumors by LC/MS-MS and corrected for tumor weight. Results Cabazitaxel treatment of castrated male mice bearing PC346C-DCC-K tumors resulted in a complete or near-complete antitumor response. In contrast, in mice supplemented with testosterone the anti-tumor effect of cabazitaxel was not significantly different from placebo (median time till TV 1,500 mm3 48 and 45 days resp.). Importantly, testosterone supplementation alone did not significantly affect tumor growth, confirming the CRPC nature of the (PC346C-DCC-K) xenograft. Interestingly, in tumors of testosterone supplemented castrated mice the intratumoral cabazitaxel concentrations were significantly decreased compared to mice that did not receive testosterone (0.39 ng cabazitaxel per mg tumor tissue vs. 1.36 ng/mg, t-test p=0.0032). Conclusions These findings indicate that circulating testosterone significantly impairs the efficacy of cabazitaxel. Testosterone supplementation may alter the metabolism of cabazitaxel, or may interfere with uptake and/or accumulation of cabazitaxel in PCa cells. We will further investigate the relationship between circulating androgens and intratumoral cabazitaxel accumulation as well as anti-tumor efficacy. The study was supported by a research grant from Sanofi Citation Format: Lisanne Mout, Corrina de Ridder, Debra Stuurman, Peter Bruijn, Ron H. Mathijssen, Ronald de Wit, Martijn P. Lolkema, Wytske M. Weerden. Testosterone abolishes cabazitaxel efficacy in an in vivo model of prostate cancer and affects intratumoral concentrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1099. doi:10.1158/1538-7445.AM2017-1099
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-1099
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    Abstract 2617: A multicenter project to test the validity and logistics surrounding the testing of AR-V7 mRNA expression in circulating tumor cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2617-2617
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2617-2617
    Abstract: Introduction: The presence of the androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has shown to be associated with resistance to anti-AR treatment with abiraterone or enzalutamide, but not to chemotherapy containing taxanes such as cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). The primary objective of this project was to set up a validated multi-center pipeline to measure AR-V7 by RT-qPCR in RNA isolated from CellSearch-enriched CTCs. This pipeline included a) the pre-analytical phase (appropriate anonymized sample collection and sample preservation), b) the analytical phase (assay performance with high analytical sensitivity, precision and specificity and c) the post-analytical phase (data evaluation and reporting). Materials and Methods: CellSearch-enirched CTCs from metastatic castration-resistant prostate cancer (mCRPC) patients were characterized by RT-qPCR. To validate the pipeline, we determined the proportion of blood samples from mCRPC patients having three or more CTCs per 7.5 mL of blood for whom an AR-V7 status can be assayed and returned to the clinician within 11 days (design PRELUDE study protocol). Results: In the range of the RNA equivalent of 0.2-12 AR-V7 positive VCaP cells the coefficient of variation (CV) for AR-V7 was 9% (n=37). The limit of detection (LOD) was 0.3 and the limit of quantification (LOQ) 3 cells in the final RT-qPCR. In none of 17 healthy blood donors an AR-V7 signal was detected, showing high diagnostic specificity (100%). No differences were observed between AR-V7 data generated by four different technicians or in two different laboratories. For the 45 patients in the PRELUDE study, thirteen patients were not eligible due to poor RNA quality (n=1) or because the blood sample did not contain enough epithelial signal (n=12). Twenty-two patients were AR-V7 negative and ten AR-V7 positive. The median, 75th and 90th percentile reporting times from blood draw to dissemination of the test results were 7, 8 and 9 days, respectively. Conclusion: This AR-V7 test with validated cut-offs, a strong intra- and inter-laboratory performance and the ability to report the outcome within a clinically acceptable time frame for the large majority of patients, met our pre-specified objectives. The AR-V7 test is now ready to be used in prospective studies (including randomized controlled trials) to test its predictive value for outcome on post-docetaxel (anti-AR of cabazitaxel) treatment. Citation Format: Anieta M. Sieuwerts, Bianca Mostert, Michelle van der Vlugt-Daane, Jaco Kraan, Corine Beaufort, Mai Van, Wendy J. Prager, Bram De Laere, Nick Beije, Paul Hamberg, Hans M. Westgeest, Metin Tascilar, Luc Y. Dirix, Wendy Onstenk, Ronald de Wit, Martijn P. Lolkema, Ron H. Mathijssen, John W. Martens, Stefan Sleijfer. A multicenter project to test the validity and logistics surrounding the testing of AR-V7 mRNA expression in circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2617.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2617
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 10
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    Individualized Pazopanib Dosing: A Prospective Feasibility Study in Cancer Patients
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 23 ( 2016-12-01), p. 5738-5746
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 23 ( 2016-12-01), p. 5738-5746
    Abstract: Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically guided individualized dosing. Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cmin was & lt;20 mg/L and toxicity was & lt;grade 3. Results: In total, 17 patients had at least one Cmin & lt;20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. Cmin in these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all Cmin levels ≥20.0 mg/L. Of these, 9 patients with a high Cmin of 51.3 mg/L (45.1%) experienced ≥grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these pati ents, Cmin remained above the threshold at 28.2 mg/L (25.3%). Conclusions: A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738–46. ©2016 AACR. See related commentary by Ornstein and Rini, p. 5626
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-1255
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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