173 results on '"Lolkema, M.P."'
Search Results
2. Streamlining clinical research: an ESMO awareness call to improve sponsoring and monitoring of clinical trials
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Perez-Gracia, J.L., primary, Penel, N., additional, Calvo, E., additional, Awada, A., additional, Arkenau, H.T., additional, Amaral, T., additional, Grünwald, V., additional, Sanmamed, M.F., additional, Castelo-Branco, L., additional, Bodoky, G., additional, Lolkema, M.P., additional, Di Nicola, M., additional, Casali, P., additional, Giuliani, R., additional, and Pentheroudakis, G., additional
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- 2023
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3. Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study
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Curigliano, G., Gómez Pardo, P., Meric-Bernstam, F., Conte, P., Lolkema, M.P., Beck, J.T., Bardia, A., Martínez García, M., Penault-Llorca, F., Dhuria, S., Tang, Z., Solovieff, N., Miller, M., Di Tomaso, E., and Hurvitz, S.A.
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- 2016
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4. The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies
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Cirkel, G.A., Weeber, F., Bins, S., Gadellaa-van Hooijdonk, C.G.M., van Werkhoven, E., Willems, S.M., van Stralen, M., Veldhuis, W.B., Ubink, I., Steeghs, N., de Jonge, M.J., Langenberg, M.H.G., Schellens, J.H.M., Sleijfer, S., Lolkema, M.P., and Voest, E.E.
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- 2016
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5. Safety and tumour-specific immunological responses of combined dendritic cell vaccination and anti-CD40 agonistic antibody treatment for patients with metastatic pancreatic cancer: protocol for a phase I, open-label, single-arm, dose-escalation study (REACtiVe-2 trial)
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Lau, S.P., Land, F.R. van 't, Burg, S.H. van der, Homs, M.Y.V., Lolkema, M.P., Aerts, J.G.J.V., Eijck, C.H.J. van, Surgery, Pulmonary Medicine, and Medical Oncology
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Adult ,Vaccines ,Clinical Trials, Phase I as Topic ,Pancreatic cancer ,General Medicine ,Dendritic Cells ,Dendritic Cell ,Cancer Vaccines ,Pancreatic Neoplasms ,SDG 3 - Good Health and Well-being ,Antineoplastic Combined Chemotherapy Protocols ,CD40 ,Humans ,Immunotherapy - Abstract
IntroductionThe prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses.Methods and analysisIn this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses.Ethics and disseminationThe Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal.Trial registration numberNL9723.
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- 2022
6. Comprehensive Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma
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Nakauma-González, J.A., Rijnders, M., Riet, Job van, Heijden, M.S. van der, Voortman, J., Cuppen, E., Mehra, N., Wilpe, S. van, Oosting, S.F., Rijstenberg, L.L., Westgeest, H.M., Zwarthoff, E.C., Wit, R. de, Veldt, A.A.M. van der, Werken, H.J.G. van de, Lolkema, M.P., Boormans, J.L., Nakauma-González, J.A., Rijnders, M., Riet, Job van, Heijden, M.S. van der, Voortman, J., Cuppen, E., Mehra, N., Wilpe, S. van, Oosting, S.F., Rijstenberg, L.L., Westgeest, H.M., Zwarthoff, E.C., Wit, R. de, Veldt, A.A.M. van der, Werken, H.J.G. van de, Lolkema, M.P., and Boormans, J.L.
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Item does not contain fulltext, Recent molecular characterization of primary urothelial carcinoma (UC) may guide future clinical decision-making. For metastatic UC (mUC), a comprehensive molecular characterization is still lacking. We analyzed whole-genome DNA and RNA sequencing data for fresh-frozen metastatic tumor biopsies from 116 mUC patients who were scheduled for palliative systemic treatment within the context of a clinical trial (NCT01855477 and NCT02925234). Hierarchical clustering for mutational signatures revealed two major genomic subtypes: GenS1 (67%), which was APOBEC-driven; and GenS2 (24%), which had a high fraction of de novo mutational signatures related to reactive oxygen species and is putatively clock-like. Significantly mutated genes (SMGs) did not differ between the genomic subtypes. Transcriptomic analysis revealed five mUC subtypes: luminal-a and luminal-b (40%), stroma-rich (24%), basal/squamous (23%), and a nonspecified subtype (12%). These subtypes differed regarding expression of key genes, SMGs, oncogenic pathway activity, and immune cell infiltration. We integrated the genomic and transcriptomic data to propose potential therapeutic options by transcriptomic subtype and for individual patients. This in-depth analysis of a large cohort of patients with mUC may serve as a reference for subtype-oriented and patient-specific research on the etiology of mUC and for novel drug development. PATIENT SUMMARY: We carried out an in-depth analysis of the molecular and genetic features of metastatic cancer involving the cells that line the urinary tract. We showed that this is a heterogeneous disease with different molecular subtypes and we identified possible targets for therapy for each subtype.
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- 2022
7. The genomic and transcriptomic landscape of advanced renal cell cancer for individualized treatment strategies
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de Joode, K., primary, van de Geer, W.S., additional, van Leenders, G.J.L.H., additional, Hamberg, P., additional, Westgeest, H.M., additional, Beeker, A., additional, Oosting, S.F., additional, van Rooijen, J.M., additional, Beerepoot, L.V., additional, Labots, M., additional, Mathijssen, R.H.J., additional, Lolkema, M.P., additional, Cuppen, E., additional, Sleijfer, S., additional, van de Werken, H.J.G., additional, and van der Veldt, A.A.M., additional
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- 2022
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8. Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors
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Langenberg, M.H.G., Witteveen, P.O., Roodhart, J., Lolkema, M.P., Verheul, H.M.W., Mergui-Roelvink, M., Brendel, E., Krätzschmar, J., Loembé, B., Nol-Boekel, A., Christensen, O., Schellens, J.H.M., and Voest, E.E.
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- 2011
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9. Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors
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Boss, D.S., Witteveen, P.O., van der Sar, J., Lolkema, M.P., Voest, E.E., Stockman, P.K., Ataman, O., Wilson, D., Das, S., and Schellens, J.H.
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- 2011
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10. 31P Genomic landscape and actionable targets as identified by whole genome sequencing and RNA sequencing in patients with advanced renal cell carcinoma
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Joode, K.D., primary, van de Geer, W.S., additional, van Leenders, G.J.L.H., additional, Hamberg, P., additional, Westgeest, H.M., additional, Beeker, A., additional, Oosting, S.F., additional, van Rooijen, J.M., additional, Beerepoot, L.V., additional, Labots, M., additional, Mathijssen, R.H., additional, Lolkema, M.P., additional, Cuppen, E., additional, Sleijfer, S., additional, van de Werken, H.J.G., additional, and Van der Veldt, A.A.M., additional
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- 2021
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11. 524P A phase I, open-label, dose-escalation trial of BI 1701963 in patients (pts) with KRAS mutated solid tumours: A snapshot analysis
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Johnson, M.L., primary, Gort, E., additional, Pant, S., additional, Lolkema, M.P., additional, Sebastian, M., additional, Scheffler, M., additional, Hwang, J., additional, Dünzinger, U., additional, Riemann, K., additional, Kitzing, T., additional, and Jänne, P.A., additional
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- 2021
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12. 95P Optimizing selection of experimental treatment for patients with advanced cancer using whole genome sequencing
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Pruis, M., primary, Groenendijk, F., additional, Badloe, S., additional, van Puffelen, A., additional, Robbrecht, D., additional, Dinjens, W., additional, Sleijfer, S., additional, von der Thüsen, J., additional, Roepman, P., additional, and Lolkema, M.P., additional
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- 2021
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13. 906P Simlukafusp α and cetuximab combination in patients with recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck
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Hansen, A.R., primary, Gomez-Roca, C.A., additional, Lolkema, M.P., additional, Verlingue, L., additional, Italiano, A., additional, Spicer, J., additional, Steeghs, N., additional, Bauman, J.E., additional, Fayette, J., additional, Niu, J., additional, Prenen, H., additional, Dejardin, D., additional, Boetsch, C., additional, Kraxner, A., additional, Evers, S., additional, Vardar, T., additional, Keshelava, N., additional, Teichgräber, V., additional, and Bonomi, M., additional
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- 2021
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14. A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors
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Gan, H.K., Millward, M., Jalving, M., Garrido-Laguna, I., Lickliter, J.D., Schellens, J.H., Lolkema, M.P., Herpen, C.M.L. van, Hug, B., Tang, L., O'Connor-Semmes, R., Gagnon, R., Ellis, C., Ganji, G., Matheny, C., Drilon, A., Gan, H.K., Millward, M., Jalving, M., Garrido-Laguna, I., Lickliter, J.D., Schellens, J.H., Lolkema, M.P., Herpen, C.M.L. van, Hug, B., Tang, L., O'Connor-Semmes, R., Gagnon, R., Ellis, C., Ganji, G., Matheny, C., and Drilon, A.
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Item does not contain fulltext, BACKGROUND: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. PATIENTS AND METHODS: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. RESULTS: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). CONCLUSION: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. IMPLICATIONS FOR PRACTICE: This first-in-human study confirms that GSK2849330 is well to
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- 2021
15. Identifying patient values impacting the decision whether to participate in early phase clinical cancer trials: A systematic review
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Lent, L.G.G. van, Jabbarian, L.J., Gurp, J.L.P. van, Hasselaar, J., Lolkema, M.P., Weert, J.C. van, Rijt, C.C. van der, Jonge, M.J. de, Lent, L.G.G. van, Jabbarian, L.J., Gurp, J.L.P. van, Hasselaar, J., Lolkema, M.P., Weert, J.C. van, Rijt, C.C. van der, and Jonge, M.J. de
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Contains fulltext : 235017.pdf (Publisher’s version ) (Open Access), BACKGROUND: For many patients with advanced cancer, the decision whether to participate in early phase clinical trials or not is complex. The decision-making process requires an in-depth discussion of patient values. We therefore aimed to synthesize and describe patient values that may affect early phase clinical trial participation. METHODS: We conducted a systematic search in seven electronic databases on patient values in relation to patients' decisions to participate in early phase clinical cancer trials. RESULTS: From 3072 retrieved articles, eleven quantitative and five qualitative studies fulfilled our inclusion criteria. We extracted ten patient values that can contribute to patients' decisions. Overall, patients who seek trial participation usually report hope, trust, quantity of life, altruism, perseverance, faith and/or risk tolerance as important values. Quality of life and humanity are main values of patients who refuse trial participation. Autonomy and social adherence can be reported by both trial seekers or refusers, dependent upon how they are manifested in a patient. CONCLUSIONS: We identified patient values that frequently play a role in the decision-making process. In the setting of discussing early phase clinical trial participation with patients, healthcare professionals need to be aware of these values. This analysis supports the importance of individual exploration of values. Patients that become aware of their values, e.g. by means of interventions focused on clarifying their values, could feel more empowered to choose. Subsequently, healthcare professionals could improve their support in a patients' decision-making process and reduce the chance of decisional conflict.
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- 2021
16. Validation of circulating steroid hormone measurements across different matrices by liquid chromatography–tandem mass spectrometry
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Snaterse, G. (Gido), van Dessel, L. (Lisanne), Taylor, A.E. (A.), Visser, J.A. (Jenny), Arlt, W. (Wiebke), Lolkema, M.P. (Martijn), Hofland, J. (Johannes), Snaterse, G. (Gido), van Dessel, L. (Lisanne), Taylor, A.E. (A.), Visser, J.A. (Jenny), Arlt, W. (Wiebke), Lolkema, M.P. (Martijn), and Hofland, J. (Johannes)
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Background: Steroid hormones are essential signalling molecules in prostate cancer (PC). However, many studies focusing on liquid biomarkers fail to take the hormonal status of these patients into account. Steroid measurements are sensitive to bias c
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- 2021
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17. Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features
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Mendelaar, P.A.J. (Pauline A.J.), Smid, M. (Marcel), Riet, J. (Job) van, Angus, L. (Lindsay), Labots, M. (Mariette), Steeghs, N. (Neeltje), Hendriks, M.P. (Mathijs P.), Cirkel, G.A. (Geert), van Rooijen, J.M. (Johan M.), Tije, A.J. (Albert Jan) ten, Lolkema, M.P. (Martijn), Cuppen, E. (Edwin), Sleijfer, S. (Stefan), Martens, J.W.M. (John), Wilting, S.M. (Saskia), Mendelaar, P.A.J. (Pauline A.J.), Smid, M. (Marcel), Riet, J. (Job) van, Angus, L. (Lindsay), Labots, M. (Mariette), Steeghs, N. (Neeltje), Hendriks, M.P. (Mathijs P.), Cirkel, G.A. (Geert), van Rooijen, J.M. (Johan M.), Tije, A.J. (Albert Jan) ten, Lolkema, M.P. (Martijn), Cuppen, E. (Edwin), Sleijfer, S. (Stefan), Martens, J.W.M. (John), and Wilting, S.M. (Saskia)
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In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.
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- 2021
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18. Limited evolution of the actionable metastatic cancer genome under therapeutic pressure
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Haar, J. Ter, Hoes, L.R., Roepman, P., Lolkema, M.P., Verheul, H.M.W., Gelderblom, H., Langen, A.J. de, Smit, E.F., Cuppen, E., Wessels, L.F.A., Voest, E.E., Haar, J. Ter, Hoes, L.R., Roepman, P., Lolkema, M.P., Verheul, H.M.W., Gelderblom, H., Langen, A.J. de, Smit, E.F., Cuppen, E., Wessels, L.F.A., and Voest, E.E.
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Contains fulltext : 238243.pdf (Publisher’s version ) (Closed access), Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment course of 231 adult patients with a representative variety of metastatic solid malignancies. Within the biopsy interval (median, 6.4 months), patients received one or multiple lines of (mostly) standard-of-care (SOC) treatments, with all major treatment modalities being broadly represented. SOC biomarkers and biomarkers for clinical trial enrollment could be identified in 23% and 72% of biopsies, respectively. For SOC genomic biomarkers, we observed full concordance between the first and the second biopsy in 99% of pairs. Of the 219 biomarkers for clinical trial enrollment that were identified in the first biopsies, we recovered 94% in the follow-up biopsies. Furthermore, a second WGS analysis did not identify additional biomarkers for clinical trial enrollment in 91% of patients. More-frequent genomic evolution was observed when considering specific genes targeted by small-molecule inhibitors or hormonal therapies (21% and 22% of cases, respectively). Together, our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities.
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- 2021
19. Cabazitaxel efficacy is strongly enhanced by continued Androgen Receptor Targeted Agents (ARTA) in Castration-Resistant Prostate Cancer (CRPC)
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Mout, L., primary, Van Royen, M.E., additional, De Ridder, C.M.A., additional, Stuurman, D., additional, Marques, R.B., additional, De Geer, W.S., additional, Van De Werken, H.J.G., additional, Mathijssen, R.H.J., additional, De Wit, R., additional, Lolkema, M.P., additional, and Van Weerden, W.M., additional
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- 2021
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20. Oligometastatic Prostate Cancer: Results of a Dutch Multidisciplinary Consensus Meeting
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Aluwini, S.S., Mehra, N., Lolkema, M.P., Oprea-Lager, D.E., Yakar, D., Stoevelaar, H., Poel, H.G. van der, Busstra, M., Jong, I.J. de, Reijke, T. de, Vries, K. de, Heijmink, S., Jenster, G., Klaver, S., Kneppers, J., Lavalaye, J., Leyten, G., Moonen, L., Nagaraj, J., Noordzij, W., Osanto, S., Oving, I., Schaake, E., Scheenen, T.W.J., Schoots, I., Sedelaar, M., Somford, D.M., Berkmortel, F.W. van den, Hulle, T. van der, Voort van Zyp, J.R.N. van der, Leeuwen, P. van, Moorselaar, J. van, Oort, I.M. van, Vogel, W., Westgeest, H., Aluwini, S.S., Mehra, N., Lolkema, M.P., Oprea-Lager, D.E., Yakar, D., Stoevelaar, H., Poel, H.G. van der, Busstra, M., Jong, I.J. de, Reijke, T. de, Vries, K. de, Heijmink, S., Jenster, G., Klaver, S., Kneppers, J., Lavalaye, J., Leyten, G., Moonen, L., Nagaraj, J., Noordzij, W., Osanto, S., Oving, I., Schaake, E., Scheenen, T.W.J., Schoots, I., Sedelaar, M., Somford, D.M., Berkmortel, F.W. van den, Hulle, T. van der, Voort van Zyp, J.R.N. van der, Leeuwen, P. van, Moorselaar, J. van, Oort, I.M. van, Vogel, W., and Westgeest, H.
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Item does not contain fulltext, BACKGROUND: Oligometastatic prostate cancer (OMPC) is a heterogeneous disease state that is imperfectly understood, and its clinical implications are unclear. OBJECTIVE: To determine the consensus of a Dutch multidisciplinary expert panel on biological aspects, treatment goals, and management of OMPC in daily clinical practice. DESIGN, SETTING, AND PARTICIPANTS: The study comprised a modified Delphi method including an explorative survey with various statements and questions, followed by a consensus meeting to discuss and determine the agreement with revised statements and related items. The panel consisted of 34 Dutch representatives from urology, medical and radiation oncology, radiology, nuclear medicine, and basic research. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement was determined with statements (five-point scale). Consensus was defined as >/=75% panel agreement with a statement. RESULTS AND LIMITATIONS: Consensus existed for 56% of statements. The panel agreed that OMPC comprises a limited metastatic spread in the hormone-sensitive setting, in both the synchronous and the metachronous presentation. Limited metastatic spread was believed to involve three to five metastases and a maximum of two organs. Prostate-specific membrane antigen positron emission tomography/computed tomography scan was currently perceived as the most accurate diagnostic imaging modality. Although there was a consensus that targeted treatment of all metastases in OMPC will delay further dissemination of the disease, opinions on specific treatment regimens were divided. Panel outcomes were limited by the lack of scientific evidence on OMPC. CONCLUSIONS: A multidisciplinary panel reached a consensus that OMPC is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should focus on both the biology and the clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC. PATIENT SUMMARY: A grou
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- 2020
21. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group
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Mosele, F. (F.), Remon, J. (J.), Mateo, J. (J.), Westphalen, C.B. (C. B.), Barlesi, F. (Fabrice), Lolkema, M.P. (Martijn), Normanno, N. (N.), Scarpa, A. (A.), Robson, M. (Mark), Meric-Bernstam, F. (F.), Wagle, N. (N.), Stenzinger, A. (A.), Bonastre, J. (J.), Bayle, A. (A.), Michiels, S. (Stefan), Bièche, I. (I.), Rouleau, E. (E.), Jezdic, S., Douillard, J.-Y. (J. Y.), Reis-Filho, J.S. (Jorge), Dienstmann, R. (R.), André, F. (F.), Mosele, F. (F.), Remon, J. (J.), Mateo, J. (J.), Westphalen, C.B. (C. B.), Barlesi, F. (Fabrice), Lolkema, M.P. (Martijn), Normanno, N. (N.), Scarpa, A. (A.), Robson, M. (Mark), Meric-Bernstam, F. (F.), Wagle, N. (N.), Stenzinger, A. (A.), Bonastre, J. (J.), Bayle, A. (A.), Michiels, S. (Stefan), Bièche, I. (I.), Rouleau, E. (E.), Jezdic, S., Douillard, J.-Y. (J. Y.), Reis-Filho, J.S. (Jorge), Dienstmann, R. (R.), and André, F. (F.)
- Abstract
Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could furt
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- 2020
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22. ESMO Clinical Research Observatory (ECRO): improving the efficiency of clinical research through rationalisation of bureaucracy
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Perez-Gracia, J.L. (Jose Luis), Awada, A. (Ahmad), Calvo, E. (Emiliano), Amaral, T. (Teresa), Arkenau, H.-T. (H.), Gruenwald, V. (Viktor), Bodoky, G. (Gyorgy), Lolkema, M.P. (Martijn), Di Nicola, M. (Massimo), Penel, N. (Nicolas), Vera, R. (Ruth), Sanmamed, M.F. (Miguel F.), Douillard, J.-Y. (Jean-Yves), Perez-Gracia, J.L. (Jose Luis), Awada, A. (Ahmad), Calvo, E. (Emiliano), Amaral, T. (Teresa), Arkenau, H.-T. (H.), Gruenwald, V. (Viktor), Bodoky, G. (Gyorgy), Lolkema, M.P. (Martijn), Di Nicola, M. (Massimo), Penel, N. (Nicolas), Vera, R. (Ruth), Sanmamed, M.F. (Miguel F.), and Douillard, J.-Y. (Jean-Yves)
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During the last years, there has been a dramatic increase in the administrative and bureaucratic burden associated with clin
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- 2020
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23. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns
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Jiao, W. (Wei), Atwal, G. (Gurnit), Polak, P. (Paz), Karlic, R. (Rosa), Cuppen, E. (Edwin), Al-Shahrour, F. (Fatima), Bailey, P.J. (Peter J.), Biankin, A.V. (Andrew), Boutros, P.C. (Paul C.), Campbell, P.J. (Peter), Chang, D.K. (David K.), Cooke, S.L. (Susanna), Deshpande, V. (Vikram), Faltas, B.M. (Bishoy M.), Faquin, W.C. (William C.), Garraway, L. (Levi), Getz, G. (Gad), Grimmond, S.M. (Sean), Haider, S.A. (Syed A.), Hoadley, K.A. (Katherine A.), Kaiser, V.B. (Vera B.), Kato, M. (Mamoru), Kübler, K. (Kirsten), Lazar, A.J. (Alexander J.), Li, C.H. (Constance H.), Louis, D.N. (David), Margolin, A. (Adam), Martin, S. (Sandra), Nahal-Bose, H.K. (Hardeep K.), Nielsen, G.P. (G. Petur), Nik-Zainal, S. (Serena), Omberg, L. (Larsson), P’ng, C. (Christine), Perry, M.D. (Marc D.), Polak, P., Rheinbay, E. (Esther), Rubin, M.A. (Mark A.), Semple, C.A. (Colin A.), Sgroi, D.C. (Dennis), Shibata, T. (Tatsuhiro), Siebert, R. (Reiner), Smith, J. (Jaclyn), Stein, L.D. (Lincoln D.), Stobbe, M.D. (Miranda D.), Sun, R.X. (Ren X.), Thai, K. (Kevin), Wright, D.W. (Derek W.), Wu, C.-L. (Chin-Lee), Yuan, K. (Ke), Zhang, J. (Junjun), Danyi, A. (Alexandra), de Ridder, J. (Jeroen), Herpen, C.M.L. (Carla), Lolkema, M.P. (Martijn), Steeghs, N. (Neeltje), Morris, Q. (Quaid), Stein, L.D. (Lincoln), Jiao, W. (Wei), Atwal, G. (Gurnit), Polak, P. (Paz), Karlic, R. (Rosa), Cuppen, E. (Edwin), Al-Shahrour, F. (Fatima), Bailey, P.J. (Peter J.), Biankin, A.V. (Andrew), Boutros, P.C. (Paul C.), Campbell, P.J. (Peter), Chang, D.K. (David K.), Cooke, S.L. (Susanna), Deshpande, V. (Vikram), Faltas, B.M. (Bishoy M.), Faquin, W.C. (William C.), Garraway, L. (Levi), Getz, G. (Gad), Grimmond, S.M. (Sean), Haider, S.A. (Syed A.), Hoadley, K.A. (Katherine A.), Kaiser, V.B. (Vera B.), Kato, M. (Mamoru), Kübler, K. (Kirsten), Lazar, A.J. (Alexander J.), Li, C.H. (Constance H.), Louis, D.N. (David), Margolin, A. (Adam), Martin, S. (Sandra), Nahal-Bose, H.K. (Hardeep K.), Nielsen, G.P. (G. Petur), Nik-Zainal, S. (Serena), Omberg, L. (Larsson), P’ng, C. (Christine), Perry, M.D. (Marc D.), Polak, P., Rheinbay, E. (Esther), Rubin, M.A. (Mark A.), Semple, C.A. (Colin A.), Sgroi, D.C. (Dennis), Shibata, T. (Tatsuhiro), Siebert, R. (Reiner), Smith, J. (Jaclyn), Stein, L.D. (Lincoln D.), Stobbe, M.D. (Miranda D.), Sun, R.X. (Ren X.), Thai, K. (Kevin), Wright, D.W. (Derek W.), Wu, C.-L. (Chin-Lee), Yuan, K. (Ke), Zhang, J. (Junjun), Danyi, A. (Alexandra), de Ridder, J. (Jeroen), Herpen, C.M.L. (Carla), Lolkema, M.P. (Martijn), Steeghs, N. (Neeltje), Morris, Q. (Quaid), and Stein, L.D. (Lincoln)
- Abstract
In cancer, the primary tumour’s organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here,as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
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- 2020
- Full Text
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24. 472P Whole genome sequencing of metastatic CRC reveals footprints from the past and present with future clinical relevance
- Author
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Mendelaar, P.A.J., primary, Smid, M., additional, Van Riet, J., additional, Angus, L., additional, Van de Werken, H.J.G., additional, Labots, M., additional, Steeghs, N., additional, Hendriks, M.P., additional, Cirkel, G.A., additional, van Rooijen, J.M., additional, Tije, A.J. ten, additional, Lolkema, M.P., additional, Cuppen, E., additional, Sleijfer, S., additional, Martens, J.W.M., additional, and Wilting, S.M., additional
- Published
- 2020
- Full Text
- View/download PDF
25. 692TiP BRCA2men: An international, multicentre, observational and ambispective study to validate the predictive value of germline BRCA2 mutations for selecting the first-line of treatment in metastatic castration-resistant prostate cancer (mCRPC)
- Author
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Cattrini, C., primary, Lozano Mejorada, R., additional, Conteduca, V., additional, Ruiz-Vico, M., additional, Lolkema, M.P., additional, Lorente, D., additional, Sandhu, S., additional, Romero Laorden, N., additional, Loriot, Y., additional, Azad, A.A., additional, Costa, L., additional, Vinceneux, A., additional, Kanesvaran, R., additional, Ürün, Y., additional, Puente, J., additional, Attard, G., additional, Mehra, N., additional, De Giorgi, U., additional, Olmos Hidalgo, D., additional, and Castro Marcos, E., additional
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- 2020
- Full Text
- View/download PDF
26. 609O Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE®) immune therapy for metastatic castration-resistant prostate cancer (mCRPC)
- Author
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Tran, B., primary, Horvath, L., additional, Dorff, T., additional, Rettig, M., additional, Lolkema, M.P., additional, Machiels, J-P., additional, Rottey, S., additional, Autio, K., additional, Greil, R., additional, Adra, N., additional, Lemech, C., additional, Minocha, M., additional, Cheng, F-C., additional, Kouros-Mehr, H., additional, and Fizazi, K., additional
- Published
- 2020
- Full Text
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27. 594P The Drug Rediscovery Protocol (DRUP): Results of the first 500 treated patients
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Hoes, L.R., primary, van der Wijngaart, H., additional, van Berge Henegouwen, J.M., additional, Zeverijn, L.J., additional, van der Velden, D.L., additional, Roepman, P., additional, de Leng, W., additional, Jansen, A.M.L., additional, van Werkhoven, E., additional, Huitema, A., additional, Smit, E.F., additional, Van Herpen, C., additional, Labots, M., additional, Hoeben, A., additional, Morreau, H., additional, Lolkema, M.P., additional, Cuppen, E., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional
- Published
- 2020
- Full Text
- View/download PDF
28. Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer
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Pruis, M.A., primary, Geurts-Giele, W.R.R., additional, von der, Thüsen J.H., additional, Meijssen, I.C., additional, Dinjens, W.N.M., additional, Aerts, J.G.J.V., additional, Dingemans, A.M.C., additional, Lolkema, M.P., additional, Paats, M.S., additional, and Dubbink, H.J., additional
- Published
- 2020
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29. Effects of dietary restriction in cancer patients receiving irinotecan
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Van Eerden, R.A.G., primary, de Man, F.M., additional, van Doorn, G.M., additional, Oomen-de Hoop, E., additional, Koolen, S.L., additional, Olieman, J.F., additional, de Bruijn, P., additional, Veraart, J.N., additional, van Halteren, H.K., additional, Sandberg, Y., additional, Moelker, A., additional, IJzermans, J.N.M., additional, Lolkema, M.P., additional, van Gelder, T., additional, Dollé, M.E.T., additional, de Bruin, R.W.F., additional, and Mathijssen, R.H.J., additional
- Published
- 2019
- Full Text
- View/download PDF
30. Comprehensive pan-cancer analysis of somatic mutations in drug transporters to reveal acquired and intrinsic drug resistance in 3149 metastatic cancer patients
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Bins, S., primary, van de Geer, W.S., additional, van Riet, J., additional, Steeghs, N., additional, Verheul, H.M.W., additional, van Herpen, C., additional, Witteveen, P.O., additional, Tjan-Heijnen, V.C.G., additional, Lolkema, M.P., additional, Voest, E.E., additional, Sleijfer, S., additional, Cuppen, E., additional, van de Werken, H.J.G., additional, and Mathijssen, R.H.J., additional
- Published
- 2019
- Full Text
- View/download PDF
31. 68Ga-PSMA guided bone biopsies for molecular diagnostics in metastatic castration resistant prostate cancer patients
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de Jong, A.C., primary, Segbers, M., additional, Smits, M., additional, Brabander, T., additional, de Wit, R., additional, Mehra, N., additional, Van der Veldt, A.A.M., additional, and Lolkema, M.P., additional
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- 2019
- Full Text
- View/download PDF
32. Pan-cancer whole genome analyses of metastatic solid tumors
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Cuppen, E., primary, Priestley, P., additional, Baber, J., additional, Lolkema, M.P., additional, Steeghs, N., additional, de Bruijn, E., additional, Duyvesteyn, K., additional, Haidari, S., additional, van Hoeck, A., additional, Roepman, P., additional, Shale, C., additional, Voda, M., additional, Tjan-Heijnen, V.C.G., additional, Bloemendal, H., additional, van Herpen, C., additional, Labots, M., additional, Witteveen, P.O., additional, Smit, E.F., additional, Sleijfer, S., additional, and Voest, E.E., additional
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- 2019
- Full Text
- View/download PDF
33. Comparison of intratumoral docetaxel exposure in cancer patients between nanoparticle entrapped docetaxel (CPC634) and conventional docetaxel (Cd): The CriTax study
- Author
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Van Eerden, R.A.G., primary, Atrafi, F., additional, vanHylckama Vlieg, M.A.M., additional, Oomen-de Hoop, E., additional, de Bruijn, P., additional, Moelker, A., additional, Lolkema, M.P., additional, Rijcken, C.J.F., additional, Hanssen, R., additional, Eskens, F.A., additional, Mathijssen, R.H.J., additional, and Koolen, S.L., additional
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- 2019
- Full Text
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34. Docetaxel efficacy in prostate cancer is affected by testosterone; unraveling clinical observations
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Mout, L., primary, Moll, J.M., additional, Chen, M., additional, De Ridder, C., additional, Gibson, A.A., additional, Stuurman, D., additional, Aghai, A., additional, Mathijssen, R.H.J, additional, Sparreboom, A., additional, De Wit, R., additional, Lolkema, M.P., additional, and Van Weerden, W.M., additional
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- 2019
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- View/download PDF
35. [Genetic testing in patients with cancer; new developments]
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Ausems, M.G.E.M., Oosterwijk, J.C, Nielsen, M., Lolkema, M.P., Hoogerbrugge, N., and Ligtenberg, M.J.
- Subjects
Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] - Abstract
Item does not contain fulltext Genetic testing in patients with cancer; new developments About 5% of patients with cancer have a causative germline mutation. When a germline mutation is detected, this may have major implications for treatment and follow-up of the patient, as well as for relatives who are at risk of carrying the mutation. Increasingly, DNA-testing of tumor tissue is being performed to identify potential druggable targets, aiming at personalized medicine. Both germline testing and tissue testing may have consequences for the patient, for treatment and for family members. Currently there is a trend towards mainstreaming of genetic testing, which implies that treating physicians will increasingly be the ones to order DNA tests. This implies that they need to be aware of the (family) consequences and pitfalls of genetic testing. It calls for close collaboration between clinical genetics and regional treating physicians, and adequate referral of patients with abnormal DNA results and those with other clues for a genetic predisposition. The aim being optimal tailored treatment for each patient and adequate cancer prevention for their relatives.
- Published
- 2019
36. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
- Author
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Dessel, Lisanne F. van, Riet, Job van, Smits, M., Zhu, Yanyun, Hamberg, P., Heijden, Michiel S. van der, Oort, Inge M. van, Mehra, N., Lolkema, M.P., Dessel, Lisanne F. van, Riet, Job van, Smits, M., Zhu, Yanyun, Hamberg, P., Heijden, Michiel S. van der, Oort, Inge M. van, Mehra, N., and Lolkema, M.P.
- Abstract
Contains fulltext : 212631.pdf (publisher's version ) (Open Access)
- Published
- 2019
37. The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies
- Author
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Angus, L., Smid, M., Wilting, S.M., Riet, Job van, Hoeck, A. Van, Nguyen, L, Nik-Zainal, S., Steenbruggen, T.G., Tjan-Heijnen, V.C., Labots, M., Riel, J. van, Bloemendal, H.J., Steeghs, N., Lolkema, M.P., Voest, E.E., Werken, H.J.G. van de, Jager, Agnes, Cuppen, E., Sleijfer, S., Martens, J.W.M., Angus, L., Smid, M., Wilting, S.M., Riet, Job van, Hoeck, A. Van, Nguyen, L, Nik-Zainal, S., Steenbruggen, T.G., Tjan-Heijnen, V.C., Labots, M., Riel, J. van, Bloemendal, H.J., Steeghs, N., Lolkema, M.P., Voest, E.E., Werken, H.J.G. van de, Jager, Agnes, Cuppen, E., Sleijfer, S., and Martens, J.W.M.
- Abstract
Item does not contain fulltext, The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.
- Published
- 2019
38. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
- Author
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van Dessel, L. (Lisanne), Riet, J. (Job) van, Smits, M. (Minke), Zhu, Y. (Yanyun), Hamberg, A.P. (Paul), Heijden, M.S. (Michiel) van der, Bergman, A.M. (Andries), Oort, I.M. (Inge) van, Wit, R. (Ronald) de, Voest, E.E. (Emile), Steeghs, N. (Neeltje), Yamaguchi, T.N. (Takafumi N.), Livingstone, J. (Julie), Boutros, P.C. (Paul C.), Martens, J.W.M. (John), Sleijfer, S. (Stefan), Cuppen, E. (Edwin), Zwart, W. (Wilbert), Werken, H.J.G. (Harmen) van de, Mehra, N. (Niven), Lolkema, M.P. (Martijn), van Dessel, L. (Lisanne), Riet, J. (Job) van, Smits, M. (Minke), Zhu, Y. (Yanyun), Hamberg, A.P. (Paul), Heijden, M.S. (Michiel) van der, Bergman, A.M. (Andries), Oort, I.M. (Inge) van, Wit, R. (Ronald) de, Voest, E.E. (Emile), Steeghs, N. (Neeltje), Yamaguchi, T.N. (Takafumi N.), Livingstone, J. (Julie), Boutros, P.C. (Paul C.), Martens, J.W.M. (John), Sleijfer, S. (Stefan), Cuppen, E. (Edwin), Zwart, W. (Wilbert), Werken, H.J.G. (Harmen) van de, Mehra, N. (Niven), and Lolkema, M.P. (Martijn)
- Abstract
Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite inst
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- 2019
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- View/download PDF
39. Circulating tumor cell enumeration and characterization in metastatic castration-resistant prostate cancer patients treated with cabazitaxel
- Author
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De Kruijff, I.E. (Ingeborg E.), Sieuwerts, A.M. (Anieta), Onstenk, W. (Wendy), Kraan, J. (Jaco), Smid, M. (Marcel), Van, M. (Mai), Van Der Vlugt-Daane, M. (Michelle), Oomen - de Hoop, E. (Esther), Mathijssen, A.H.J. (Ron), Lolkema, M.P. (Martijn), Wit, R. (Ronald) de, Hamberg, A.P. (Paul), Meulenbeld, H.J. (Hielke), Beeker, A. (Aart), Creemers, G.J.M. (Geert-Jan), Martens, J.W.M. (John), Sleijfer, S. (Stefan), De Kruijff, I.E. (Ingeborg E.), Sieuwerts, A.M. (Anieta), Onstenk, W. (Wendy), Kraan, J. (Jaco), Smid, M. (Marcel), Van, M. (Mai), Van Der Vlugt-Daane, M. (Michelle), Oomen - de Hoop, E. (Esther), Mathijssen, A.H.J. (Ron), Lolkema, M.P. (Martijn), Wit, R. (Ronald) de, Hamberg, A.P. (Paul), Meulenbeld, H.J. (Hielke), Beeker, A. (Aart), Creemers, G.J.M. (Geert-Jan), Martens, J.W.M. (John), and Sleijfer, S. (Stefan)
- Abstract
(1) Background: Markers identifying which patients with metastatic, castration-resistant prostate cancer (mCRPC) will benefit from cabazitaxel therapy are currently lacking. Therefore, the aim of this study was to identify markers associated with outcome to cabazitaxel therapy based on counts and gene expression profiles of circulating tumor cells (CTCs). (2) Methods: From 120 mCRPC patients, CellSearch enriched CTCs were obtained at baseline and after 6 weeks of cabazitaxel therapy. Furthermore, 91 genes associated with prostate cancer were measured in mRNA of these CTCs. (3) Results: In 114 mCRPC patients with an evaluable CTC count, the CTC count was independently associated with poor progression-free survival (PFS) and overall survival (OS) in multivariable analysis with other commonly used variables associated with outcome in mCRPC (age, prostate specific antigen (PSA), alkaline phosphatase, lactate dehydrogenase (LDH), albumin, hemoglobin), together with alkaline phosphatase and hemoglobin. A five-gene expression profile was generated to predict for outcome to cabazitaxel therapy. However, even though this signature was associated with OS in univariate analysis, this was not the case in the multivariate analysis for OS nor for PFS. (4) Conclusion: The established five-gene expression profile in CTCs was not independently associated with PFS nor OS. However, along with alkaline phosphatase and hemoglobin, CTC-count is independently associated with PFS and OS in mCRPC patients who are treated with cabazitaxel.
- Published
- 2019
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40. Pan-cancer whole-genome analyses of metastatic solid tumours
- Author
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Priestley, P., Baber, J., Lolkema, M.P., Steeghs, N., Bruijn, E. de, Shale, C., Duyvesteyn, K., Haidari, S., Hoeck, A. Van, Onstenk, W., Roepman, P., Voda, M., Bloemendal, H.J., Tjan-Heijnen, V.C., Herpen, C.M.L. van, Labots, M., Witteveen, P.O., Smit, E.F., Sleijfer, S., Voest, E.E., Cuppen, E., Priestley, P., Baber, J., Lolkema, M.P., Steeghs, N., Bruijn, E. de, Shale, C., Duyvesteyn, K., Haidari, S., Hoeck, A. Van, Onstenk, W., Roepman, P., Voda, M., Bloemendal, H.J., Tjan-Heijnen, V.C., Herpen, C.M.L. van, Labots, M., Witteveen, P.O., Smit, E.F., Sleijfer, S., Voest, E.E., and Cuppen, E.
- Abstract
Contains fulltext : 215492.pdf (publisher's version ) (Open Access), Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106x and 38x, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.
- Published
- 2019
41. Phase I investigator’s perceptions to ‘supersized seamless trials in oncology'
- Author
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Ma, B.B.Y., primary, van der Velden, N., additional, Mo, F., additional, Loong, H.H., additional, Siu, L., additional, Goh, B.C., additional, Bang, Y.-J., additional, Lin, C.-C., additional, Desai, J., additional, and Lolkema, M.P., additional
- Published
- 2018
- Full Text
- View/download PDF
42. Clinical activity, safety, and PK/PD from a phase I study of RO6874281, a fibroblast activation protein (FAP) targeted interleukin-2 variant (IL-2v)
- Author
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Melero, I., primary, Castanon Alvarez, E., additional, Mau-Sorensen, M., additional, Lassen, U.N., additional, Lolkema, M.P., additional, Robbrecht, D.G., additional, Gomez-Roca, C.A., additional, Martin-Liberal, J., additional, Tabernero, J., additional, Ros, W., additional, Ahmed, S., additional, Isambert, N., additional, Piper Lepoutre, H., additional, Boetsch, C., additional, Charo, J., additional, Evers, S., additional, Teichgräber, V., additional, and Schellens, J.H.M., additional
- Published
- 2018
- Full Text
- View/download PDF
43. In-depth assessment of metastatic prostate cancer with high tumour mutational burden
- Author
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Mehra, N., primary, van Riet, J., additional, Smits, M., additional, Westdorp, H., additional, Gorris, M., additional, van Ee, T., additional, van der Doelen, M., additional, van Oort, I., additional, Sedelaar, M., additional, Textor, J., additional, Cuppen, E., additional, Grunberg, K., additional, Ligtenberg, M.J.L., additional, Zwart, W., additional, Bergman, A., additional, van de Werken, H.J.G., additional, Schalken, J., additional, de Vries, I.J.M., additional, Lolkema, M.P., additional, and Gerritsen, W.R., additional
- Published
- 2018
- Full Text
- View/download PDF
44. In-depth assessment of metastatic prostate cancer with high tumour mutational burden
- Author
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Mehra, N. (N.), Riet, J. (Job) van, Smits, M. (M.), Westdorp, H. (Harm), Gorris, M. (M.), van Ee, T. (T.), van der Doelen, M. (M.), Oort, I.M. (Inge) van, Sedelaar, M. (M.), Textor, J. (J.), Cuppen, E. (Edwin), Grunberg, K. (K.), Ligtenberg, M.J. (Marjolijn), Zwart, W. (Wilbert), Bergman, A.M. (Andries), Werken, H.J.G. (Harmen) van de, Schalken, J.A. (Jack), Vries, I.J.M. (Jolanda) de, Lolkema, M.P. (Martijn), Gerritsen, W.R. (Winald), Mehra, N. (N.), Riet, J. (Job) van, Smits, M. (M.), Westdorp, H. (Harm), Gorris, M. (M.), van Ee, T. (T.), van der Doelen, M. (M.), Oort, I.M. (Inge) van, Sedelaar, M. (M.), Textor, J. (J.), Cuppen, E. (Edwin), Grunberg, K. (K.), Ligtenberg, M.J. (Marjolijn), Zwart, W. (Wilbert), Bergman, A.M. (Andries), Werken, H.J.G. (Harmen) van de, Schalken, J.A. (Jack), Vries, I.J.M. (Jolanda) de, Lolkema, M.P. (Martijn), and Gerritsen, W.R. (Winald)
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- 2018
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45. High-throughput isolation of circulating tumor DNA
- Author
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van Dessel, L. (Lisanne), Vitale, S.R. (Silvia), Peeters, A.M.A. (Annemiek), Wilting, S.M. (Saskia), van der Vlugt-Daane, M, Oomen - de Hoop, E. (Esther), Sleijfer, S. (Stefan), Martens, J.W.M. (John), Jansen, M.P.H.M. (Maurice), Lolkema, M.P. (Martijn), van Dessel, L. (Lisanne), Vitale, S.R. (Silvia), Peeters, A.M.A. (Annemiek), Wilting, S.M. (Saskia), van der Vlugt-Daane, M, Oomen - de Hoop, E. (Esther), Sleijfer, S. (Stefan), Martens, J.W.M. (John), Jansen, M.P.H.M. (Maurice), and Lolkema, M.P. (Martijn)
- Abstract
The emerging interest in circulating tumor DNA (ctDNA) analyses for clinical trials has necessitated the development of a high-throughput method for fast, reproducible, and efficient isolation of ctDNA. Currently, the majority of ctDNA studies use the manual QIAamp (QA) platform to isolate DNA from blood. The purpose of this study was to compare two competing automated DNA isolation platforms [Maxwell (MX) and QIAsymphony (QS)] to the current ‘gold standard’ QA to facilitate high-throughput processing of samples in prospective trials. We obtained blood samples from healthy blood donors and metastatic cancer patients for plasma isolation. Total cell-free DNA (cfDNA) quantity was assessed by TERT quantitative PCR. Recovery efficiency was investigated by quantitative PCR analysis of spiked-in synthetic plant DNA. In addition, a b-actin fragmentation assay was performed to determine the amount of contamination by genomic DNA from lysed leukocytes. ctDNA quality was assessed by digital PCR for somatic variant detection. cfDNA quantity and recovery efficiency were lowest using the MX platform, whereas QA and QS showed a comparable performance. All platforms preferentially isolated small (136 bp) DNA fragments over large (420 and 2000 bp) DNA fragments. Detection of the number variant and wild-type molecules was most comparable between QA and QS. However, there was no significant difference in variant allele frequency comparing QS and MX to QA. In summary, we show that the QS platform has comparable performance to QA, the ‘gold standard’, and outperformed the MX platform depending on the readout used. We conclude that the QS can replace the more laborious QA platform, especially when high-throughput cfDNA isolation is needed.
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- 2018
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46. Influence of enzalutamide on cabazitaxel pharmacokinetics: A Drug–Drug interaction study in metastatic castration-resistant prostate cancer (mCRPC) patients
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Belderbos, B.P.S.I. (Bodine), Bins, S. (Sander), Leeuwen, R.W.F. (Roelof) van, Oomen-De Hoop, E. (Esther), van der Meer, N. (Nelly), Bruijn, P.J. (Peter) de, Hamberg, A.P. (Paul), Overkleeft, E.N.M. (Esther N.M.), Deure, W.M. (Wendy) van der, Lolkema, M.P. (Martijn), Wit, R. (Ronald) de, Mathijssen, A.H.J. (Ron), Belderbos, B.P.S.I. (Bodine), Bins, S. (Sander), Leeuwen, R.W.F. (Roelof) van, Oomen-De Hoop, E. (Esther), van der Meer, N. (Nelly), Bruijn, P.J. (Peter) de, Hamberg, A.P. (Paul), Overkleeft, E.N.M. (Esther N.M.), Deure, W.M. (Wendy) van der, Lolkema, M.P. (Martijn), Wit, R. (Ronald) de, and Mathijssen, A.H.J. (Ron)
- 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 ¼ 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0–24h of cabazitaxel was 181 ngh/mL (95% CI, 150–219 ngh/mL) in cycle 3 and 234 ngh/mL (95% CI, 209–261 ngh/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.
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- 2018
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47. Preferences to Receive Unsolicited Findings of Germline Genome Sequencing in a Large Population of Cancer Patients
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Bijlsma, R.M., primary, Wouters, R.H.P., additional, Wessels, H., additional, Sleijfer, S., additional, Beerepoot, L.V., additional, Bokkel Huinink, D. ten, additional, van Cruijsen, H., additional, Heijns, J., additional, Lolkema, M.P., additional, Steeghs, N., additional, van Voorthuizen, T., additional, Vulink, A.J.E., additional, Witteveen, P.O., additional, Ausems, M.G.E.M., additional, Bredenoord, A.L., additional, May, A.M., additional, and Voest, Emile E., additional
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- 2018
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48. Implementation of a Multicenter Biobanking Collaboration for Next-Generation Sequencing-Based Biomarker Discovery Based on Fresh Frozen Pretreatment Tumor Tissue Biopsies.
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Bins, S., Cirkel, G.A., Gadellaa-van Hooijdonk, C.G.M., Weeber, F., Numan, I.J., Bruggink, A.H., Diest, P.J. van, Willems, S.M., Veldhuis, W.B., Heuvel, M. van den, Knegt, R.J. de, Koudijs, M.J., Werkhoven, E. van, Mathijssen, R.H., Cuppen, E., Sleijfer, S., Schellens, J.H., Voest, E.E., Langenberg, M.H., Jonge, M.J. de, Steeghs, N., Lolkema, M.P., Bins, S., Cirkel, G.A., Gadellaa-van Hooijdonk, C.G.M., Weeber, F., Numan, I.J., Bruggink, A.H., Diest, P.J. van, Willems, S.M., Veldhuis, W.B., Heuvel, M. van den, Knegt, R.J. de, Koudijs, M.J., Werkhoven, E. van, Mathijssen, R.H., Cuppen, E., Sleijfer, S., Schellens, J.H., Voest, E.E., Langenberg, M.H., Jonge, M.J. de, Steeghs, N., and Lolkema, M.P.
- Abstract
01 januari 2017, Item does not contain fulltext, BACKGROUND: The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image-guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis. PATIENTS AND METHODS: Image-guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor-rich areas. Safety of the image-guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure. RESULTS: Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups. CONCLUSION: Image-guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank. The Oncologist 2017;22:33-40Implications for Practice: This study shows that it is safe to perform image-guided biopsy procedures to obtain fresh frozen tumor samples and that it is feasible to use these biopsies for biomarker discovery purposes in a Dutch multicenter collaboration. F
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- 2017
49. Testosterone Diminishes Cabazitaxel Efficacy and Intratumoral Accumulation in a Prostate Cancer Xenograft Model
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Mout, L. (Lisanne), Wit, R. (Ronald) de, Stuurman, D. (Debra), Verhoef, E.I. (Esther), Mathijssen, A.H.J. (Ron), Ridder, C.M.A. (Corrina) de, Lolkema, M.P. (Martijn), Weerden, W.M. (Wytske) van, Mout, L. (Lisanne), Wit, R. (Ronald) de, Stuurman, D. (Debra), Verhoef, E.I. (Esther), Mathijssen, A.H.J. (Ron), Ridder, C.M.A. (Corrina) de, Lolkema, M.P. (Martijn), and Weerden, W.M. (Wytske) van
- Abstract
Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents.
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- 2017
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50. Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study
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Weeber, F. (Fleur), Cirkel, G.A. (Geert), Hoogstraat, M. (Marlous), Bins, S. (Sander), Gadellaa-Van Hooijdonk, C.G.M. (C. G M), Ooft, S.N. (Salo), Werkhoven, E.D. (E.) van, Willems, S.M. (Stefan Martin), van Stralen, M. (Marijn), Veldhuis, W.B. (Wouter), Besselink, N. (Nicolle), Horlings, H.M. (Hugo M.), Steeghs, N. (Neeltje), Jonge, M.J.A. (Maja) de, Langenberg, M.H. (Marlies), Wessels, L. (Lodewyk), Cuppen, E. (Edwin), Schellens, J.H.M. (Jan), Sleijfer, S. (Stefan), Lolkema, M.P. (Martijn), Voest, E.E. (Emile), Weeber, F. (Fleur), Cirkel, G.A. (Geert), Hoogstraat, M. (Marlous), Bins, S. (Sander), Gadellaa-Van Hooijdonk, C.G.M. (C. G M), Ooft, S.N. (Salo), Werkhoven, E.D. (E.) van, Willems, S.M. (Stefan Martin), van Stralen, M. (Marijn), Veldhuis, W.B. (Wouter), Besselink, N. (Nicolle), Horlings, H.M. (Hugo M.), Steeghs, N. (Neeltje), Jonge, M.J.A. (Maja) de, Langenberg, M.H. (Marlies), Wessels, L. (Lodewyk), Cuppen, E. (Edwin), Schellens, J.H.M. (Jan), Sleijfer, S. (Stefan), Lolkema, M.P. (Martijn), and Voest, E.E. (Emile)
- Abstract
Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation. Results: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test). Conclusion: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies.
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- 2017
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