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1. Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Author

Dayton, Talya L., Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F.M., Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S., Hackeng, Wenzel M., Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A.A., Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F.M., Hartemink, Koen J., Klomp, Houke M., Borel Rinkes, Inne H.M., Dingemans, Anne-Marie, Valk, Gerlof D., Vriens, Menno R., Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, and Clevers, Hans

Published
2023
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4. Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Author

Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, Clevers, Hans, Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, and Clevers, Hans

Abstract

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.

Published
2023

5. Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Author

CMM Groep Maurice, Cancer, MS Endocriene Oncologie, Pathologie Groep Brosens, Pathologie Pathologen staf, MS CGO, Regenerative Medicine and Stem Cells, Heelkunde Opleiding, CMM, Hubrecht Institute with UMC, Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, Clevers, Hans, CMM Groep Maurice, Cancer, MS Endocriene Oncologie, Pathologie Groep Brosens, Pathologie Pathologen staf, MS CGO, Regenerative Medicine and Stem Cells, Heelkunde Opleiding, CMM, Hubrecht Institute with UMC, Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, and Clevers, Hans

Published
2023

6. Postoperative radiotherapy in stage I-III Merkel cell carcinoma

Author

Levy, Sonja, primary, Blankenstein, Stephanie A., additional, Grünhagen, Dirk Jan, additional, Jalving, Mathilde, additional, Hamming-Vrieze, Olga, additional, Been, Lukas B., additional, Tans, Lisa, additional, van Akkooi, Alexander C.J., additional, and Tesselaar, Margot E.T., additional

Published
2022
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7. First-line everolimus and cisplatin in patients with advanced extrapulmonary neuroendocrine carcinoma:a nationwide phase 2 single-arm clinical trial

Author

Levy, Sonja, Verbeek, Wieke H.M., Eskens, Ferry A.L.M., van den Berg, José G., de Groot, Derk Jan A., van Leerdam, Monique E., Tesselaar, Margot E.T., Levy, Sonja, Verbeek, Wieke H.M., Eskens, Ferry A.L.M., van den Berg, José G., de Groot, Derk Jan A., van Leerdam, Monique E., and Tesselaar, Margot E.T.

Abstract

Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) are an aggressive subgroup of neuroendocrine neoplasms (NEN). Advanced EP-NEC is generally treated with platinum-based cytotoxic regimens, but progressive disease occurs rapidly, resulting in a poor prognosis. Genetic alterations in the mammalian target for rapamycin (mTOR) pathway have been identified in NEN, providing a rationale for treatment with the mTOR-inhibitor everolimus. Methods: A prospective phase 2 single-arm study included patients with advanced EP-NEC from three Dutch NEN expertise centres between March 2016 and January 2020. Treatment consisted of cisplatin 75 mg/m2 every 3 weeks in combination with daily everolimus 7.5 mg for a maximum of six cycles, followed by maintenance everolimus until disease progression. Primary endpoint was disease control rate (DCR), defined as the sum of overall response rate (ORR) plus the rate of stable disease according to RECIST 1.1, assessed at 9-week intervals. Toxicity was evaluated according to CTCAE version 5.0. Results: Thirty-nine patients, with a median age of 64 years (range: 28–74), of whom 20 (51%) were male, were enrolled. DCR was 82.1% (95% confidence interval (CI): 66.4–92.4), with an ORR of 58.9% (CI: 42.1–74.4). Median duration of response was 6.4 (CI: 5.8–7.0) months and median progression-free survival was 6.0 (CI: 4.3–7.8) months. Three patients (8%) had durable responses lasting > 12 months. Median overall survival was 8.7 (CI: 7.8–9.6) months. Most common grade 3/4 toxicities were haematological (36%) and renal (21%). Conclusion: Everolimus in combination with cisplatin is an effective first-line treatment option for advanced EP-NEC, especially in highly selected patients. Trial registration: Clinicaltrials.gov, NCT02695459, https://clinicaltrials.gov/ct2/show/NCT02695459.

Published
2022

8. Postoperative radiotherapy in stage I-III Merkel cell carcinoma

Author

Levy, Sonja, Blankenstein, Stephanie A, Grünhagen, Dirk Jan, Jalving, Mathilde, Hamming-Vrieze, Olga, Been, Lukas B, Tans, Lisa, van Akkooi, Alexander C J, Tesselaar, Margot E T, Levy, Sonja, Blankenstein, Stephanie A, Grünhagen, Dirk Jan, Jalving, Mathilde, Hamming-Vrieze, Olga, Been, Lukas B, Tans, Lisa, van Akkooi, Alexander C J, and Tesselaar, Margot E T

Abstract

BACKGROUND: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands.METHODS: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related death, cox regression was performed for overall mortality. Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication.RESULTS: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and reduced overall mortality, but not with MCC-related mortality. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p = 0.012) and PORT (SDH 0.45, p = 0.044) were associated with recurrence, and ≥ 4 positive lymph nodes (SDH 3.24, p = 0.024) were associated with MCC-related mortality.CONCLUSIONS: PORT was associated with less recurrences and reduced overall mortality in patients with stage I-III MCC, but not with MCC-related mortality. Trends in overall survival benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account.

Published
2022

9. ASO Visual Abstract: Primary Tumour Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumours (NET)-A Comparison of Upfront Surgical Resection versus a Watch-and-Wait Strategy in Two Specialist NET Centres

Author

MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, Tesselaar, Margot E T, MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, and Tesselaar, Margot E T

Published
2022

10. Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers

Author

MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, Tesselaar, Margot E T, MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, and Tesselaar, Margot E T

Published
2022

11. Four decades of experience with carcinoid heart disease: An analysis of 84 patients

Author

MS Endocriene Oncologie, CTC, Circulatory Health, Cancer, Levy, Sonja, Korse, Catherina E, de Groot, Andre C A, Meijer, Ronald C A, Tesselaar, Margot E T, Valk, Gerlof D, MS Endocriene Oncologie, CTC, Circulatory Health, Cancer, Levy, Sonja, Korse, Catherina E, de Groot, Andre C A, Meijer, Ronald C A, Tesselaar, Margot E T, and Valk, Gerlof D

Published
2022

12. Elevated Serotonin and NT-proBNP Levels Predict and Detect Carcinoid Heart Disease in a Large Validation Study

Author

Experimentele Afd. Cardiologie 2, Team Medisch, Circulatory Health, Onderzoek Cardiovasculair Reg. Med., Regenerative Medicine and Stem Cells, MS Endocriene Oncologie, Cancer, Levy, Sonja, Kilgallen, Aoife B, Korse, Catharina M, Oerlemans, Marish I F J, Sluijter, Joost P G, van Laake, Linda W, Valk, Gerlof D, Tesselaar, Margot E T, Experimentele Afd. Cardiologie 2, Team Medisch, Circulatory Health, Onderzoek Cardiovasculair Reg. Med., Regenerative Medicine and Stem Cells, MS Endocriene Oncologie, Cancer, Levy, Sonja, Kilgallen, Aoife B, Korse, Catharina M, Oerlemans, Marish I F J, Sluijter, Joost P G, van Laake, Linda W, Valk, Gerlof D, and Tesselaar, Margot E T

Published
2022

15. Well-Differentiated Bronchopulmonary Neuroendocrine Tumors: More Than One Entity

Author

van den Broek, Medard F.M., primary, Levy, Sonja, additional, Buikhuisen, Wieneke A., additional, Dijke, Kim, additional, Hartemink, Koen J., additional, van Leeuwaarde, Rachel S., additional, Vriens, Menno R., additional, Tesselaar, Margot E.T., additional, Valk, Gerlof D., additional, de Herder, Wouter, additional, Dekkers, Olaf, additional, van de Ven, Annenienke, additional, Havekes, Bas, additional, Drent, Madeleine, additional, Bisschop, Peter, additional, Zandee, Wouter, additional, and Valk, Gerlof, additional

Published
2021
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16. Driver mutations occur frequently in metastases of well-differentiated small intestine neuroendocrine tumours

Author

Team 2 Hemat, MS Endocriene Oncologie, Externen Med. Onco, Cancer, Samsom, Kris G., Levy, Sonja, van Veenendaal, Linde M., Roepman, Paul, Kodach, Liudmila L., Steeghs, Neeltje, Valk, Gerlof D., Wouter Dercksen, M., Kuhlmann, Koert F.D., Verbeek, Wieke H.M., Meijer, Gerrit A., Tesselaar, Margot E.T., van den Berg, José G., Team 2 Hemat, MS Endocriene Oncologie, Externen Med. Onco, Cancer, Samsom, Kris G., Levy, Sonja, van Veenendaal, Linde M., Roepman, Paul, Kodach, Liudmila L., Steeghs, Neeltje, Valk, Gerlof D., Wouter Dercksen, M., Kuhlmann, Koert F.D., Verbeek, Wieke H.M., Meijer, Gerrit A., Tesselaar, Margot E.T., and van den Berg, José G.

Published
2021

18. Survival in Patients with Neuroendocrine Tumours of the Small Intestine: Nomogram Validation and Predictors of Survival

Author

Levy, Sonja, primary, van Veenendaal, Linde M., additional, Korse, Catharina M., additional, Breekveldt, Emilie C.H., additional, Verbeek, Wieke H.M., additional, Vriens, Menno R., additional, Kuhlmann, Koert F.D., additional, van den Berg, José G., additional, Valk, Gerlof D., additional, and Tesselaar, Margot E.T., additional

Published
2020
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19. Avelumab for advanced Merkel cell carcinoma in the Netherlands:a real-world cohort

Author

Levy, Sonja, Aarts, Maureen J B, Eskens, Ferry A L M, Keymeulen, Kristien B M I, Been, Lukas B, Grünhagen, Dirk, van Akkooi, Alexander, Jalving, Mathilde, Tesselaar, Margot E T, Levy, Sonja, Aarts, Maureen J B, Eskens, Ferry A L M, Keymeulen, Kristien B M I, Been, Lukas B, Grünhagen, Dirk, van Akkooi, Alexander, Jalving, Mathilde, and Tesselaar, Margot E T

Abstract

BACKGROUND: Merkel cell carcinoma (MCC) is associated with high recurrence rates and poor survival when metastatic disease is present. The immune checkpoint inhibitor avelumab has shown high response rates (RRs) and durable responses in patients with advanced MCC (aMCC) in clinical trials. To date, only results from clinical trials, patients treated in an expanded access program and very small numbers of patients have been reported. In this study, detailed real-world efficacy and toxicity data of avelumab in patients with aMCC are reported.METHODS: Patients with aMCC treated in four dedicated referral centers in the Netherlands were analyzed from February 2017 until December 2019. Patients were included if they had received at least one administration of avelumab, regardless of previous lines of therapy. Patient data were collected retrospectively from patient records. Primary endpoints were response rate (RR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.RESULTS: Fifty-four patients received avelumab. Eight (15%) patients had locally advanced disease (laMCC). In 40 (74%) patients, avelumab was first-line treatment, these included all patients with laMCC. The median follow-up was 8.9 (range 0.5-35.9) months. RR was 57% (n=31) with 24% (n=13) of patients achieving a complete response. The median DOR was 8.4 (range 1.3-22.1) months and 23 (43%) patients had an ongoing response at the end of the study. The median PFS was 8.6 (95% CI 1.6-15.5) months, and the median OS was 25.8 (95% CI 9.1-42.4) months. Six (11%) patients experienced grade 3 toxicity. No grade 4-5 toxicity was seen.CONCLUSIONS: In this real-world cohort, clinical efficacy and toxicity outcomes in clinical practice were in line with results from clinical trials and showed relatively high RRs and durable responses in patients with aMCC.

Published
2020

20. Survival in patients with neuroendocrine tumours of the small intestine: Nomogram validation and predictors of survival

Author

MS Endocriene Oncologie, Heelkunde Opleiding, MS CGO, Cancer, Levy, Sonja, van Veenendaal, Linde M., Korse, Catharina M., Breekveldt, Emilie C.H., Verbeek, Wieke H.M., Vriens, Menno R., Kuhlmann, Koert F.D., van den Berg, José G., Valk, Gerlof D., Tesselaar, Margot E.T., MS Endocriene Oncologie, Heelkunde Opleiding, MS CGO, Cancer, Levy, Sonja, van Veenendaal, Linde M., Korse, Catharina M., Breekveldt, Emilie C.H., Verbeek, Wieke H.M., Vriens, Menno R., Kuhlmann, Koert F.D., van den Berg, José G., Valk, Gerlof D., and Tesselaar, Margot E.T.

Published
2020

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