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151. Feasibility of whole‐genome sequencing‐based tumor diagnostics in routine pathology practice

Author

Samsom, Kris G, primary, Schipper, Luuk J, additional, Roepman, Paul, additional, Bosch, Linda JW, additional, Lalezari, Ferry, additional, Klompenhouwer, Elisabeth G, additional, de Langen, Adrianus J, additional, Buffart, Tineke E, additional, Riethorst, Immy, additional, Schoenmaker, Lieke, additional, Schout, Daoin, additional, van der Noort, Vincent, additional, van den Berg, Jose G, additional, de Bruijn, Ewart, additional, van der Hoeven, Jacobus JM, additional, van Snellenberg, Hans, additional, van der Kolk, Lizet E, additional, Cuppen, Edwin, additional, Voest, Emile E, additional, Meijer, Gerrit A, additional, and Monkhorst, Kim, additional

Published
2022
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153. Neoadjuvant atezolizumab plus docetaxel/oxaliplatin/capecitabine in non-metastatic gastric and gastroesophageal junction adenocarcinoma: The PANDA trial.

Author

Verschoor, Yara L., primary, Kodach, Liudmila, additional, van den Berg, José, additional, van Sandick, Johanna W., additional, van Dieren, Jolanda, additional, Balduzzi, Sara, additional, Grootscholten, Cecile, additional, Veenhof, Xander, additional, Hartemink, Koen, additional, Vollebergh, Marieke A., additional, Owers, E.C., additional, Bartels-Rutten, Annemarieke, additional, den Hartog, Peggy, additional, van Leerdam, Monique E, additional, Schumacher, Ton, additional, Voest, Emile E., additional, Haanen, John B. A. G., additional, and Chalabi, Myriam, additional

Published
2022
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154. Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: Final clinical analysis of the NICHE study.

Author

Verschoor, Yara L., primary, van den Berg, José, additional, Beets, Geerard, additional, Sikorska, Karolina, additional, Aalbers, Arend, additional, van Lent, Anja, additional, Grootscholten, Cecile, additional, Huibregtse, Inge, additional, Marsman, Hendrik, additional, Oosterling, Steven, additional, van de Belt, Marieke, additional, Kok, Marleen, additional, Schumacher, Ton, additional, van Leerdam, Monique E, additional, Haanen, John B. A. G., additional, Voest, Emile E., additional, and Chalabi, Myriam, additional

Published
2022
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158. A Comparison of Post-marketing Measures Imposed by Regulatory Agencies to Confirm the Tissue-Agnostic Approach

Author

Mulder, Jorn, van Stuijvenberg, Odile C., van Hennik, Paula B., Voest, Emile E., Pasmooij, Anna M.G., Stoyanova-Beninska, Violeta, de Boer, Anthonius, Mulder, Jorn, van Stuijvenberg, Odile C., van Hennik, Paula B., Voest, Emile E., Pasmooij, Anna M.G., Stoyanova-Beninska, Violeta, and de Boer, Anthonius

Abstract

There are currently four anti-cancer medicinal products approved for a tissue-agnostic indication. This is an indication based on a common biological characteristic rather than the tissue of origin. To date, the regulatory experience with tissue-agnostic approvals is limited. Therefore, we compared decision-making aspects of the first tissue-agnostic approvals between the Food and Drug Administration (FDA), European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (PMDA). Post-marketing measures (PMMs) related to the tissue-agnostic indication were of specific interest. The main data source was the publicly available review documents. The following data were collected: submission date, approval date, clinical trials and datasets, and PMMs. At the time of data collection, the FDA and PMDA approved pembrolizumab, larotrectinib, and entrectinib for a tissue-agnostic indication, while the EMA approved larotrectinib and entrectinib for a tissue-agnostic indication. There were differences in analysis sets (integrated vs. non-integrated), submission dates and requests for data updates between agencies. All agencies had outstanding issues that needed to be addressed in the post-market setting. For pembrolizumab, larotrectinib and entrectinib, the number of imposed PMMs varied between one and eight, with the FDA requesting the most PMMs compared to the other two agencies. All agencies requested at least one PMM per approval to address the remaining uncertainties related to the tissue-agnostic indication. The FDA and EMA requested data from ongoing and proposed trials, while the PMDA requested data from use-result surveys. Confirmation of benefit in the post-marketing setting is an important aspect of tissue-agnostic approvals, regardless of agency. Nonetheless, each approach to confirm benefit has its inherent limitations. Post-marketing data will be essential for the regulatory and clinical decisions-making of medicinal products with a tissue-agnosti

Published
2022

159. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, Peeper, Daniel S., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, and Peeper, Daniel S.

Published
2022

160. Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Author

Hoes, Louisa R., van Berge Henegouwen, Jade M., van der Wijngaart, Hanneke, Zeverijn, Laurien J., van der Velden, Daphne L., van de Haar, Joris, Roepman, Paul, de Leng, Wendy J., Jansen, Anne M.L., van Werkhoven, Erik, van der Noort, Vincent, Huitema, Alwin D.R., Gort, Eelke H., de Groot, Jan Willem B., Kerver, Emile D., de Groot, Derk Jan, Erdkamp, Frans, Beerepoot, Laurens V., Hendriks, Mathijs P., Smit, Egbert F., van der Graaf, Winette T.A., van Herpen, Carla M.L., Labots, Mariette, Hoeben, Ann, Morreau, Hans, Lolkema, Martijn P., Cuppen, Edwin, Gelderblom, Hans, Verheul, Henk M.W., Voest, Emile E., Hoes, Louisa R., van Berge Henegouwen, Jade M., van der Wijngaart, Hanneke, Zeverijn, Laurien J., van der Velden, Daphne L., van de Haar, Joris, Roepman, Paul, de Leng, Wendy J., Jansen, Anne M.L., van Werkhoven, Erik, van der Noort, Vincent, Huitema, Alwin D.R., Gort, Eelke H., de Groot, Jan Willem B., Kerver, Emile D., de Groot, Derk Jan, Erdkamp, Frans, Beerepoot, Laurens V., Hendriks, Mathijs P., Smit, Egbert F., van der Graaf, Winette T.A., van Herpen, Carla M.L., Labots, Mariette, Hoeben, Ann, Morreau, Hans, Lolkema, Martijn P., Cuppen, Edwin, Gelderblom, Hans, Verheul, Henk M.W., and Voest, Emile E.

Abstract

Purpose: 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.

Published
2022

161. Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Author

Kester, Lennart, Seinstra, Danielle, van Rossum, Annelot G J, Vennin, Claire, Hoogstraat, Marlous, van der Velden, Daphne, Opdam, Mark, van Werkhoven, Erik, Hahn, Kerstin, Nederlof, Iris, Lips, Ester H, Mandjes, Ingrid A M, van Leeuwen-Stok, A Elise, Canisius, Sander, van Tinteren, Harm, Imholz, Alex L T, Portielje, Johanneke E A, Bos, Monique E M M, Bakker, Sandra D, Rutgers, Emiel J, Horlings, Hugo M, Wesseling, Jelle, Voest, Emile E, Wessels, Lodewyk F A, Kok, Marleen, Oosterkamp, Hendrika M, van Oudenaarden, Alexander, Linn, Sabine C, van Rheenen, Jacco, Kester, Lennart, Seinstra, Danielle, van Rossum, Annelot G J, Vennin, Claire, Hoogstraat, Marlous, van der Velden, Daphne, Opdam, Mark, van Werkhoven, Erik, Hahn, Kerstin, Nederlof, Iris, Lips, Ester H, Mandjes, Ingrid A M, van Leeuwen-Stok, A Elise, Canisius, Sander, van Tinteren, Harm, Imholz, Alex L T, Portielje, Johanneke E A, Bos, Monique E M M, Bakker, Sandra D, Rutgers, Emiel J, Horlings, Hugo M, Wesseling, Jelle, Voest, Emile E, Wessels, Lodewyk F A, Kok, Marleen, Oosterkamp, Hendrika M, van Oudenaarden, Alexander, Linn, Sabine C, and van Rheenen, Jacco

Abstract

PURPOSE: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.EXPERIMENTAL DESIGN: Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available.RESULTS: This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types.CONCLUSIONS: From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.

Published
2022

162. Harmonising patient-access programmes: the Dutch DRUG Access Protocol platform

Author

Palliatieve Zorg, Externen Med. Onco, Zeverijn, Laurien J., van Waalwijk van Doorn-Khosrovani, Sahar Barjesteh, van Roy, Anke A.M.G.Pisters, Timmers, Lonneke, Ly Tran, T. H., de Boer, Jolanda E., de Wit, Gijsbrecht F., Geurts, Birgit S., Gelderblom, Hans, Verheul, Henk M.W., Blijlevens, Nicole, Wymenga, A. N.Machteld, Eskens, Ferry A.L.M., Smit, Egbert F., Bloemendal, Haiko J., Voest, Emile E., Palliatieve Zorg, Externen Med. Onco, Zeverijn, Laurien J., van Waalwijk van Doorn-Khosrovani, Sahar Barjesteh, van Roy, Anke A.M.G.Pisters, Timmers, Lonneke, Ly Tran, T. H., de Boer, Jolanda E., de Wit, Gijsbrecht F., Geurts, Birgit S., Gelderblom, Hans, Verheul, Henk M.W., Blijlevens, Nicole, Wymenga, A. N.Machteld, Eskens, Ferry A.L.M., Smit, Egbert F., Bloemendal, Haiko J., and Voest, Emile E.

Published
2022

164. Can Drug Repurposing Accelerate Precision Oncology?

Author

Externen Med. Onco, Cancer, Schipper, Luuk J., Zeverijn, Laurien J., Garnett, Mathew J., Voest, Emile E., Externen Med. Onco, Cancer, Schipper, Luuk J., Zeverijn, Laurien J., Garnett, Mathew J., and Voest, Emile E.

Published
2022

165. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Externen Med. Onco, Cancer, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, Peeper, Daniel S., Externen Med. Onco, Cancer, Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, and Peeper, Daniel S.

Published
2022

166. Delivering precision oncology to patients with cancer

Author

Externen Med. Onco, Cancer, Mateo, Joaquin, Steuten, Lotte, Aftimos, Philippe, André, Fabrice, Davies, Mark, Garralda, Elena, Geissler, Jan, Husereau, Don, Martinez-Lopez, Iciar, Normanno, Nicola, Reis-Filho, Jorge S., Stefani, Stephen, Thomas, David M., Westphalen, C. Benedikt, Voest, Emile, Externen Med. Onco, Cancer, Mateo, Joaquin, Steuten, Lotte, Aftimos, Philippe, André, Fabrice, Davies, Mark, Garralda, Elena, Geissler, Jan, Husereau, Don, Martinez-Lopez, Iciar, Normanno, Nicola, Reis-Filho, Jorge S., Stefani, Stephen, Thomas, David M., Westphalen, C. Benedikt, and Voest, Emile

Published
2022

168. Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

Author

Externen Med. Onco, Schipper, Luuk J., Monkhorst, Kim, Samsom, Kris G., Bosch, Linda J.W., Snaebjornsson, Petur, Boven, Hester van, Roepman, Paul, van der Kolk, Lizet E., van Houdt, Winan J., van der Graaf, Winette T.A., Meijer, Gerrit A., Voest, Emile E., Externen Med. Onco, Schipper, Luuk J., Monkhorst, Kim, Samsom, Kris G., Bosch, Linda J.W., Snaebjornsson, Petur, Boven, Hester van, Roepman, Paul, van der Kolk, Lizet E., van Houdt, Winan J., van der Graaf, Winette T.A., Meijer, Gerrit A., and Voest, Emile E.

Published
2022

169. Feasibility of whole-genome sequencing-based tumor diagnostics in routine pathology practice

Author

CMM Groep Cuppen, Externen Med. Onco, Cancer, Pathologie Groep Van Diest, Samsom, Kris G, Schipper, Luuk J, Roepman, Paul, Bosch, Linda Jw, Lalezari, Ferry, Klompenhouwer, Elisabeth G, de Langen, Adrianus J, Buffart, Tineke E, Riethorst, Immy, Schoenmaker, Lieke, Schout, Daoin, van der Noort, Vincent, van den Berg, Jose G, de Bruijn, Ewart, van der Hoeven, Jacobus Jm, van Snellenberg, Hans, van der Kolk, Lizet E, Cuppen, Edwin, Voest, Emile E, Meijer, Gerrit A, Monkhorst, Kim, CMM Groep Cuppen, Externen Med. Onco, Cancer, Pathologie Groep Van Diest, Samsom, Kris G, Schipper, Luuk J, Roepman, Paul, Bosch, Linda Jw, Lalezari, Ferry, Klompenhouwer, Elisabeth G, de Langen, Adrianus J, Buffart, Tineke E, Riethorst, Immy, Schoenmaker, Lieke, Schout, Daoin, van der Noort, Vincent, van den Berg, Jose G, de Bruijn, Ewart, van der Hoeven, Jacobus Jm, van Snellenberg, Hans, van der Kolk, Lizet E, Cuppen, Edwin, Voest, Emile E, Meijer, Gerrit A, and Monkhorst, Kim

Published
2022

170. Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Author

Pathologie Moleculair, Cancer, Externen Med. Onco, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Medisch Oncologische Disciplines, Pathologie, Kester, Lennart, Seinstra, Danielle, van Rossum, Annelot G.J., Vennin, Claire, Hoogstraat, Marlous, van der Velden, Daphne, Opdam, Mark, van Werkhoven, Erik, Hahn, Kerstin, Nederlof, Iris, Lips, Ester H., Mandjes, Ingrid A.M., van Leeuwen-Stok, A. Elise, Canisius, Sander, van Tinteren, Harm, Imholz, Alex L.T., Portielje, Johanneke E.A., Bos, Monique E.M.M., Bakker, Sandra D., Rutgers, Emiel J., Horlings, Hugo M., Wesseling, Jelle, Voest, Emile E., Wessels, Lodewyk F.A., Kok, Marleen, Oosterkamp, Hendrika M., van Oudenaarden, Alexander, Linn, Sabine C., van Rheenen, Jacco, Pathologie Moleculair, Cancer, Externen Med. Onco, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Medisch Oncologische Disciplines, Pathologie, Kester, Lennart, Seinstra, Danielle, van Rossum, Annelot G.J., Vennin, Claire, Hoogstraat, Marlous, van der Velden, Daphne, Opdam, Mark, van Werkhoven, Erik, Hahn, Kerstin, Nederlof, Iris, Lips, Ester H., Mandjes, Ingrid A.M., van Leeuwen-Stok, A. Elise, Canisius, Sander, van Tinteren, Harm, Imholz, Alex L.T., Portielje, Johanneke E.A., Bos, Monique E.M.M., Bakker, Sandra D., Rutgers, Emiel J., Horlings, Hugo M., Wesseling, Jelle, Voest, Emile E., Wessels, Lodewyk F.A., Kok, Marleen, Oosterkamp, Hendrika M., van Oudenaarden, Alexander, Linn, Sabine C., and van Rheenen, Jacco

Published
2022

171. Patients With Rare Cancers in the Drug Rediscovery Protocol (DRUP) benefit from Genomics - Guided Treatment

Author

Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Apotheek O&O&O, MS Medische Oncologie, Externen Med. Onco, CMM, CMM Groep Cuppen, Hoes, Louisa R, van Berge Henegouwen, Jade M, van der Wijngaart, Hanneke, Zeverijn, Laurien J, van der Velden, Daphne L, van de Haar, Joris, Roepman, Paul, de Leng, Wendy J, Jansen, Anne M L, van Werkhoven, Erik, van der Noort, Vincent, Huitema, Alwin D R, Gort, Eelke H, de Groot, Jan Willem B, Kerver, Emile D, de Groot, Derk Jan, Erdkamp, Frans, Beerepoot, Laurens V, Hendriks, Mathijs P, Smit, Egbert F, van der Graaf, Winette T A, van Herpen, Carla M L, Labots, Mariette, Hoeben, Ann, Morreau, Hans, Lolkema, Martijn P, Cuppen, Edwin, Gelderblom, Hans J, Verheul, Henk M W, Voest, Emile E, Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Apotheek O&O&O, MS Medische Oncologie, Externen Med. Onco, CMM, CMM Groep Cuppen, Hoes, Louisa R, van Berge Henegouwen, Jade M, van der Wijngaart, Hanneke, Zeverijn, Laurien J, van der Velden, Daphne L, van de Haar, Joris, Roepman, Paul, de Leng, Wendy J, Jansen, Anne M L, van Werkhoven, Erik, van der Noort, Vincent, Huitema, Alwin D R, Gort, Eelke H, de Groot, Jan Willem B, Kerver, Emile D, de Groot, Derk Jan, Erdkamp, Frans, Beerepoot, Laurens V, Hendriks, Mathijs P, Smit, Egbert F, van der Graaf, Winette T A, van Herpen, Carla M L, Labots, Mariette, Hoeben, Ann, Morreau, Hans, Lolkema, Martijn P, Cuppen, Edwin, Gelderblom, Hans J, Verheul, Henk M W, and Voest, Emile E

Published
2022

175. Delivering precision oncology to patients with cancer

Author

Mateo, Joaquin, primary, Steuten, Lotte, additional, Aftimos, Philippe, additional, André, Fabrice, additional, Davies, Mark, additional, Garralda, Elena, additional, Geissler, Jan, additional, Husereau, Don, additional, Martinez-Lopez, Iciar, additional, Normanno, Nicola, additional, Reis-Filho, Jorge S., additional, Stefani, Stephen, additional, Thomas, David M., additional, Westphalen, C. Benedikt, additional, and Voest, Emile, additional

Published
2022
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176. Base editing screens map mutations affecting IFNγ signalling in cancer

Author

Coelho, Matthew A., primary, Karakoc, Emre, additional, Bhosle, Shriram, additional, Gonçalves, Emanuel, additional, Burgold, Thomas, additional, Cooper, Sarah, additional, Cattaneo, Chiara M., additional, Veninga, Vivien, additional, Consonni, Sarah, additional, Dinçer, Cansu, additional, Vieira, Sara F., additional, Gibson, Freddy, additional, Barthorpe, Syd, additional, Hardy, Claire, additional, Rein, Joel, additional, Thomas, Mark, additional, Voest, Emile, additional, Bassett, Andrew, additional, and Garnett, Mathew J., additional

Published
2022
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177. The Molecular Tumor Board Portal supports clinical decisions and automated reporting for precision oncology

Author

Tamborero, David, Dienstmann, Rodrigo, Rachid, Maan Haj, Boekel, Jorrit, Lopez-Fernandez, Adria, Jonsson, Markus, Razzak, Ali, Braña, Irene, De Petris, Luigi, Yachnin, Jeffrey, Baird, Richard D., Loriot, Yohann, Massard, Christophe, Martin-Romano, Patricia, Opdam, Frans, Schlenk, Richard F., Vernieri, Claudio, Masucci, Michele, Villalobos, Xenia, Chavarria, Elena, Anand, Shubha, Baars, Danny, Bajalica-Lagercrantz, Svetlana, Baird, Richard, Bierkens, Mariska, Blomqvist, Lennart, Bono, Costanza, Doherty, Gary J., Forest, Arnauld, Fornerone, Valentina, Gabaldi, Paola, Haglund, Felix, Hartman, Johan, Horak, Peter, Jutzi, Tanja, Kasanicki, Mary, Kreutzfeldt, Simon, Le Cornet, Lucian, Lewensohn, Rolf, Lindberg, Johan, Lopez, Carlos, Lundqvist, Andreas, Martin, Jose-Ezequiel, Meijer, Gerrit, Muñoz, Susana, Camus, Maud Ngo, Nicotra, Claudio, Nuciforo, Paolo, Oberrauch, Petra, Östling, Päivi, Pelz, Laura, Piris-Gimenez, Alejandro, Provenzano, Elena, Rouleau, Etienne, Rowell, John, Saavedra, Omar, Scoazec, Giovanni, Seamon, Kenneth, Tischkowitz, Marc, van der Kolk, Lizet, van der Noll, Ruud, Vieito, Maria, Vis, Daniel, Vivancos, Ana, von Gertten, Christina, Wennborg, Anders, Wessels, Lodewyk, Wirta, Valtteri, Balmaña, Judith, Apolone, Giovanni, Caldas, Carlos, Bergh, Jonas, Ernberg, Ingemar, Fröhling, Stefan, Garralda, Elena, Karlsson, Claes, Tabernero, Josep, Voest, Emile, Rodon, Jordi, Lehtiö, Janne, Institut Català de la Salut, [Tamborero D, Rachid MH, Boekel J, Jonsson M] Department of Oncology and Pathology, Karolinska Institutet, Science for Life Laboratory, Stockholm, Sweden. [Dienstmann R] Medical Oncology, Oncology Data Science, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Lopez-Fernandez A, Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Braña I, Garralda E, Tabernero J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Villalobos X, Chavarria E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Rodon J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, USA, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Cancer Research, profesiones sanitarias::medicina::medicina interna::oncología médica [DISCIPLINAS Y OCUPACIONES], Oncology, Medicina personalitzada, Medicina clínica - Presa de decisions, Càncer - Diagnòstic, Health Occupations::Medicine::Internal Medicine::Medical Oncology [DISCIPLINES AND OCCUPATIONS]
Abstract

Cancer; Cancer genetics Cáncer; Genética del cáncer Càncer; Genètica del càncer There is a growing need for systems that efficiently support the work of medical teams at the precision-oncology point of care. Here, we present the implementation of the Molecular Tumor Board Portal (MTBP), an academic clinical decision support system developed under the umbrella of Cancer Core Europe that creates a unified legal, scientific and technological platform to share and harness next-generation sequencing data. Automating the interpretation and reporting of sequencing results decrease the need for time-consuming manual procedures that are prone to errors. The adoption of an expert-agreed process to systematically link tumor molecular profiles with clinical actions promotes consistent decision-making and structured data capture across the connected centers. The use of information-rich patient reports with interactive content facilitates collaborative discussion of complex cases during virtual molecular tumor board meetings. Overall, streamlined digital systems like the MTBP are crucial to better address the challenges brought by precision oncology and accelerate the use of emerging biomarkers. Open access funding provided by Karolinska Institute

Published
2022

178. Harmonising patient-access programmes: the Dutch DRUG Access Protocol platform

Author

Zeverijn, Laurien J, van Waalwijk van Doorn-Khosrovani, Sahar Barjesteh, van Roy, Anke A M G Pisters, Timmers, Lonneke, Ly Tran, T H, de Boer, Jolanda E, de Wit, Gijsbrecht F, Geurts, Birgit S, Gelderblom, Hans, Verheul, Henk M W, Blijlevens, Nicole, Wymenga, A N Machteld, Eskens, Ferry A L M, Smit, Egbert F, Bloemendal, Haiko J, and Voest, Emile E

Published
2022
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181. Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

Author

Roodhart, Jeanine M.L., Daenen, Laura G.M., Stigter, Edwin C.A., Prins, Henk-Jan, Gerrits, Johan, Houthuijzen, Julia M., Gerritsen, Marije G., Schipper, Henk S., Backer, Marieke J.G., van Amersfoort, Miranda, Vermaat, Joost S.P., Moerer, Petra, Ishihara, Kenji, Kalkhoven, Eric, Beijnen, Jos H., Derksen, Patrick W.B., Medema, Rene H., Martens, Anton C., Brenkman, Arjan B., and Voest, Emile E.

Published
2011
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182. Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Author

Hoes, Louisa R., primary, van Berge Henegouwen, Jade M., additional, van der Wijngaart, Hanneke, additional, Zeverijn, Laurien J., additional, van der Velden, Daphne L., additional, van de Haar, Joris, additional, Roepman, Paul, additional, de Leng, Wendy J., additional, Jansen, Anne M.L., additional, van Werkhoven, Erik, additional, van der Noort, Vincent, additional, Huitema, Alwin D.R., additional, Gort, Eelke H., additional, de Groot, Jan Willem B., additional, Kerver, Emile D., additional, de Groot, Derk Jan, additional, Erdkamp, Frans, additional, Beerepoot, Laurens V., additional, Hendriks, Mathijs P., additional, Smit, Egbert F., additional, van der Graaf, Winette T.A., additional, van Herpen, Carla M.L., additional, Labots, Mariette, additional, Hoeben, Ann, additional, Morreau, Hans, additional, Lolkema, Martijn P., additional, Cuppen, Edwin, additional, Gelderblom, Hans, additional, Verheul, Henk M.W., additional, and Voest, Emile E., additional

Published
2022
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183. Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

Author

Schipper, Luuk J., primary, Monkhorst, Kim, additional, Samsom, Kris G., additional, Bosch, Linda J.W., additional, Snaebjornsson, Petur, additional, van Boven, Hester, additional, Roepman, Paul, additional, van der Kolk, Lizet E., additional, van Houdt, Winan J., additional, van der Graaf, Winette T.A., additional, Meijer, Gerrit A., additional, and Voest, Emile E., additional

Published
2022
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184. Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Author

Kester, Lennart, primary, Seinstra, Danielle, additional, van Rossum, Annelot G.J., additional, Vennin, Claire, additional, Hoogstraat, Marlous, additional, van der Velden, Daphne, additional, Opdam, Mark, additional, van Werkhoven, Erik, additional, Hahn, Kerstin, additional, Nederlof, Iris, additional, Lips, Ester H., additional, Mandjes, Ingrid A.M., additional, van Leeuwen-Stok, A. Elise, additional, Canisius, Sander, additional, van Tinteren, Harm, additional, Imholz, Alex L.T., additional, Portielje, Johanneke E.A., additional, Bos, Monique E.M.M., additional, Bakker, Sandra D., additional, Rutgers, Emiel J., additional, Horlings, Hugo M., additional, Wesseling, Jelle, additional, Voest, Emile E., additional, Wessels, Lodewyk F.A., additional, Kok, Marleen, additional, Oosterkamp, Hendrika M., additional, van Oudenaarden, Alexander, additional, Linn, Sabine C., additional, and van Rheenen, Jacco, additional

Published
2021
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185. Extension of Indication for Authorised Oncology Products in the European Union: A Joint Effort of Multiple Stakeholders

Author

Mulder, Jorn, primary, Verjans, Robin, additional, Verbaanderd, Ciska, additional, Pean, Elias, additional, Weemers, Just, additional, Leufkens, Hubert G. M., additional, Pignatti, Francesco, additional, de Boer, Anthonius, additional, Voest, Emile E., additional, Stoyanova-Beninska, Violeta V., additional, and Pasmooij, Anna M. G., additional

Published
2021
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186. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Author

Zhang, Zhengkui, Kong, Xiangjun, Ligtenberg, Maarten A., van Hal-van Veen, Susan E., Visser, Nils L., de Bruijn, Beaunelle, Stecker, Kelly, van der Helm, Pim W., Kuilman, Thomas, Hoefsmit, Esmée P., Vredevoogd, David W., Apriamashvili, Georgi, Baars, Beau, Voest, Emile E., Klarenbeek, Sjoerd, Altelaar, Maarten, Peeper, Daniel S., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
function-based genome-wide screens, Ubiquitin-Protein Ligases, NF-KAPPA-B, T cells, NK cells, Research & Experimental Medicine, ESCAPE, Biochemistry, immunotherapy resistance, General Biochemistry, Genetics and Molecular Biology, ACTIVATION, NATURAL-KILLER-CELLS, INFLAMMATION, CLASS-I, SUPPRESSES, Science & Technology, COMPLEX, Biochemistry, Genetics and Molecular Biology(all), Tumor Necrosis Factor-alpha, Ubiquitination, bystander killing, Cell Biology, CANCER, Killer Cells, Natural, Medicine, Research & Experimental, Tumor Escape, Life Sciences & Biomedicine, Genetics and Molecular Biology(all), ACQUIRED-RESISTANCE
Abstract

Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK and CD8+ T cell pressure. We identify all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitizes cancer cells to NK and CD8+ T cell killing. This occurs in a tumor necrosis factor (TNF)-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and greatly enhances bystander killing of MHC antigen-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers. ispartof: CELL REPORTS MEDICINE vol:3 issue:6 ispartof: location:United States status: published

Published
2021

188. Support systems to guide clinical decision-making in precision oncology: The Cancer Core Europe Molecular Tumor Board Portal

Author

Tamborero, David, Dienstmann, Rodrigo, Rachid, Maan Haj, Boekel, Jorrit, Baird, Richard, Braña, Irene, De Petris, Luigi, Yachnin, Jeffrey, Massard, Christophe, Opdam, Frans L, Schlenk, Richard, Vernieri, Claudio, Garralda, Elena, Masucci, Michele, Villalobos, Xenia, Chavarria, Elena, Cancer Core Europe Consortium, Calvo, Fabien, Fröhling, Stefan, Eggermont, Alexander, Apolone, Giovanni, Voest, Emile E, Caldas, Carlos, Tabernero, Josep, Ernberg, Ingemar, Rodon, Jordi, Lehtiö, Janne, Rachid, Maan Haj [0000-0002-6380-209X], Baird, Richard [0000-0001-7071-6483], Fröhling, Stefan [0000-0001-7907-4595], Voest, Emile E [0000-0001-8249-9586], Caldas, Carlos [0000-0003-3547-1489], Tabernero, Josep [0000-0002-2495-8139], Lehtiö, Janne [0000-0002-8100-9562], and Apollo - University of Cambridge Repository

Subjects
Europe, Neoplasms, Clinical Decision-Making, Humans, Molecular Targeted Therapy, Precision Medicine, Medical Oncology
Abstract

To the editor: the optimal management of cancer patients is increasingly dependent on individualized treatments guided by tumor sequencing data. As comprehensive genomic tests become routine in many disease settings and academic centers promote omics-guided clinical trial recruitment, accurate and scalable data interpretation represents a major challenge. The meticulous task of matching tumor alterations with approved or experimental therapies relies heavily on the expertise of each center.

Published
2020
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189. γδ T cells are effectors of immune checkpoint blockade in mismatch repair-deficient colon cancers with antigen presentation defects

Author

de Vries, Natasja L., primary, van de Haar, Joris, additional, Veninga, Vivien, additional, Chalabi, Myriam, additional, Ijsselsteijn, Marieke E., additional, van der Ploeg, Manon, additional, van den Bulk, Jitske, additional, Ruano, Dina, additional, Haanen, John B., additional, Schumacher, Ton N., additional, Wessels, Lodewyk F.A., additional, Koning, Frits, additional, de Miranda, Noel F.C.C., additional, and Voest, Emile E., additional

Published
2021
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190. The Porto European Cancer Research Summit 2021

Author

Ringborg, Ulrik, primary, Berns, Anton, additional, Celis, Julio E., additional, Heitor, Manuel, additional, Tabernero, Josep, additional, Schüz, Joachim, additional, Baumann, Michael, additional, Henrique, Rui, additional, Aapro, Matti, additional, Basu, Partha, additional, Beets‐Tan, Regina, additional, Besse, Benjamin, additional, Cardoso, Fátima, additional, Carneiro, Fátima, additional, van den Eede, Guy, additional, Eggermont, Alexander, additional, Fröhling, Stefan, additional, Galbraith, Susan, additional, Garralda, Elena, additional, Hanahan, Douglas, additional, Hofmarcher, Thomas, additional, Jönsson, Bengt, additional, Kallioniemi, Olli, additional, Kásler, Miklós, additional, Kondorosi, Eva, additional, Korbel, Jan, additional, Lacombe, Denis, additional, Carlos Machado, José, additional, Martin‐Moreno, José M., additional, Meunier, Francoise, additional, Nagy, Péter, additional, Nuciforo, Paolo, additional, Oberst, Simon, additional, Oliveiera, Júlio, additional, Papatriantafyllou, Maria, additional, Ricciardi, Walter, additional, Roediger, Alexander, additional, Ryll, Bettina, additional, Schilsky, Richard, additional, Scocca, Grazia, additional, Seruca, Raquel, additional, Soares, Marta, additional, Steindorf, Karen, additional, Valentini, Vincenzo, additional, Voest, Emile, additional, Weiderpass, Elisabete, additional, Wilking, Nils, additional, Wren, Amanda, additional, and Zitvogel, Laurence, additional

Published
2021
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191. Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Author

van der Wijngaart, Hanneke, primary, Hoes, Louisa R., additional, van Berge Henegouwen, J. Maxime, additional, van der Velden, Daphne L., additional, Zeverijn, Laurien J., additional, Roepman, Paul, additional, van Werkhoven, Erik, additional, de Leng, Wendy W.J., additional, Jansen, Anne M.L., additional, Mehra, Niven, additional, Robbrecht, Debbie G.J., additional, Labots, Mariette, additional, de Groot, Derk Jan A., additional, Hoeben, Ann, additional, Hamberg, Paul, additional, Gelderblom, Hans, additional, Voest, Emile E., additional, and Verheul, Henk M.W., additional

Published
2021
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193. Functional precision oncology using patient-derived assays: bridging genotype and phenotype

Author

van Renterghem, Allard W. J., van de Haar, Joris, and Voest, Emile E.

Abstract

Genomics-based precision medicine has revolutionized oncology but also has inherent limitations. Functional precision oncology is emerging as a complementary approach that aims to bridge the gap between genotype and phenotype by modelling individual tumours in vitro. These patient-derived ex vivo models largely preserve several tumour characteristics that are not captured by genomics approaches and enable the functional dissection of tumour vulnerabilities in a personalized manner. In this Review, we discuss several examples of personalized functional assays involving tumour organoids, spheroids and explants and their potential to predict treatment responses and drug-induced toxicities in individual patients. These developments have opened exciting new avenues for precision oncology, with the potential for successful clinical applications in contexts in which genomic data alone are not informative. To implement these assays into clinical practice, we outline four key barriers that need to be overcome: assay success rates, turnaround times, the need for standardized conditions and the definition of in vitro responders. Furthermore, we discuss novel technological advances such as microfluidics that might reduce sample requirements, assay times and labour intensity and thereby enable functional precision oncology to be implemented in routine clinical practice.

Published
2023
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194. Codon-specific KRASmutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer

Author

van de Haar, Joris, Ma, Xuhui, Ooft, Salo N., van der Helm, Pim W., Hoes, Louisa R., Mainardi, Sara, Pinato, David J., Sun, Kristi, Salvatore, Lisa, Tortora, Giampaolo, Zurlo, Ina Valeria, Leo, Silvana, Giampieri, Riccardo, Berardi, Rossana, Gelsomino, Fabio, Merz, Valeria, Mazzuca, Federica, Antonuzzo, Lorenzo, Rosati, Gerardo, Stavraka, Chara, Ross, Paul, Rodriquenz, Maria Grazia, Pavarana, Michele, Messina, Carlo, Iveson, Timothy, Zoratto, Federica, Thomas, Anne, Fenocchio, Elisabetta, Ratti, Margherita, Depetris, Ilaria, Cergnul, Massimiliano, Morelli, Cristina, Libertini, Michela, Parisi, Alessandro, De Tursi, Michele, Zanaletti, Nicoletta, Garrone, Ornella, Graham, Janet, Longarini, Raffaella, Gobba, Stefania Maria, Petrillo, Angelica, Tamburini, Emiliano, La Verde, Nicla, Petrelli, Fausto, Ricci, Vincenzo, Wessels, Lodewyk F. A., Ghidini, Michele, Cortellini, Alessio, Voest, Emile E., and Valeri, Nicola

Abstract

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAScodon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAFmutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n= 800 patients) and found that KRASG12mutations (n= 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P= 0.0031, adjusted interaction P= 0.015). For patients with KRASG12mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n= 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P= 0.85). In contrast, patients with KRASG13mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n= 60; HR = 0.29; 95% CI = 0.15–0.55; P< 0.001). In isogenic cell lines and patient-derived organoids, KRASG12mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

Published
2023
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198. Detailed imaging and genetic analysis reveal a secondary BRAFL505H resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib

Author

Hoogstraat, Marlous, Gadellaa-van Hooijdonk, Christa G., Ubink, Inge, Besselink, Nicolle J. M., Pieterse, Mark, Veldhuis, Wouter, van Stralen, Marijn, Meijer, Eelco F. J., Willems, Stefan M., Hadders, Michael A., Kuilman, Thomas, Krijgsman, Oscar, Peeper, Daniel S., Koudijs, Marco J., Cuppen, Edwin, Voest, Emile E., and Lolkema, Martijn P.

Published
2015
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