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1. A new method to quantify the effect of co-medication on the efficacy of abiraterone in metastatic castration-resistant prostate cancer patients

Author

Bertalan Fekete, Lili Bársony, Krisztina Biró, Fruzsina Gyergyay, Lajos Géczi, Attila Patócs, and Barna Budai

Subjects
abiraterone acetate, co-medication, drug-drug interactions, metastatic castration-resistant prostate cancer, overall survival, treatment duration, Therapeutics. Pharmacology, RM1-950
Abstract

Background and Objective: Patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) have co-morbidities treated with different drugs. The aim was to quantify the potential effect of co-medications on AA treatment duration (TD) and overall survival (OS).Methods: A new parameter, called “individual drug score” (IDS) was calculated by summing the “drug score”-s (DS) of all co-medications for each patient. The DS was determined by quantifying the effect of a given co-drug on enzymes involved in steroidogenesis and metabolism of AA. The correlation between log (IDS) and TD was tested by non-linear curve fit. Kaplan-Meier method and multivariate Cox regression was used for analysis of TD and OS.Results: The IDS and TD of AA+prednisolone showed a dose-response correlation (n = 166). Patients with high IDS had significantly longer TD and OS (p

Published
2023
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2. Atezolizumab for the treatment of advanced recurrent basal cell carcinoma and urothelial carcinoma of bladder: a case report

Author

Zsófia Küronya, Tímea Danyi, Tímea Balatoni, Gabriella Liszkay, Erika Tóth, Krisztina Biró, and Lajos Géczi

Subjects
Advanced basal cell carcinoma, Metastatic muscle-invasive bladder cancer, PD-L1 inhibitor, Checkpoint inhibitor, Atezolizumab, Medicine
Abstract

Abstract Background The use of checkpoint inhibitors has become increasingly important in the treatment of different cancers, including advanced muscle-invasive urothelial cancer and even in basal cell carcinoma. We present the case of a patient with advanced basal cell carcinoma and metastatic muscle-invasive urothelial cancer, who was treated with the programmed death-ligand 1 inhibitor, atezolizumab for both cancers. Case presentation A 72-year-old Caucasian female patient, with a history of smoking without any comorbidities developed periocular basal cell carcinoma, which was surgically removed but relapsed 4 years later. Surgical excision was carried out twice, but with positive margins, therefore definitive radiotherapy was given. Subsequently, the patient developed non-muscle-invasive papillary urothelial carcinoma, which was removed by transurethral resection. Follow-up was irregular owing to the patient’s inadequate compliance, and within 2 years, the patient’s cancer relapsed and histology confirmed muscle-invasive urothelial carcinoma. Definitive radiochemotherapy was not accepted by the patient. Meanwhile, the patient’s basal cell carcinoma had also progressed, despite receiving vismodegib therapy. Therefore, the patient was administered epirubicin-cisplatin. Having reached the maximum cumulative dose of epirubicin, treatment with this chemotherapeutic agent could not be continued. The patient developed bladder cancer metastasis in her left suprainguinal lymph nodes. Owing to the presence of both types of tumors, programmed death-ligand 1 inhibitor atezolizumab treatment was chosen. In just over 1 year, the patient received 17 cycles of atezolizumab altogether, which was tolerated well without any adverse or side effects. Follow-up imaging scans indicated complete remission of the metastatic bladder cancer and stable disease of the basal cell carcinoma. The patient subsequently passed away in hospital due to a complication of COVID-19 infection. Conclusions Our patient attained stable disease in advanced basal cell carcinoma and complete remission in metastatic muscle-invasive urothelial cancer after receiving programmed death-ligand 1 inhibitor, atezolizumab, therapy. To our knowledge, this is the first paper to report the use of programmed death-ligand 1 inhibitor, atezolizumab, as treatment for advanced basal cell carcinoma. This case may also be of interest for clinicians when treating patients with two synchronous cancers.

Published
2022
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3. Low socioeconomic position is a risk factor for delay to treatment and mortality of testicular cancer patients in Hungary, a prospective study

Author

Zsófia Küronya, Georgina Fröhlich, Andrea Ladányi, Tamás Martin, Lajos Géczi, Fruzsina Gyergyai, Orsolya Horváth, Gergő Kiszner, Ágnes Kovács, Tamás Dienes, Enikő Lénárt, Krisztián Nagyiványi, Tibor Szarvas, Mihály Szőnyi, Attila Tóth, and Krisztina Biró

Subjects
Testicular cancer, Socioeconomic position, Patient delay, Public aspects of medicine, RA1-1270
Abstract

Abstract Background In Hungary, the mortality rate for testicular germ cell cancer (TGCC) is 0,9/100000 which is significantly higher than the EU average. We prospectively evaluated the effect of socioeconomic position on patient delay and therapy outcomes. Methods Questionnaires on subjective social status (MacArthur Subjective Status Scale), objective socioeconomic position (wealth, education, and housing data), and on patient’s delay were completed by newly diagnosed TGCC patients. Results Patients belonged to a relatively high socioeconomic class, a university degree was double the Hungarian average, Cancer-specific mortality in the highest social quartile was 1.56% while in the lowest social quartile 13.09% (p = 0.02). In terms of patient delay, 57.2% of deceased patients waited more than a year before seeking help, while this number for the surviving patients was 8.0% (p = 0.0000). Longer patient delay was associated with a more advanced stage in non-seminoma but not in seminoma, the correlation coefficient for non-seminoma was 0.321 (p

Published
2021
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4. Discrimination of Deletion and Duplication Subtypes of the Deleted in Azoospermia Gene Family in the Context of Frequent Interloci Gene Conversion.

Author

Tibor Vaszkó, János Papp, Csilla Krausz, Elena Casamonti, Lajos Géczi, and Edith Olah

Subjects
Medicine, Science
Abstract

Due to its palindromic setup, AZFc (Azoospermia Factor c) region of chromosome Y is one of the most unstable regions of the human genome. It contains eight gene families expressed mainly in the testes. Several types of rearrangement resulting in changes in the cumulative copy number of the gene families were reported to be associated with diseases such as male infertility and testicular germ cell tumors. The best studied AZFc rearrangement is gr/gr deletion. Its carriers show widespread phenotypic variation from azoospermia to normospermia. This phenomenon was initially attributed to different gr/gr subtypes that would eliminate distinct members of the affected gene families. However, studies conducted to confirm this hypothesis have brought controversial results, perhaps, in part, due to the shortcomings of the utilized subtyping methodology. This proof-of-concept paper is meant to introduce here a novel method aimed at subtyping AZFc rearrangements. It is able to differentiate the partial deletion and partial duplication subtypes of the Deleted in Azoospermia (DAZ) gene family. The keystone of the method is the determination of the copy number of the gene family member-specific variant(s) in a series of sequence family variant (SFV) positions. Most importantly, we present a novel approach for the correct interpretation of the variant copy number data to determine the copy number of the individual DAZ family members in the context of frequent interloci gene conversion.Besides DAZ1/DAZ2 and DAZ3/DAZ4 deletions, not yet described rearrangements such as DAZ2/DAZ4 deletion and three duplication subtypes were also found by the utilization of the novel approach. A striking feature is the extremely high concordance among the individual data pointing to a certain type of rearrangement. In addition to being able to identify DAZ deletion subtypes more reliably than the methods used previously, this approach is the first that can discriminate DAZ duplication subtypes as well.

Published
2016
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5. Docetaxel with or without Ramucirumab after Platinum-Based Chemotherapy and Checkpoint Inhibitors in Advanced Urothelial Carcinoma: A Pre-Specified Subgroup Analysis from the Phase 3 RANGE Trial

Author

Alexandra Drakaki, Simon Chowdhury, Chia-Chi Lin, Daniel Keizman, Michiel S. van der Heijden, Daniel P. Petrylak, Jae-Lyun Lee, Kim N. Chi, Sergio Bracarda, Daniel Castellano, Georgios Gakis, Andrea Necchi, Lajos Géczi, Ulka N. Vaishampayan, Annamaria Zimmermann, Thomas Powles, Conor J. Kirby, Katherine M Bell-McGuinn, Aude Flechon, Drakaki, A., Kirby, C. J., Van Der Heijden, M. S., Petrylak, D. P., Powles, T., Chi, K. N., Flechon, A., Necchi, A., Geczi, L., Lee, J. -L., Gakis, G., Bracarda, S., Chowdhury, S., Lin, C. -C., Keizman, D., Vaishampayan, U. N., Zimmermann, A. H., Bell-Mcguinn, K., Castellano, D., and Graduate School

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, ramucirumab, Urology, medicine.medical_treatment, Population, Subgroup analysis, Immune checkpoint inhibitor, Placebo, Ramucirumab, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, education, urothelial carcinoma, education.field_of_study, Chemotherapy, VEGFR inhibitor, Proportional hazards model, business.industry, Hazard ratio, platinum-refractory, 030104 developmental biology, Docetaxel, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

BACKGROUND: The phase 3 RANGE trial found ramucirumab/docetaxel improved progression-free survival (PFS) versus placebo/docetaxel (median 4.1 vs 2.8 months; hazard ratio [HR] = 0.757, p = 0.0118) for treatment of platinum-refractory metastatic urothelial carcinoma (UC). Some patients received an immune checkpoint inhibitor (ICI) prior to RANGE. In other studies, unselected patients with platinum-refractory UC exhibited an overall response rate (ORR) of 15–31% to ICIs. OBJECTIVE: Efficacy and safety data from the subgroup of patients treated with prior ICI were examined using prespecified analyses to compare outcomes between RANGE treatment arms. METHODS: Randomized, double-blind RANGE study (n = 530) took place July 2015-April 2017 in 23 countries. Forty-five patients (8.5%) received prior ICI. PFS was evaluated using the Kaplan-Meier method and unstratified Cox proportional hazards model. RESULTS: 17 ramucirumab/docetaxel arm, 28 placebo/docetaxel arm patients were treated with an ICI. The prior-ICI ramucirumab subgroup had worse Bellmunt scores at baseline versus placebo (score of 2-3 : 70.6% vs 25%, respectively). Most patients (84.4%) received the ICI immediately following platinum and immediately prior to RANGE. ORR to prior ICI was 6.7% Responses were achieved by 5/17 (29.4%) on ramucirumab/docetaxel, compared to 2/28 (7.1%) on placebo/docetaxel. Median PFS was 3.15 months on ramucirumab/docetaxel versus 2.73 months on placebo/docetaxel (HR = 0.786, 95% CI = 0.404–1.528, p = 0.4877). The frequency of grade≥3 adverse events was similar between arms. Limitations include sample size and treatment setting of the analyzed population. CONCLUSIONS: Ramucirumab/docetaxel may provide a clinical benefit with acceptable safety in the third-line setting for metastatic UC patients whose disease has progressed on both prior platinum chemotherapy and ICI therapy.

Published
2020

6. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants:Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Author

Christi J. van Asperen, Leigha Senter, Javier Benitez, Kenneth Offit, Marco Montagna, Irene L. Andrulis, Phuong L. Mai, Yen Y. Tan, Lidia Moserle, Sara Torres-Esquius, Trinidad Caldés, Orland Diez, Daniel R. Barnes, Åke Borg, Daniel Barrowdale, Joanne Ngeow, Siranoush Manoukian, Soo Hwang Teo, Maria A. Caligo, Inge Søkilde Pedersen, Jennifer T. Loud, Marta Santamariña, Amanda E. Toland, Anna Marie Mulligan, Irene Konstantopoulou, Antonis C. Antoniou, Paul A. James, Eitan Friedman, Barbara Wappenschmidt, Marc Tischkowitz, Laura Papi, Ana Osorio, Georgia Chenevix-Trench, Eva Machackova, Pedro Pinto, Keivan Majidzadeh-A, Bernardo Bonanni, Kristiina Aittomäki, Berardino Porfirio, Johanna Rantala, Valentina Silvestri, Bent Ejlertsen, Melissa C. Southey, Ramunas Janavicius, Elisabetta Landucci, Liene Nikitina-Zake, Lajos Géczi, Saundra S. Buys, Angela R. Solano, Sarah Colonna, Ana Vega, Fabienne Lesueur, Frans B. L. Hogervorst, Goska Leslie, David E. Goldgar, Peter J. Hulick, Rosa B. Barkardottir, Kristin K. Zorn, Elisa Alducci, Miguel de la Hoya, Fergus J. Couch, Laura Ottini, Anne-Marie Gerdes, Uffe Birk Jensen, Ute Hamann, Christoph Engel, Allison W. Kurian, Douglas F. Easton, Annabeth Høgh Petersen, Alessandra Viel, Linda Steele, Zoe Steinsnyder, Ava Kwong, Alicia Barroso, Eric Hahnen, Mads Thomassen, Maria Rossing, Rita K. Schmutzler, Wendy K. Chung, Angel Izquierdo, Barak Rosenzweig, Jeroen Vierstraete, Mark H. Greene, Lenka Foretova, Jeffrey N. Weitzel, Paolo Radice, Muhammad Usman Rashid, Katherine L. Nathanson, Lesley McGuffog, Ian G. Campbell, John L. Hopper, Laura Cortesi, Christian F. Singer, Sook-Yee Yoon, Lídia Feliubadaló, Bjarni A. Agnarsson, Susan M. Domchek, Vijai Joseph, Manuel R. Teixeira, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Jacques Simard, Yuan Chun Ding, Carlo Capalbo, Florentia Fostira, Greet Wieme, Mary Beth Terry, Kathleen Claes, Olufunmilayo I. Olopade, Pedro Pérez-Segura, Heli Nevanlinna, D. Gareth Evans, Edith Olah, Michael T. Parsons, Claudine Isaacs, Miquel Angel Pujana, Timothy R. Rebbeck, Gord Glendon, Susan L. Neuhausen, Judy Kirk, Sue K. Park, Esther M. John, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, University of Helsinki, HUS Gynecology and Obstetrics, Biosciences, and Department of Obstetrics and Gynecology

Subjects
Male, Cancer Research, endocrine system diseases, GUIDELINES, 0302 clinical medicine, Neoplasms, Medicine, 030212 general & internal medicine, Prospective cohort study, skin and connective tissue diseases, GENE-ENVIRONMENT INTERACTION, Original Investigation, RISK, Aged, 80 and over, education.field_of_study, BRCA1 Protein, Middle Aged, BRCA2 Protein/genetics, 3. Good health, PROSTATE-CANCER, Phenotype, Oncology, 030220 oncology & carcinogenesis, Male breast cancer, Cohort study, Adult, medicine.medical_specialty, Adolescent, Population, 3122 Cancers, MUTATION CARRIERS, 03 medical and health sciences, Young Adult, Breast cancer, Internal medicine, BREAST-CANCER, Humans, education, Germ-Line Mutation, Aged, Retrospective Studies, BRCA2 Protein, business.industry, Cancer, Correction, Retrospective cohort study, Odds ratio, medicine.disease, BRCA1 Protein/genetics, business, Neoplasms/diagnosis
Abstract

Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P

Published
2020

7. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Author

Henriette Roed Nielsen, Judith Balmaña, Anne-Marie Gerdes, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Douglas F. Easton, Linda Steele, Ava Kwong, Sung Won Kim, Bjarni A. Agnarsson, Piera Rizzolo, Angela R. Solano, Mads Thomassen, Johannes Lemke, Grazia Artioli, Heli Nevanlinna, Johanna I. Kiiski, Frans B. L. Hogervorst, Jong Won Lee, Diana Eccles, Mark H. Greene, Marc Tischkowitz, David E. Goldgar, Angela R. Bradbury, Javier Benitez, Marie Navratilova, Dominique Stoppa-Lyonnet, Arjen R. Mensenkamp, Alfons Meindl, Zisun Kim, Nadine Tung, Agnes Jager, Matthew L. Freedman, Ana Osorio, Norbert Arnold, Doris Steinemann, Inge Søkilde Pedersen, Patricia Llovet, Rob B. van der Luijt, Vivek L Patel, Munaza Ahmed, Lidia Moserle, Irene Konstantopoulou, Jackie Cook, Jacques Simard, Joan Brunet, Johanna Rantala, Kai-ren Ong, Carole Brewer, Joe Dennis, Sook-Yee Yoon, Hanne Meijers-Heijboer, Roberta Villa, Katie Snape, Louise Izatt, Ana Peixoto, Susan M. Domchek, Nina Ditsch, D. Gareth Evans, Tara M. Friebel, Sue K. Park, Katherine L. Nathanson, Lenka Foretova, Miguel Angel Pujana, Edith Olah, Hélène Schuster, Raymonda Varon-Mateeva, Silvia Tognazzo, Payal D. Shah, Oskar T. Johannsson, Hans Ehrencrona, Paul Gesta, Ian G. Campbell, Drakoulis Yannoukakos, Mirjam Larsen, Anthony V. D'Amico, Liene Nikitina-Zake, Davide Bondavalli, Valérie Bonadona, Paul A. James, Alan Donaldson, Antonis C. Antoniou, Bernd Auber, Andrew K. Godwin, Denise Molina Gomes, Jihyoun Lee, Laurence Faivre, Almuth Caliebe, Pilar Garre, Siddhartha Yadav, Julika Borde, Pedro Pérez-Segura, Birgitte Bertelsen, Paolo Peterlongo, Michael T. Parsons, John L. Hopper, Bruno Buecher, Goska Leslie, Shan Wang-Gohrke, Amanda B. Spurdle, T.M. Mooij, Juliane Ramser, kConFab Investigators, Lídia Feliubadaló, Susanne E. Boonen, Bernard Peissel, Anna von Wachenfeldt, Timothy R. Rebbeck, Christi J. van Asperen, Víctor Lorca, Estela Carrasco, Elisa Alducci, Ulrike Faust, Karin Kast, Gord Glendon, Saundra S. Buys, Fergus J. Couch, Mariarosaria Calvello, Istvan Bodrogi, Kathryn J. Ruddy, Philipp Wagner, Fabienne Lesueur, Evan L. Busch, Hebon Investigators, Laura Cortesi, Christian F. Singer, Ute Hamann, Giuseppe Damante, Stefania Tommasi, Esther M. John, Jacopo Azzollini, Cristina Zanzottera, Angelica M. Gutierrez-Barrera, Emmanuelle Mouret-Fourme, Claire Saule, Rosa B. Barkardottir, Kristin K. Zorn, Kerstin Rhiem, Uffe Birk Jensen, Mark Pomerantz, Yuan Chun Ding, Alison H. Trainer, Marco Montagna, Vijai Joseph, Domenico Palli, Kwang-Pil Ko, Angel M. Cronin, Susan L. Neuhausen, Dieter Niederacher, Laura Ottini, Angela Toss, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Caroline M. Seynaeve, Ileana Carnevali, Adalgeir Arason, Rosalind A. Eeles, Annie T W Chu, Florentia Fostira, Greet Wieme, Brita Arver, Charlotte Kvist Lautrup, Christoph Engel, Marion Gauthier-Villars, Daniel Barrowdale, Caroline Maria Rossing, Kenneth Offit, Kathleen Claes, Olufunmilayo I. Olopade, Penny Soucy, Alicia Barroso, Manuel R. Teixeira, Wendy K. Chung, Gero Kramer, Tsun Leung Chan, Agostina Stradella, Debra Frost, Noura Mebirouk, Liselotte P. van Hest, Esther Darder, Valentina Silvestri, Annabeth Høgh Petersen, Lesley McGuffog, Andrea Gehrig, Mary Porteous, Matti A. Rookus, Lizet E. van der Kolk, Siranoush Manoukian, Lone Sunde, Conxi Lázaro, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Claus-Eric Ott, Christian Sutter, Paolo Radice, Veronica Medici, Georgia Chenevix-Trench, Vanesa García-Barberán, Kristiina Aittomäki, Amanda E. Toland, Anna Marie Mulligan, Véronique Mari, Bernd Dworniczak, Lynn Martin, Lara Della Puppa, Phuong L. Mai, George Fountzilas, Yen Y. Tan, Simona Agata, Torben A Kruse, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Thomas Dyrso Jensen, Åke Borg, Mark E. Robson, Jennifer T. Loud, Vivian Y. Shin, Irene López-Perolio, Leigha Senter, Irene L. Andrulis, Rosa Scarpitta, Angela F. Brady, Annika Lindblom, Diana Torres, Lotte Nylandsted Krogh, Barbara Wappenschmidt, Muhammad Rashid, Jeroen Vierstraete, Mary B. Daly, Annelie Liljegren, Frederieke H. van der Baan, Eunyoung Kang, Alessandra Viel, Santiago Cabezas-Camarero, Eric Hahnen, Laura Matricardi, Marinus J. Blok, Edmond S. K. Ma, Maria Grazia Tibiletti, Catarina Santos, Julian Adlard, Soo Hwang Teo, Giuseppe Giannini, Jan Hauke, Peter J. Hulick, Miguel de la Hoya, Clare Miller, Bernardo Bonanni, Bent Ejlertsen, Lajos Géczi, Liliana Varesco, Orland Diez, N Herold, Christine Lasset, Adrià López-Fernández, Min Hyuk Lee, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Medical Oncology, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Leslie, Goska [0000-0001-5756-6222], Adlard, Julian [0000-0002-1693-0435], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barnes, Daniel R [0000-0002-3781-7570], Brunet, Joan [0000-0003-1945-3512], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian G [0000-0002-7773-4155], Claes, Kathleen BM [0000-0003-0841-7372], Darder, Esther [0000-0002-7764-1397], Dennis, Joe [0000-0003-4591-1214], Dworniczak, Bernd [0000-0003-4981-7903], Eeles, Rosalind A [0000-0002-3698-6241], Ehrencrona, Hans [0000-0002-5589-3622], Ejlertsen, Bent [0000-0001-8761-714X], Evans, D Gareth [0000-0002-8482-5784], Garre, Pilar [0000-0001-8285-4138], Greene, Mark H [0000-0003-1852-9239], Hulick, Peter J [0000-0001-8397-4078], Jager, Agnes [0000-0002-7713-1450], James, Paul [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Joseph, Vijai [0000-0002-7933-151X], Kim, Sung-Won [0000-0002-1413-2800], Kim, Zisun [0000-0002-1413-2800], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Matricardi, Laura [0000-0002-0241-1810], Gomes, Denise Molina [0000-0002-2836-9008], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Palli, Domenico [0000-0002-5558-2437], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Peterlongo, Paolo [0000-0001-6951-6855], Petersen, Annabeth Høgh [0000-0002-4503-6942], Pujana, Miguel Angel [0000-0003-3222-4044], Ruddy, Kathryn J [0000-0001-6298-332X], Scarpitta, Rosa [0000-0001-7590-3827], Shah, Payal D [0000-0001-5874-3390], Silvestri, Valentina [0000-0003-0712-9379], Southey, Melissa C [0000-0002-6313-9005], Spurdle, Amanda B [0000-0003-1337-7897], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Sunde, Lone [0000-0002-8479-165X], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], van der Luijt, Rob B [0000-0002-0018-1089], Vierstraete, Jeroen [0000-0001-7909-6620], Wieme, Greet [0000-0003-2718-5300], Yadav, Siddhartha [0000-0003-4630-9903], Antoniou, Antonis C [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, and CCA - Cancer biology and immunology

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, PHENOTYPE, INCREASE, Prostate cancer, 0302 clinical medicine, Risk Factors, Young adult, skin and connective tissue diseases, Aged, 80 and over, Prostate cancer risk, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESSENGER-RNA DECAY, BRCA1 Protein, Genomics, GERMLINE MUTATIONS, Middle Aged, Prognosis, OVARIAN, CARRIERS, 3. Good health, 030220 oncology & carcinogenesis, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Tumor suppressor gene, Urology, Association (object-oriented programming), 3122 Cancers, MEDLINE, Article, Young Adult, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, BRCA1, BRCA2, Prostate Cancer, Pathogenic sequence variant location, Risk estimation, Journal Article, Genetic predisposition, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Risk factor, Genetic Association Studies, Aged, BRCA2 Protein, IDENTIFICATION, business.industry, Prostatic Neoplasms, medicine.disease, GENE, Confidence interval, APC, 030104 developmental biology, Mutation, 3111 Biomedicine, business
Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Published
2020

8. Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract

Author

Marija Gamulin, Simon Fear, Thomas Powles, Lajos Géczi, Cora N. Sternberg, Fernando Lopez-Rios, Yohann Loriot, Craig Gedye, Xavier Garcia del Muro, Giuseppe Luigi Banna, Ugo De Giorgi, Friedemann Zengerling, Ignacio Duran, Nicholas D. James, Aristotelis Bamias, Sabine de Ducla, Daniel Castellano, Cristina Masini, Axel S. Merseburger, and Ernest Choy

Subjects
Male, Autoimmune diseases, atezolizumab, autoimmune disease, central nervous system metastases, immunotherapy, nonurothelial carcinoma, PD-L1, real world, steroid, urothelial carcinoma, Nonurothelial carcinoma, 030232 urology & nephrology, Metastasis, 0302 clinical medicine, Antineoplastic Agents, Immunological, Autoimmune disease, Clinical endpoint, Atezolizumab, Fatigue, education.field_of_study, Malalties autoimmunitàries, Central nervous system metastases, Real world, Anemia, Middle Aged, Colitis, Progression-Free Survival, Anorexia, Survival Rate, Tolerability, 030220 oncology & carcinogenesis, Esteroides, Hypertension, Retreatment, Urinary Tract Infections, Disease Progression, Steroids, Urothelial carcinoma, Female, Immunotherapy, medicine.medical_specialty, Urologic Neoplasms, Metastatic Urothelial Carcinoma, Urology, Population, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Metàstasi, Internal medicine, medicine, Carcinoma, Humans, Adverse effect, education, Steroid, Aged, Carcinoma, Transitional Cell, business.industry, medicine.disease, Clinical trial, Asthenia, business
Abstract

Background Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab. Objective To determine the safety and efficacy of atezolizumab in an international real-world setting. Design, setting, and participants Between November 2016 and March 2018 (median follow-up 12.7mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406). Intervention Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity. Outcome measurements and statistical analysis The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Results and limitations The median treatment duration was 2.8mo (range 0–19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7mo (95% confidence interval [CI] 7.8–9.9). The 6-mo OS rate was 60% (95% CI 57–63%), median PFS was 2.2mo (95% CI 2.1–2.4), and the ORR was 13% (95% CI 11–16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0mo (95% CI 8.8–11.9) and 6-mo OS was 65% (95% CI 61–69%). Conclusions SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options. Patient summary In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients.

Published
2019

9. Serum levels of MicroRNA-371a-3p (M371 Test) as a new biomarker of testicular germ cell tumors: results of a prospective multicentric study

Author

Jennifer Kranz, Richard Cathomas, Christian D. Fankhauser, Wolfgang Loidl, Werner Wosniok, Emanuela Trenti, Klaus Eredics, Carsten Bokemeyer, Hermann Reichegger, Björn Haben, Stefan Zastrow, Gazanfer Belge, Sven Peine, Jörg Sommer, Julia Heinzelbecker, Alexander Winter, Jann Frederik Cremers, Silke Gillessen, Marius Bolten, Martin Pichler, Friedemann Zengerling, Arlo Radtke, Christoph Oing, Klaus-Peter Dieckmann, Thomas Hermanns, Marcus Hentrich, Hanjo Belz, Cord Matthies, Lajos Géczi, Christian Ruf, Ulrike Eckardt, Axel Heidenreich, Anja Lorch, Petra Anheuser, Renate Pichler, Sebastian Melchior, Johannes Hammel, Susanne Krege, and Christian Wülfing

Subjects
0301 basic medicine, Adult, Male, Cancer Research, Adolescent, Medizin, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Testicular Neoplasms, Predictive Value of Tests, microRNA, Biomarkers, Tumor, Medicine, Humans, Chorionic Gonadotropin, beta Subunit, Human, Circulating MicroRNA, Prospective Studies, Aged, L-Lactate Dehydrogenase, business.industry, ORIGINAL REPORTS, Middle Aged, Neoplasms, Germ Cell and Embryonal, Testicular germ cell, Seminoma, Europe, MicroRNAs, 030104 developmental biology, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer research, Biomarker (medicine), Urologic Oncology, alpha-Fetoproteins, business, Orchiectomy, Biomarkers
Abstract

PURPOSE Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT. PATIENTS AND METHODS In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase. RESULTS For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p. CONCLUSION The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.

Published
2019

10. Genome-wide linkage screen for testicular germ cell tumour susceptibility loci

Author

D. Timothy Bishop, Radka Lohynska, Robert Huddart, Douglas F. Easton, Ludmila Liubchenko, Katherine L. Nathanson, Michael R. Stratton, Barbara L. Weber, Kelly-Anne Phillips, Parry Guilford, Michael Friedlander, Hans Stoll, Stéphane Richard, Catherine Bonaïti-Pellié, T. Oliver, Wilma Ormiston, Katherine M. Tucker, Mark H. Greene, Joan Kramer, David Forman, Elizabeth A. Rapley, Lawrence H. Einhorn, Gedske Daugaard, Axel Heidenreich, Sergei Tjulandin, Walter P. Weber, Michael A.S. Jewett, David W. Hogg, Sophie D. Fosså, Peter Albers, Rachel Linger, Lajos Géczi, Lola Johnson, Darshna Dudakia, Mary L. McMaster, Ketil Heimdal, István Bodrogi, Victoria K. Cortessis, Edith Olah, Peter A. Daly, Gillian P. Crockford, Agnès Chompret, Sarah Hockley, Kaniewski, Nadine, Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Saint James's University Hospital, Section of Cancer Genetics, Institute of cancer research, Academic Radiotherapy Unit, Dept of Medical Oncology, Division of Medicine, University of New South Wales [Sydney] (UNSW)-Prince of Wales Hospital Randwick, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Princess Margaret Hospital, University of Toronto, Dept of Radiotherapy and Oncology, University hospital of Prague, Dept of Oncology, Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service d'urologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dept of Urological Oncology, Phillips university, Department of Urology, Klinikum Kassel GmbH, Department of Molecular Genetics and Department of Chemotherapy, National Institute of Oncology, Department of Medical Oncology, St James's hospital, Cancer Genetics Laboratory, University of Otago [Dunedin, Nouvelle-Zélande], Departments of Clinical Cancer Research and genetics, Rikshospitalet-Radiumhospitalet Trust, Laboratory of Clinical Genetics, Institute of Clinical Oncology, Medical Oncology, University Hospital Basel [Basel], Cancer Epidemiology, University of Leeds-Cookridge Hospital, Barts and The London Queen Mary's School of Medicine, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Department of Preventive Medicine, Keck School of Medicine [Los Angeles], University of Southern California (USC)-University of Southern California (USC), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), and University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]

Subjects
Male, Genetic Linkage, MESH: Pedigree, Locus (genetics), Pedigree chart, Biology, MESH: Chromosomes, Human, X, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Testicular Neoplasms, Gene mapping, Genetic linkage, Genetics, Genetic predisposition, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), MESH: Genome, Human, 030304 developmental biology, MESH: Testicular Neoplasms, Chromosomes, Human, X, 0303 health sciences, MESH: Humans, Genome, Human, Genetic heterogeneity, MESH: Genetic Heterogeneity, MESH: Genetic Predisposition to Disease, Chromosome Mapping, Family aggregation, General Medicine, Neoplasms, Germ Cell and Embryonal, Human genetics, MESH: Male, Pedigree, 3. Good health, MESH: Lod Score, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, MESH: Neoplasms, Germ Cell and Embryonal, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Lod Score, MESH: Chromosome Mapping, MESH: Female, MESH: Linkage (Genetics)
Abstract

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease.

Published
2017

11. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Author

Daniel P Petrylak, Ronald de Wit, Kim N Chi, Alexandra Drakaki, Cora N Sternberg, Hiroyuki Nishiyama, Daniel Castellano, Syed Hussain, Aude Fléchon, Aristotelis Bamias, Evan Y Yu, Michiel S van der Heijden, Nobuaki Matsubara, Boris Alekseev, Andrea Necchi, Lajos Géczi, Yen-Chuan Ou, Hasan Senol Coskun, Wen-Pin Su, Miriam Hegemann, Ivor J Percent, Jae-Lyun Lee, Marcello Tucci, Andrey Semenov, Fredrik Laestadius, Avivit Peer, Giampaolo Tortora, Sufia Safina, Xavier Garcia del Muro, Alejo Rodriguez-Vida, Irfan Cicin, Hakan Harputluoglu, Ryan C Widau, Astra M Liepa, Richard A Walgren, Oday Hamid, Annamaria H Zimmermann, Katherine M Bell-McGuinn, Thomas Powles, Suet-Lai Shirley Wong, Thean Hsiang Tan, Elizabeth Jane Hovey, Timothy Dudley Clay, Siobhan Su Wan Ng, Annemie Rutten, Jean-Pascal Machiels, Herlinde Dumez, Susanna Yee-Shan Cheng, Kim Nguyen Chi, Cristiano Ferrario, Lisa Sengeloev, Niels Viggo Jensen, Constance Thibault, Brigitte Laguerre, Florence Joly, Aude Flechon, Stéphane Culine, Catherine Becht, Günter Niegisch, Michael Stöckle, Marc-Oliver Grimm, Georgios Gakis, Wolfgang Schultze-Seemann, Haralambos Kalofonos, Dimitrios Mavroudis, Christos Papandreou, Vasilis Karavasilis, Janos Révész, Lajos Geczi, Eli Rosenbaum, Raya Leibowitz-Amit, Daniel Kejzman, David Sarid, Giorgio Vittorio Scagliotti, Sergio Bracarda, Francesco Massari, Takahiro Osawa, Naoto Miyajima, Nobuo Shinohara, Fumimasa Fukuta, Chikara Ohyama, Wataru Obara, Shinichi Yamashita, Yoshihiko Tomita, Koji Kawai, Satoshi Fukasawa, Masafumi Oyama, Junji Yonese, Masayoshi Nagata, Motohide Uemura, Kazuo Nishimura, Mutsushi Kawakita, Hiroyuki Tsunemori, Katsuyoshi Hashine, Junichi Inokuchi, Akira Yokomizo, Satoshi Nagamori, Hyo Jin Lee, Se Hoon Park, Sun Young Rha, Yu Jung Kim, Yun-Gyoo Lee, Leticia Vazquez Cortés, Claudia Lorena Urzua Flores, Reinoud J B Blaisse, Fransiscus L G Erdkamp, Maureen J B Aarts, Joanna Wojcik-Tomaszewska, Piotr Tomczak, Bozena Sikora-Kupis, Michael Schenker, Alina Amalia Herzal, Anghel Adrian Udrea, Petr Karlov, Sufia Z Safina, Roman Fomkin, Enrique Grande Pulido, F Xavier García Del Muro, Juan Ignacio Delgado Mignorance, Daniel Castellano Gauna, Alejo Rodríguez-Vida, Yu-Li Su, Chien-Liang Lin, Chia-Chi Lin, Su-Peng Yeh, Irfan Çiçin, Mustafa Erman, Yuksel Urun, Yurii Golovko, Igor Bondarenko, Ivan Sinielnikov, Simon Crabb, Isabel Syndikus, Robert Huddart, Santhanam Sundar, Simon Chowdhury, Naveed Sarwar, Thomas Flaig, Chong Xian Pan, Daniel Petrylak, James Schwarz, Ivor Percent, Jennifer Cultrera, John Hainsworth, Benjamin Herms, William Lawler, Thomas Lowe, Scott Tagawa, Jeanny Aragon-Ching, Ulka Vaishampayan, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Service d'oncologie médicale, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Medische Oncologie (9), Petrylak, Dp, de Wit, R, Chi, Kn, Drakaki, A, Sternberg, Cn, Nishiyama, H, Castellano, D, Hussain, S, Flechon, A, Bamias, A, Yu, Ey, van der Heijden, M, Matsubara, N, Alekseev, B, Necchi, A, Geczi, L, Ou, Yc, Coskun, H, Su, Wp, Hegemann, M, Percent, Ij, Lee, Jl, Tucci, M, Semenov, A, Laestadius, F, Peer, A, Tortora, G, Safina, S, del Muro, Xg, Rodriguez-Vida, A, Cicin, I, Harputluoglu, H, Widau, Rc, Liepa, Am, Walgren, Ra, Hamid, O, Zimmermann, Ah, Bell-McGuinn, Km, Powles, T, and Medical Oncology

Subjects
0301 basic medicine, Male, Internationality, medicine.medical_treatment, Phases of clinical research, Docetaxel, Kaplan-Meier Estimate, Gastroenterology, 2ND-LINE THERAPY, 0302 clinical medicine, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Medicine, ramucirab, Medicine (all), Antibodies, Monoclonal, General Medicine, Middle Aged, OPEN-LABEL, Prognosis, Neoadjuvant Therapy, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Taxoids, medicine.drug, Adult, medicine.medical_specialty, Metastatic Urothelial Carcinoma, Urology, Locally advanced, BLADDER-CANCER, Placebo, Antibodies, Monoclonal, Humanized, Risk Assessment, Ramucirumab, Antibodies, Disease-Free Survival, Double blind, II TRIAL, 03 medical and health sciences, LUNG-CANCER, Aged, Carcinoma, Transitional Cell, Double-Blind Method, Humans, Neoplasm Invasiveness, Neoplasm Staging, Proportional Hazards Models, Survival Analysis, Urinary Bladder Neoplasms, Internal medicine, BREAST-CANCER, In patient, Adverse effect, Platinum, Chemotherapy, FACTOR RECEPTOR-2, Settore MED/06 - ONCOLOGIA MEDICA, business.industry, Carcinoma, TRANSITIONAL-CELL-CARCINOMA, Surgery, Discontinuation, Regimen, Ramucirumab, docetaxel, 030104 developmental biology, ENDOTHELIAL GROWTH-FACTOR, Transitional Cell, business, FOLLOW-UP
Abstract

Summary Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company.

Published
2017

12. The International Testicular Cancer Linkage Consortium: A Clinicopathologic Descriptive Analysis of 461 Familial Malignant Testicular Germ Cell Tumor Kindred

Author

Ludmila Liubchenko, Michael R. Stratton, Katherine M. Tucker, Sergei Tjulandin, Robert Huddart, Gedske Daugaard, Hans Stoll, Catherine Bonaïti-Pellié, Kelly-Anne Phillips, Douglas F. Easton, Larissa A. Korde, Ketil Heimdal, Sophie D. Fosså, Radka Lohynska, Peter Albers, Peter A. Daly, E. Olah, István Bodrogi, Axel Heidenreich, David W. Hogg, Parry Guilford, Darshna Dudakia, Walter P. Weber, Michael Friedlander, Katherine L. Nathanson, Elizabeth A. Rapley, Mark H. Greene, Lawrence H. Einhorn, D. Timothy Bishop, Stéphane Richard, Michael A.S. Jewett, Phuong L. Mai, Lajos Géczi, and University of Groningen

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Testicular neoplasms, Epidemiology, Urology, Cousin, Population, Testicular Germ Cell Tumor, Hernia, Inguinal, Clinicopathologic characteristics, Article, Familial, Internal medicine, Cryptorchidism, medicine, Humans, ANTICIPATION, education, Testicular cancer, POPULATION, Gynecology, FATHER, education.field_of_study, business.industry, TESTIS, Family aggregation, Cancer, Seminoma, Neoplasms, Germ Cell and Embryonal, medicine.disease, SUSCEPTIBILITY GENES, Malignant Testicular Germ Cell Tumor, OF-THE-LITERATURE, RISK-FACTORS, EXPERIENCE, business
Abstract

Objectives: Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but it is unclear if familial TGCT represents a unique entity with distinct clinicopathologic characteristics. Here we describe a collection of familial TGCT cases from an international consortium, in an effort to elucidate any clinical characteristics that are specific to this population. Materials and methods: Families with >= 2 cases of TGCT enrolled at 18 of the sites participating in the International Testicular Cancer Linkage Consortium were included. We analyzed clinicopathologic characteristics of 985 cases from 461 families. Results: A majority (88.5%) of families had only 2 cases of TGCT. Men with seminoma (50% of cases) had an older mean age at diagnosis than nonseminoma cases (P = 0.001). Among individuals with a history of cryptorchidism. TGCT was more likely to occur in the ipsilateral testis (kappa = 0.65). Cousin pairs appeared to represent a unique group, with younger age at diagnosis and a higher prevalence of cryptorchidism than other families. Conclusions: Clinicopathologic characteristics in these familial TGCT cases were similar to those generally described for nonfamilial eases. However, we observed a unique presentation of familial TGCT among cousin pairs. Additional studies are needed to further explore this observation. Published by Elsevier Inc.

Published
2009

13. Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors

Author

Gedske Daugaard, Sophie D. Fosså, Sergei Tjulandin, Walter P. Weber, Douglas F. Easton, Rachel Linger, Dominique Stoppa-Lyonnet, Peter Albers, David W. Hogg, Parry Guilford, Robert Huddart, Michael Friedlander, Peter A. Daly, Ketil Heimdal, Michael A.S. Jewett, Darshna Dudakia, Michael R. Stratton, Katherine L. Nathanson, Hans Stoll, Lajos Géczi, Mary L. McMaster, Catherine Bonaïti-Pellié, Stéphane Richard, Elizabeth A. Rapley, Lawrence H. Einhorn, Mark H. Greene, Victoria K. Cortessis, Edith Olah, Agnès Chompret, Axel Heidenreich, Radka Lohynska, Katherine M. Tucker, Kelly-Anne Phillips, D. Timothy Bishop, Larissa A. Korde, Ludmila Liubchenko, István Bodrogi, Section of Cancer Genetics, Institute of cancer research, Academic Radiotherapy Unit, Dept of Medical Oncology, Division of Medicine, University of New South Wales [Sydney] (UNSW)-Prince of Wales Hospital Randwick, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Princess Margaret Hospital, University of Toronto, Dept of Radiotherapy and Oncology, University hospital of Prague, Dept of Oncology, Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service d'urologie, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Centre de Recherches Biologiques, CERB, Génomes et cancer (GC (FRE2939)), Département de Pédiatrie, Institut Gustave Roussy (IGR), Epidémiologie des cancers, Institut National de la Santé et de la Recherche Médicale (INSERM), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de Génétique Oncologique, Institut Curie [Paris], Département de génétique, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie génétique, Dept of Urological Oncology, Phillips university, Department of Urology, Klinikum Kassel GmbH, Department of Molecular Genetics and Department of Chemotherapy, National Institute of Oncology, Department of Medical Oncology, St James's hospital, Cancer Genetics Laboratory, University of Otago [Dunedin, Nouvelle-Zélande], Departments of Clinical Cancer Research and genetics, Rikshospitalet-Radiumhospitalet Trust, Laboratory of Clinical Genetics, Institute of Clinical Oncology, Medical Oncology, University Hospital Basel [Basel], Google Inc., Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Barts and The London Queen Mary's School of Medicine, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Department of Preventive Medicine, Keck School of Medicine [Los Angeles], University of Southern California (USC)-University of Southern California (USC), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Saint James's University Hospital, University of New South Wales [Sydney] ( UNSW ) -Prince of Wales Hospital Randwick, Peter MacCallum Cancer Centre, University of Toronto-Princess Margaret Hospital, Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Génomes et cancer ( GC (FRE2939) ), Institut Gustave Roussy ( IGR ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique épidémiologique et structures des populations humaines ( Inserm U535 ), Epidémiologie, sciences sociales, santé publique ( IFR 69 ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of Otago, Institut de Physique et Chimie des Matériaux de Strasbourg ( IPCMS ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, University of Cambridge [UK] ( CAM ), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Neoplasm Proteins, Cancer Research, DNA Mutational Analysis, medicine.disease_cause, Polymerase Chain Reaction, law.invention, 0302 clinical medicine, law, Polymorphism (computer science), Family history, MESH: DNA Mutational Analysis, MESH : Polymerase Chain Reaction, Polymerase chain reaction, MESH: Testicular Neoplasms, Genetics, 0303 health sciences, Mutation, MESH: Genetic Predisposition to Disease, Neoplasms, Germ Cell and Embryonal, Neoplasm Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Neoplasms, Germ Cell and Embryonal, MESH : Mutation, Germ cell, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], MESH: Mutation, MESH : Male, MESH : DNA Mutational Analysis, Biology, MESH : Family Health, Article, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH : Neoplasms, Germ Cell and Embryonal, Testicular Neoplasms, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, MESH : Testicular Neoplasms, [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT], Gene, 030304 developmental biology, Family Health, MESH: Humans, MESH : Humans, Cancer, MESH: Polymerase Chain Reaction, medicine.disease, MESH: Male, MESH: Family Health, MESH : Genetic Predisposition to Disease
Abstract

A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents.

Published
2008

14. Single-course bleomycin, etoposide, and cisplatin (1xBEP) as adjuvant treatment in testicular nonseminoma clinical stage 1: outcome, safety, and risk factors for relapse in a population-based study

Author

Klaus-Peter Dieckmann, Tomas Pokrivcak, Lajos Geczi, David Niehaus, Inken Dralle-Filiz, Cord Matthies, Tamas Dienes, Stefanie Zschäbitz, Pia Paffenholz, Tanja Gschliesser, Renate Pichler, Michal Mego, Pia Bader, Friedemann Zengerling, Julia Heinzelbecker, Philipp Krausewitz, Susanne Krege, Gaetano Aurilio, Cem Aksoy, Marcus Hentrich, Christoph Seidel, Péter Törzsök, Tim Nestler, Matthaeus Majewski, Andreas Hiester, Tomas Buchler, Sonia Vallet, Hana Studentova, Sandra Schönburg, Dora Niedersüß-Beke, Julia Ring, Emanuela Trenti, Axel Heidenreich, Christian Wülfing, Hendrik Isbarn, Uwe Pichlmeier, and Martin Pichler

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: Clinical stage 1 (CS1) nonseminomatous (NS) germ cell tumors involve a 30% probability of relapse upon surveillance. Adjuvant chemotherapy with one course of bleomycin, etoposide, and cisplatin (1xBEP) can reduce this risk to pT2 was significantly associated with relapse rate. Conclusion: The relapse rate of 3.1% found in this population of NS CS1 patients treated with 1xBEP at the routine care level was not inferior to the median rate of 2.3% reported from a meta-analysis of controlled trials. Also, the cure rate of relapses of 77% is consistent with the previously reported rate of 80%. This study clearly shows that the 1xBEP regimen represents a safe treatment for NS CS1 patients.

Published
2022
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15. Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m 2 ) and the Currently Approved Dose (25 mg/m 2 ) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer-PROSELICA.

Author

Eisenberger M, Hardy-Bessard AC, Kim CS, Géczi L, Ford D, Mourey L, Carles J, Parente P, Font A, Kacso G, Chadjaa M, Zhang W, Bernard J, and de Bono J

Subjects
Aged, Disease-Free Survival, Docetaxel, Dose-Response Relationship, Drug, Humans, Kaplan-Meier Estimate, Male, Taxoids therapeutic use, Antineoplastic Agents administration & dosage, Prostatic Neoplasms, Castration-Resistant drug therapy, Taxoids administration & dosage
Abstract

Purpose Cabazitaxel 25 mg/m 2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m 2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.

Published
2017
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