108 results on '"Kerstin Rhiem"'
Search Results
2. Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer
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Kerstin Rhiem, Silke Zachariae, Anke Waha, Sabine Grill, Anna Hester, Michael Golatta, Marion van Mackelenbergh, Tanja Fehm, Tanja Schlaiß, Tim Ripperger, Susanne Ledig, Cornelia Meisel, Dorothee Speiser, Kristina Veselinovic, Christopher Schröder, Isabell Witzel, Julia Gallwas, Bernhard H.F. Weber, Christine Solbach, Bariyhe Aktas, Eric Hahnen, Christoph Engel, and Rita Schmutzler
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Oncology ,Surgery - Abstract
Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis. Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19–78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression. Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes (BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years (n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21–1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years. Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.
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- 2023
3. Ovarian cancer onset across differentBRCAmutation types: a view to a more tailored approach forBRCAmutated patients
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Claudia Marchetti, Beyhan Ataseven, Chiara Cassani, Carolina Maria Sassu, Luigi Congedo, Marco D'Indinosante, Serena Cappuccio, Kerstin Rhiem, Eric Hahnen, Emanuela Lucci Cordisco, Eloisa Arbustini, Philipp Harter, Angelo Minucci, Giovanni Scambia, and Anna Fagotti
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BRCA2 Protein ,Surgical Oncology ,Settore MED/40 - GINECOLOGIA E OSTETRICIA ,Settore MED/06 - ONCOLOGIA MEDICA ,Oncology ,BRCA1 Protein ,Obstetrics and Gynecology ,Ovarian Cancer - Abstract
ObjectiveTo evaluate the role of different specific types of germline breast cancer susceptibilityBRCAmutations on the age of onset of high grade serous ovarian cancer.MethodsThis was a multicenter, international, retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations inBRCA1/2genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type ofBRCA1/2genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared.ResultsExcluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. TheBRCA1gene was affected in 324 (68.4%) cases, whileBRCA2was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer betweenBRCA1andBRCA2patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in theBRCA1andBRCA2subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55).ConclusionDifferent types of germlineBRCAmutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer.
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- 2022
4. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer
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C.E. Geyer, J.E. Garber, R.D. Gelber, G. Yothers, M. Taboada, L. Ross, P. Rastogi, K. Cui, A. Arahmani, G. Aktan, A.C. Armstrong, M. Arnedos, J. Balmaña, J. Bergh, J. Bliss, S. Delaloge, S.M. Domchek, A. Eisen, F. Elsafy, L.E. Fein, A. Fielding, J.M. Ford, S. Friedman, K.A. Gelmon, L. Gianni, M. Gnant, S.J. Hollingsworth, S.-A. Im, A. Jager, Ó. Þ Jóhannsson, S.R. Lakhani, W. Janni, B. Linderholm, T.-W. Liu, N. Loman, L. Korde, S. Loibl, P.C. Lucas, F. Marmé, E. Martinez de Dueñas, R. McConnell, K.-A. Phillips, M. Piccart, G. Rossi, R. Schmutzler, E. Senkus, Z. Shao, P. Sharma, C.F. Singer, T. Španić, E. Stickeler, M. Toi, T.A. Traina, G. Viale, G. Zoppoli, Y.H. Park, R. Yerushalmi, H. Yang, D. Pang, K.H. Jung, A. Mailliez, Z. Fan, I. Tennevet, J. Zhang, T. Nagy, G.S. Sonke, Q. Sun, M. Parton, M.A. Colleoni, M. Schmidt, A.M. Brufsky, W. Razaq, B. Kaufman, D. Cameron, C. Campbell, A.N.J. Tutt, Paul Sevelda, Ferdinand Haslbauer, Monika Penzinger, Leopold Öhler, Christoph Tinchon, Richard Greil, Sonja Heibl, Rupert Bartsch, Viktor Wette, Christian F. Singer, Claudia Pasterk, Ruth Helfgott, Gunda Pristauz-Telsnigg, Herbert Stöger, Angsar Weltermann, Daniel Egle, Irene Thiel, David Fuchs, Holger Rumpold, Kathrin Strasser-Weippl, Beate Rautenberg, Volkmar Müller, Marcus Schmidt, Stefan Paepke, Mustafa Aydogdu, Christoph Thomssen, Joachim Rom, Christine Mau, Peter Fasching, Uwe-Jochen Göhring, Thorsten Kühn, Stefanie Noeding, Sherko Kümmel, John Hackmann, Elmar Stickeler, Abhishek Joshi, Joanna Dewar, Michael Friedlander, Kelly-Anne Phillips, Yoland Antill, Natasha Woodward, Ehtesham Abdi, Susan Tiley, Mathew George, David Boadle, Annabel Goodwin, Andre van der Westhuizen, George Kannourakis, Nicholas Murray, Nicole McCarthy, Judith Kroep, Maaike de Boer, Joan Heijns, Agnes Jager, Franciscus Erdkamp, Sandra Bakker, Gabe S. Sonke, Amer Sami, John Mackey, Catherine Prady, Andrea Eisen, Christine Desbiens, Erica Patocskai, Cristiano Ferrario, Karen Gelmon, Louise Bordeleau, Haji Chalchal, Saroj Niraula, null ido wolf, Elżbieta Senkus, François Duhoux, null Randal d’Hondt, Sylvie Luce, Daphné t’Kint de Roodenbeke, Konstantinos Papadimitriou, Marleen Borms, Claire Quaghebeur, William Jacot, Etienne Brain, Laurence Venat-Bouvet, Alain Lortholary, Zbigniew Nowecki, Fátima Cardoso, Richard Hayward, Santiago Bella, Mauricio Fernández Lazzaro, Norma Pilnik, Luis E. Fein, Cesar Blajman, Guillermo Lerzo, Mirta Varela, Juan Jose Zarba, Diego Kaen, Maria Victoria Constanzo, Joke Tio, Wulf Siggelkow, Christian Jackisch, Eva Maria Grischke, Dirk Zahm, Sara Tato-Varela, Sabine Schmatloch, Peter Klare, Andrea Stefek, Kerstin Rhiem, Oliver Hoffmann, Mustafa Deryal, Isolde Gröll, Peter Ledwon, Christoph Uleer, Petra Krabisch, Jochem Potenberg, Maren Darsow, Tjoung-Won Park-Simon, Heinz-Gert Höffkes, Till-Oliver Emde, Gerd Graffunder, Oliver Tomé, Dirk Forstmeyer, Jürgen Terhaag, Christoph Salat, Karin Kast, Steffi Weniger, Carsten Schreiber, Bernhard Heinrich, Max Dieterich, Michaela Penelope Wüllner, Raquel Andrés Conejero, José Ángel García Sáenz, Lourdes Calvo Martinez, Angels Arcusa Lanza, Serafín Morales Murillo, Fernando Henao Carrasco, Salvador Blanch Tormo, Isabel Álvarez López, Juan Ignacio Delgado Mingorance, Elena Álvarez Gomez, Marta Santisteban, Josefina Cruz Jurado, Vanesa Quiroga, Manuel Ruiz Borrego, Eduardo Martínez de Dueñas, Jose Enrique Alés Martínez, Juan De la Haba, Noelia Martínez Jañez, Álvaro Rodríguez Lescure, Antonio Antón Torres, Gema Llort Crusades, Santiago González-Santiago, Antonia Marquez Aragones, Ana Laura Ortega, Agusti Barnadas Molins, José Ignacio Chacón López-Muñiz, Miguel Martín Jiménez, Ana Santaballa Bertrán, César Rodríguez, Lucía González Cortijo, Elisabetta Cretella, Laura Cortesi, Enzo Maria Ruggeri, Claudio Verusio, Stefania Gori, Andrea Bonetti, Anna Maria Mosconi, Oskar Johannsson, Guy Jerusalem, Patrick Neven, Tünde Nagy, Graziella Pinotti, Marco A. Colleoni, Antonio Bernardo, Lorenzo Gianni, Eraldo Bucci, Laura Biganzoli, Konstantin Dedes, Urban Novak, Khalil Zaman, Jeremy Braybrooke, Matthew Winter, Daniel Rea, Muireann Kelleher, Sophie Barrett, Stephen Chan, Tamas Hickish, Jane Hurwitz, John Conibear, Apurna Jegannathen, Marina Parton, Andrew Tutt, Rozenn Allerton, Annabel Borley, Anne Armstrong, Ellen Copson, Nicola Levitt, Jean Abraham, Timothy Perren, Rebecca Roylance, Kazushige Ishida, Tatsuya Toyama, Norikazu Masuda, Junichiro Watanabe, Eriko Tokunaga, Takayuki Kinoshita, Yoshiaki Rai, Masahiro Takada, Yasuhiro Yanagita, Rikiya Nakamura, Takahiro Nakayama, Yasuto Naoi, Hiroji Iwata, Seigo Nakamura, Masato Takahashi, Kenjiro Aogi, Koichiro Tsugawa, Hirofumi Mukai, Toshimi Takano, Akihiko Osaki, Nobuaki Sato, Hideko Yamauchi, Yutaka Tokuda, Mitsuya Ito, Takeki Sugimoto, Shakeela W. Bahadur, Patricia A. Ganz, Min J. Lu, Monica M. Mita, James Waisman, Jonathan A. Polikoff, Melinda L. Telli, Samantha A. Seaward, J. Marie Suga, Lara N. Durna, Jennifer Fu Carney, Alex Menter, Ajithkumar Puthillath, Nitin Rohatgi, James H. Feusner, Kristie A. Bobolis, Peter D. Eisenberg, Derrick Wong, Virginia F. Borges, Alexander T. Urquhart, Erin W. Hofstatter, Edward C. McCarron, Claudine Isaacs, Pia Herbolsheimer, Ramya Varadarajan, Adam Raben, Ruby Anne E. Deveras, Frances Valdes-Albini, Reshma L. Mahtani, Jane L. Meisel, Bradley T. Sumrall, Cheryl F. Jones, Samuel N. Ofori, Kenneth N.M. Sumida, Mark Karwal, Deborah W. Wilbur, (Joe) Singh, David M. Spector, John Schallenkamp, Douglas E. Merkel, Shelly S. Lo, Pam G. Khosla, Massimo Cristofanilli, Lisa Flaum, Kent F. Hoskins, Melody A. Cobleigh, Elyse A. Lambiase, Olwen M. Hahn, Ira A. Oliff, Bryan A. Faller, James L. Wade, Nafisa D. Burhani, Amaryllis Gil, Harvey E. Einhorn, Anna M.V. Storniolo, Brian K. Chang, Maitri Kalra, Erwin L. Robin, Bilal Ansari, Priyanka Sharma, Shaker R. Dakhil, Richard L. Deming, John T. Cole, David S. Hanson, Augusto C. Ochoa, Judy E. Garber, Harvey Zimbler, Deborah K. Armstrong, Katherine H.R. Tkaczuk, David A. Riseberg, Brian M. O'Connor, Thomas H. Openshaw, Dana Zakalik, Cynthia M. Vakhariya, Anne F. Schott, Michael S. Simon, Thomas J. Doyle, Tareq Al Baghdadi, Amy VanderWoude, Patrick J. Flynn, Richard T. Zera, Bret E.B. Friday, Kathryn J. Ruddy, Ron Smith, null Ademuyiwa, Foluso Olabisi, Robert Ellis, Jay W. Carlson, null Marchello, Benjamin T, Edward A. Levine, Paul K. Marcom, Cameron B. Harkness, Antoinette R. Tan, William J. Charles, Charles S. Kuzma, Shonda Asaad, James E. Radford, Preston D. Steen, Madhu Unnikrishnan, Grant R. Seeger, Kirsten M.H. Leu, Mehmet S. Copur, Ralph J. Hauke, Gamini S. Soori, Bradley A. Arrick, Jennifer G. Reeder, Deborah L. Toppmeyer, Zoneddy R. Dayao, Sylvia Adams, Eleni Andreopoulou, Magnuson Allison, Jesus D. Anampa Mesias, Ruby Sharma, Bhuvaneswari Ramaswamy, Aaron T. Gerds, Robert R. Shenk, Howard M. Gross, Shruti Trehan, Wajeeha Razaq, Abdul H. Mansoor, Christie J. Hilton, Adam M. Brufsky, Chanh Huynh, Nabila Chowdhury, Susan M. Domchek, Elin R. Sigurdson, Terrence P. Cescon, Marc A. Rovito, Albert S. DeNittis, Victor G. Vogel, Thomas B. Julian, L.E. Boyle, Luis Baez-Diaz, Frank J. Brescia, John E. Doster, Robert D. Siegel, Lucas Wong, Tejal Patel, Julie R. Nangia, Catherine A. Jones, George M. Cannon, Harry D. Bear, Hetal Vachhani, Mary Wilkinson, Marie E. Wood, Fengting Yan, Xingwei Sui, Carol M. van Haelst, Jennifer M. Specht, Ying Zhuo, Rubina Qamar, Matthew L. Ryan, Abigail Stockham, Shamsuddin Virani, Arlene A. Gayle, Steven J. Jubelirer, Sobha Kurian, Mohamad A. Salkeni, Niklas Loman, Barbro Linderholm, Gustav Silander, Anna-Lotta Hallbeck, Anna von Wachenfeldt Väppling, Elsa Curtit, Catarina Cardoso, Sofia Braga, Miguel Abreu, Mafalda Casa-Nova, Mónica Nave, Eva María Ciruelos Gil, Judith Balmaña Gelpi, Adela Fernández Ortega, Josep Gumà Padró, Begoña Bermejo de las Heras, María González Cao, Juan Cueva Bañuelos, Jesús Alarcon Company, Gemma Viñas Villaró, Laura García Estevez, Jens Huober, Steffi Busch, Tanja Fehm, Antje Hahn, Andrea Grafe, Thomas Noesselt, Thomas Dewitz, Harald Wagner, Christina Bechtner, Michael Weigel, Hans-Christian Kolberg, Thomas Decker, Jörg Thomalla, Tobias Hesse, Nadia Harbeck, Jan Schröder Jens-Uwe Blohmer, Marc Wolf Sütterlin, Renske Altena, Chang-Fang Chiu, Shin-Cheh Chen, Ming-Feng Hou, Yuan-Ching Chang, Shang-Hung Chen, Shou-Tung Chen, Chiun-Sheng Huang, Dah-Cherng Yeh, Jyh-Cherng Yu, Ling-Ming Tseng, Wei-Pang Chung, Audrey Mailliez, Thierry Petit, Suzette Delaloge, Christelle Lévy, Philippe Dalivoust, Jean-Marc Extra, Marie-Ange Mouret-Reynier, Anne-Claire Hardy-Bessard, Hélène Simon, Tiffenn L'Haridon, Alice Mege, Sylvie Giacchetti, Camille Chakiba-Brugere, Alain Gratet, Virginie Pottier, Jean-Marc Ferrero, Isabelle Tennevet, Christophe Perrin, Jean-Luc Canon, Sofie Joris, Zhimin Shao, Binghe Xu, ZeFei Jiang, Qiang Sun, Kunwei Shen, Da Pang, Jin Zhang, Shui Wang, Hongjian Yang, Ning Liao, Hong Zheng, Peifen Fu, Chuangui Song, Yongsheng Wang, Zhimin Fan, Cuizhi Geng, Olivier Tredan, László Landherr, Bella Kaufman, Rinat Yerushalmi, Beatrice Uziely, Pierfranco Conte, Claudio Zamagni, Giampaolo Bianchini, Michelino De Laurentiis, Carlo Tondini, Vittorio Gebbia, Mariangela Ciccarese, Tomasz Sarosiek, Jacek Mackiewicz, Anna Słowińska, Ewa Kalinka, Tomasz Huzarski, Seock-Ah Im, Kyung Hae Jung, Joo Hyuk Sohn, Jee Hyun Kim, Keun Seok Lee, Yeon Hee Park, Kyoung Eun Lee, Yee Soo Chae, Eun Kyung Cho, Institut Català de la Salut, [Geyer CE Jr] NRG Oncology/NSABP Foundation, Pittsburgh, USA. Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, USA. [Garber JE] Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA. [Gelber RD] Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA. Harvard T.H. Chan School of Public Health, Boston, USA. Frontier Science Foundation, Boston, USA. [Yothers G] NRG Oncology/NSABP Foundation, Pittsburgh, USA. Department of Biostatistics, University of Pittsburgh, Pittsburgh, USA. [Taboada M] Oncology Biometrics Department, AstraZeneca, Macclesfield, UK. [Ross L] Department of Data Management, Frontier Science (Scotland), Kincraig, Scotland, UK. [Balmaña J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Medical Oncology, Public Health, Virology, Department of Psychology, Education and Child Studies, Internal Medicine, General Practice, and Child and Adolescent Psychiatry / Psychology
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Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,Medicaments antineoplàstics - Ús terapèutic ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Breast Neoplasms ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,olaparib ,Article ,breast cancer ,SDG 3 - Good Health and Well-being ,BRCA1/2 ,células::células germinativas [ANATOMÍA] ,Humans ,Other subheadings::/therapeutic use [Other subheadings] ,Cells::Germ Cells [ANATOMY] ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Otros calificadores::/uso terapéutico [Otros calificadores] ,BRCA1 Protein ,PARP inhibition ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS] ,adjuvant therapy ,Hematology ,Cèl·lules germinals ,Germ Cells ,Oncology ,Mama - Càncer - Tractament ,Phthalazines ,Female ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS] - Abstract
Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.
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- 2022
5. Abstract P4-06-13: Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study
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Peter A. Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Sabine Seiler, Wolfgang D. Schmitt, Christoph Uleer, Gabriele Doering, Kerstin Rhiem, Andreas Schneeweiss, Carsten Denkert, Rita K. Schmutzler, Eric Hahnen, Michael Untch, Valentina Nekljudova, Jens-Uwe Blohmer, and Sibylle Loibl
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Cancer Research ,Oncology - Abstract
Background: The GeparOLA study was designed to evaluate the efficacy and safety of the combination of paclitaxel (P) plus olaparib (O) as part of neoadjuvant chemotherapy (NACT) in patients with human epidermal growth factor receptor 2 (HER2)-negative, either hormone receptor (HR)-positive or HR-negative and homologous recombination deficiency (HRD) defined as having a g/tBRCA mutation and/or a high HRD score. Primary analysis showed a pCR rate of 55.1% (90% CI 44.5%-65.3%) with PO and 48.6% (90% CI 34.3%-63.2%) with P plus carboplatinum (Cb). The PO combination could not exclude a pCR rate of ≤55% in the PO arm but was significantly better tolerated. Analysis on the stratified subgroups showed higher pCR rates with PO in the cohorts of patients < 40 years and HR-positive tumors (Fasching Ann Oncol 2020). Here, we report long-term data. Methods: GeparOLA (NCT02789332) was a non-comparative, multicenter, prospective, randomized, open-label, phase II trial. Patients with primary HER2-negative breast cancer, HRD and indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and TNBC or cT1c and Ki-67 >20%) were randomly assigned to receive either P 80 mg/m2 weekly plus O 100 mg twice daily for 12 weeks or P plus Cb area under the curve 2 (AUC2) weekly for 12 weeks, both followed by four cycles of either 2-weekly or 3-weekly epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2. Primary endpoint was pCR (ypT0/is ypN0) rate after NACT with PO followed by EC. Long-term efficacy endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). The time-to-event endpoints analysis is planned with median follow-up of at least 4 years and a follow-up completeness of at least 80%. Results: Between September 2016 and July 2018, 274 patients were screened, of whom 107 were randomized and 106 (PO N=69; PCb N=37) started treatment. The median age was 47.0 years (range 25.0-71.0); 32 patients were aged < 40 years; 36.2% of patients had cT1 tumors and 31.8% were cN-positive; the majority (86.8%) had grade 3 tumors and a Ki-67>20% (89.6%). Seventy-seven patients (72.6%) had TNBC. After a median follow-up of 49.8 months (range 0.1-69.1), 18 (15 in PO; 3 in PCb) iDFS events and 7 (6 in PO; 1 in PCb) deaths were reported. The 4-year survival rates are shown in the table below. iDFS (HR PO to PCb=2.86 [95%CI 0.83-9.9], log-rank p=0.081), DDFS (HR =3.03 [95%CI 0.67-13.67], log-rank p=0.129), and OS (HR=3.27 [95%CI 0.39-27.2], log-rank p=0.244) tended to be inferior with olaparib. Patients without g/tBRCA mutation seem to benefit from the use of carboplatinum (7/30 iDFS/DDFS events in PO; 0/16 in PCb, log-rank p=0.037, HR n.a.). Conclusions: In patients with HER2-negative and HRD breast cancer the use of olaparib instead of carboplatinum although showing comparable pCR rates, tended to result in an overall inferior outcome. This was mainly driven by the patients without a g/tBRCA mutation. In patients with a g/t BRCA mutation no difference between olaparib and carboplatinum was seen. Key words: Olaparib, HER2-negative breast cancer, HRD, survival Funding: The study was financially supported by AstraZeneca Citation Format: Peter A. Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Sabine Seiler, Wolfgang D. Schmitt, Christoph Uleer, Gabriele Doering, Kerstin Rhiem, Andreas Schneeweiss, Carsten Denkert, Rita K. Schmutzler, Eric Hahnen, Michael Untch, Valentina Nekljudova, Jens-Uwe Blohmer, Sibylle Loibl. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-13.
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- 2023
6. Incidence and Prognostic Impact of Deleterious Germline Mutations in Primary Advanced Ovarian Carcinoma Patients
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Majdi Imterat, Philipp Harter, Kerstin Rhiem, Florian Heitz, Stephanie Schneider, Nicole Concin, Malak Moubarak, Julia Welz, Vasileios Vrentas, Alexander Traut, Eric Hahnen, Rita Schmutzler, Andreas du Bois, and Beyhan Ataseven
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Cancer Research ,Oncology ,BRCA1/2 ,RAD51C/D ,BRIP1 ,PALB2 ,ovarian cancer ,survival - Abstract
Data on deleterious variants in genes other than BRCA1/2 remain limited. A retrospective cohort study was performed, including primary OC cases with TruRisk® germline gene panel testing between 2011 and 2020. Patients with testing after relapse were excluded. The cohort was divided into three groups: (A) no mutations, (B) deleterious BRCA1/2 mutations, and (C) deleterious mutations in other genes. A total of 702 patients met the inclusion criteria. Of these 17.4% (n = 122) showed BRCA1/2 mutations and a further 6.0% (n = 42) in other genes. Three-year overall survival (OS) of the entire cohort was significantly longer in patients with germline mutations (85%/82.8% for cohort B/C vs. 70.2% for cohort A, p < 0.001) and 3-year progression-free survival (PFS) only for cohort B (58.1% vs. 36.9%/41.6% in cohort A/C, p = 0.002). In multivariate analysis for the subgroup of advanced-stages of high-grade serous OC, both cohorts B/C were found to be independent factors for significantly better outcome, cohort C for OS (HR 0.46; 95% CI 0.25–0.84), and cohort B for both OS and PFS (HR 0.40; 95% CI 0.27–0.61 and HR 0.49; 95% CI 0.37–0.66, respectively). Germline mutations were detected in a quarter of OC patients, and a quarter of those in genes other than BRCA1/2. Germline mutations demonstrate in our cohort a prognostic factor and predict better prognosis for OC patients.
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- 2023
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7. Implementing HRD Testing in Routine Clinical Practice on Patients with Primary High-Grade Advanced Ovarian Cancer
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Florian Heitz, Beyhan Ataseven, Claudia Staniczok, Carsten Denkert, Kerstin Rhiem, Eric Hahnen, Sebastian Heikaus, Malak Moubarak, Julia Welz, Timoleon Dagres, Vasilios Vrentas, Mareike Bommert, Stephanie Schneider, Nicole Concin, and Philipp Harter
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Cancer Research ,BRCA1/2 ,PARP inhibitor ,Oncology ,homologue recombination deficiency ,primary high-grade advanced ovarian cancer ,tumor testing - Abstract
The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the BRCA1/2 status. This study included patients with a primary diagnosis of HG-AOC treated between December 2019 and December 2021. The HRD status was measured using the Myriad myChoice® test on all the patients with an indication for tumor HRD testing. Germline testing was conducted on all the patients using the TruRisk® panel as recommended by the national guidelines. HRD testing was requested for 190 patients, and, for 163 patients (85.8%), an HRD test result was available. An HRD test result could not be reported in 27 patients due to an insufficient tumor yield. The median time that it took to receive the HRD test results was 37 days (range of 8–97). In total, an HRD was present in 44.7% (73/163) of the patients based on a GIS ≥ 42 in 42.9% of the patients and based on a tumor BRCA1/2 mutation in 3 cases (all with a GIS < 42). The germline testing results were available for 148 patients, and, in 18 patients (12.2%), a deleterious germline mutation was detected. Of the 27 patients without sufficient HRD testing, BRCA1/2 germline testing results were available for 19 patients (70.4%), and a deleterious germline mutation was detected in 2 patients (7.4%). The implementation of HRD testing is feasible, and the results become available for treatment decisions in a timely manner for most patients. The prerequisite for HRD testing with the Myriad myChoice® test is a sufficient amount of tumor tissue. The cotesting of HRD and BRCA1/2 germline testing should be aimed for in order to enable optimal and timely treatment decisions on maintenance therapy as well as to test patients on whom the HRD test will not be evaluable.
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- 2023
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8. Psychological factors and the uptake of preventative measures in BRCA1/2 pathogenic variant carriers: results of a prospective cohort study
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Julia Dick, Anja Tüchler, Anne Brédart, Frank Vitinius, Kirsten Wassermann, Kerstin Rhiem, and Rita K. Schmutzler
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Oncology ,Genetics (clinical) - Abstract
Background Women carrying BRCA1/2 pathogenic variants are exposed to elevated risks of developing breast cancer (BC) and are faced by a complex decision-making process on preventative measures, i.e., risk-reducing mastectomy (RRM), and intensified breast surveillance (IBS). In this prospective cohort study we investigated the effect of anxiety, personality factors and coping styles on the decision-making process on risk management options in women with pathogenic variants in BRCA1/2. Methods Breast cancer unaffected and affected women with a pathogenic variant in the BRCA1 or BRCA2 gene were psychologically evaluated immediately before (T0), 6 to 8 weeks (T1) and 6 to 8 months (T2) after the disclosure of their genetic test results. Uptake of RRM and IBS was assessed at T2. Psychological data were gathered using questionnaires on risk perception, personality factors, coping styles, decisional conflict, depression and anxiety, including the Hospital Anxiety and Depression Scale (HADS). We performed tests on statistical significance and fitted a logistic regression based on significance level. Results A total of 98 women were included in the analysis. Baseline anxiety levels in women opting for RRM were high but decreased over time, while they increased in women opting for intensified breast surveillance (IBS). Elevated levels of anxiety after genetic test result disclosure (T1) were associated with the decision to undergo RRM (p Conclusions Considering psychosocial factors influencing the decision-making process of women with pathogenic variants in BRCA1/2 may help improving their genetic and psychological counselling. When opting for IBS they may profit from additional medical and psychological counselling. Trial registration Retrospectively registered at the German Clinical Trials Register under DRKS00027566 on January 13, 2022.
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- 2022
9. Physical activity and Mediterranean diet as potential modulators of osteoprotegerin and soluble RANKL in gBRCA1/2 mutation carriers: results of the lifestyle intervention pilot study LIBRE-1
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Christoph Engel, Jacqueline Lammert, M Basrai, B. Seethaler, Stephan C. Bischoff, Leonie Neirich, Sabine Grill, Thorsten Schmidt, Juliane Ramser, Kerstin Rhiem, Marion Kiechle, Maryam Yahiaoui-Doktor, Rita K. Schmutzler, Uwe Niederberger, Anne S. Quante, Martin Halle, and Anika Berling-Ernst
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musculoskeletal diseases ,Lifestyle intervention ,Cancer Research ,medicine.medical_specialty ,BRCA1/2 mutation carriers ,Mediterranean diet ,Physical fitness ,Breast Neoplasms ,Pilot Projects ,Diet, Mediterranean ,Breast cancer ,Osteoprotegerin ,Internal medicine ,Humans ,Medicine ,Prospective Studies ,Fatty acids ,Clinical Trial ,OPG ,RANKL ,Physical activity ,Receptor ,Exercise ,Life Style ,Randomized Controlled Trials as Topic ,BRCA2 Protein ,chemistry.chemical_classification ,biology ,BRCA1 Protein ,business.industry ,RANK Ligand ,ddc ,Endocrinology ,Oncology ,chemistry ,Mutation ,biology.protein ,Biomarker (medicine) ,Female ,business ,Polyunsaturated fatty acid - Abstract
Purpose Emerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations. Methods Serum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups. Results The lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = − 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871). Conclusion Findings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.
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- 2021
10. Breast cancer characteristics and surgery among women with Li‐Fraumeni syndrome in Germany—A retrospective cohort study
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Christian P. Kratz, Nicola Dikow, Hans-Peter Sinn, Christine Fischer, Sabine Grill, Huu P. Nguyen, Karin Kast, Kerstin Rhiem, Nina Ditsch, Sarah Schott, Christian Sutter, Simone Hettmer, Nathalie Rippinger, and Friedrich W. Cremer
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Adult ,Cancer Research ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Breast surgery ,Population ,cancer predisposition ,Breast Neoplasms ,Mastectomy, Segmental ,Li-Fraumeni Syndrome ,Contralateral Prophylactic Mastectomy ,Breast cancer ,Risk Factors ,Germany ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,TP53 ,ddc:610 ,education ,RC254-282 ,Research Articles ,Li‐Fraumeni syndrome ,Mastectomy ,Retrospective Studies ,education.field_of_study ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,hereditary breast cancer ,Retrospective cohort study ,breast surgery ,Middle Aged ,Ductal carcinoma ,medicine.disease ,Surgery ,prophylactic surgery ,Oncology ,Patient Satisfaction ,Lymphatic Metastasis ,Axilla ,Population study ,Female ,Neoplasm Recurrence, Local ,business ,Cancer Prevention ,Research Article - Abstract
Background Women with Li‐Fraumeni syndrome (LFS) have elevated breast cancer (BC) risk. Optimal BC treatment strategies in this population are yet unknown. Methods BC subtypes and treatment were retrospectively investigated between December 2016 and January 2019 in a multicentre study. BC risks were evaluated according to the type of surgery. Results Thirty‐five women of our study population (35/44; 79.5%) had developed 36 breast lesions at first diagnosis at a mean age of 34 years. Those breast lesions comprised 32 invasive BCs (89%), three ductal carcinoma in situ alone (8%) and one malignant phyllodes tumour (3%). BCs were mainly high‐grade (18/32), of no special type (NST; 31/32), HER2‐enriched (11/32) or luminal‐B‐(like)‐type (10/32). Affected women (n = 35) received breast‐conserving surgery (BCS, n = 17) or a mastectomy (ME, n = 18) including seven women with simultaneous contralateral prophylactic mastectomy (CPM) at first diagnosis. Nineteen women suffered 20 breast or locoregional axillary lesions at second diagnosis with mean age of 36. Median time between first and second diagnosis was 57 months; median time to contra‐ and ipsilateral recurrence depended on surgical strategies (BCS: 46 vs. unilateral ME: 93 vs. bilateral ME > 140 months). Women with a primary treatment of solitaire therapeutic ME suffered from contralateral BC earlier compared to those with therapeutic ME and CPM (median: 93 vs. >140 months). Conclusion Aggressive BC subtypes occur among women with LFS. Surgical treatment, i.e. ME and CPM, may prolong time to a second BC diagnosis. Conclusion on long‐term survival benefit is pending. Individual competing tumour risks and long‐term outcomes need to be taken into consideration., Women with Li‐Fraumeni Syndrome face challenging breast cancer risks. Therapeutic or contralateral prophylactic mastectomy can be associated with a prolonged median time to develop contralateral breast cancer.
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- 2021
11. Risk-Adjusted Cancer Screening and Prevention (RiskAP): Complementing Screening for Early Disease Detection by a Learning Screening Based on Risk Factors
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Per Hall, Diana Eccles, Peter Dabrock, Sabine C. Linn, Tade Spranger, Peter Devilee, Judith Balmaña, Kerstin Rhiem, Stefania Boccia, Björn Schmitz-Luhn, Bettina Borisch, Christiane Woopen, Alexander Katalinic, Wolfgang Gaissmaier, Dominique Stoppa-Lyonnet, Stefanie Houwaart, Rita K. Schmutzler, Paul D.P. Pharoah, Marc van den Bulcke, Karin Kast, Jacek Gronwald, Johannes Jozef Marten van Delden, Stefan Huster, Sowmiya Moorthie, Günter Emons, Institut Català de la Salut, [Schmutzler RK] Center Familial Breast and Ovarian Cancer and Center of Integrated Oncology (CIO), University Hospital Cologne, Cologne, Germany. [Schmitz-Luhn B] Cologne Center for Ethics, Rights, Economics, and Social Sciences of Health (ceres), University of Cologne, and Research Unit Ethics, University Hospital of Cologne, Cologne, Germany. [Borisch B] Institute of Global Health, University of Geneva, Geneva, Switzerland. [Devilee P] Leids Universitair Medisch Zentrum, Universiteit Leiden, Leiden, The Netherlands. [Eccles D] Clinical Trials Unit, University of Southampton, Southampton, UK. [Hall P] Karolinska Institutet, Stockholm, Sweden. [Balmaña J] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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ELSI ethical ,Otros calificadores::Otros calificadores::/prevención & control [Otros calificadores] ,medicine.medical_specialty ,social implications ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,diagnóstico::diagnóstico precoz::detección precoz del cáncer [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Review Article ,Risk-adjusted prevention ,técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Individual risk ,Other subheadings::Other subheadings::/prevention & control [Other subheadings] ,Breast cancer ,ddc:150 ,Cancer screening ,Medicine ,Mama - Càncer - Diagnòstic ,Intensive care medicine ,Settore MED/42 - IGIENE GENERALE E APPLICATA ,legal ,Risk adjusted ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Cancer prevention ,business.industry ,Early disease ,Evidence-generating care ,Mama - Càncer - Factors de risc ,Increased risk ,Mama - Càncer - Prevenció ,Oncology ,Preventive intervention ,Risk-adjusted prevention · Breast cancer · Evidencegenerating care · ELSI ethical, legal, social implications ,Surgery ,Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Genetic risk factor ,business ,ELSI ethical, legal, social implications ,Diagnosis::Early Diagnosis::Early Detection of Cancer [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] - Abstract
Breast cancer; Evidence-generating care; Risk-adjusted prevention Cáncer de mama; Atención generadora de evidencia; Prevención ajustada al riesgo Càncer de mama; Atenció generadora d'evidències; Prevenció ajustada al risc Background: Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action. Summary: Therefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept. The project was funded by the German Federal Ministry of Health (grant No. 2515FSB401 to Rita Schmutzler and Christiane Woopen) for supporting the international expert meetings, and a grant of the EU Horizon 2020 program, BRIDGES (grant No. 634935, PI Peter Devilee, WP5-PI Rita Schmutzler), for the compilation of the most recent findings of genetic risk prediction.
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- 2021
12. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials
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Toralf Reimer, Wolfgang Janni, Hans Tesch, Kristina Lübbe, Theresa Link, Carsten Denkert, Marianne Just, Jenny Furlanetto, Frederik Marmé, Erich Solomayer, Christian Jackisch, Wolfgang D. Schmitt, Kerstin Rhiem, Mattea Reinisch, Fenja Seither, A Forberger, Peter A. Fasching, Bruno Valentin Sinn, Michael Untch, Sibylle Loibl, Claus Hanusch, Valentina Nekljudova, Christine Solbach, Jens-Uwe Blohmer, Sabine Seiler, Sabine Schmatloch, Andreas Schneeweiss, Elmar Stickeler, Pauline Wimberger, Jens Huober, Marcus Schmidt, Laura Michel, Oliver Stötzer, and Eric Hahnen
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Random assignment ,business.industry ,medicine.medical_treatment ,Cancer ,Combination chemotherapy ,medicine.disease ,Logistic regression ,Clinical trial ,Breast cancer ,Internal medicine ,Cohort ,medicine ,skin and connective tissue diseases ,business - Abstract
Summary Background The development of anti-HER2 antibody–drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis. Methods In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426 ; GeparOcto, NCT02125344 ; GeparX, NCT02682693 ; Gain-2 neoadjuvant, NCT01690702 ) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46·6 months (IQR 35·0–52·3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival. Findings A total of 1098 (47·5%) of 2310 tumours were HER2-low-positive and 1212 (52·5%) were HER2-zero. 703 (64·0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36·7%) of 1212 patients with HER2-zero tumours (p Interpretation Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies. Funding German Cancer Aid (Deutsche Krebshilfe).
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- 2021
13. Long‑term survival of a BRCA2 mutation carrier following second ovarian cancer relapse using PARPi therapy: A case report
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Kathrin Bredow, Britta Blümcke, Stephanie Schneider, Michael Püsken, Rita Schmutzler, and Kerstin Rhiem
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Cancer Research ,Oncology - Published
- 2022
14. Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy
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Valentina Nekljudova, Christian Jackisch, Kerstin Rhiem, Jenny Furlanetto, Volker Möbus, Rita K. Schmutzler, Jens Huober, Jens Uwe Blohmer, Peter Klare, Bianca Lederer, Christoph Salat, Kristina Lübbe, Theresa Link, Fergus J. Couch, Eric Hahnen, Peter A. Fasching, Claus Hanusch, Ingo Bauerfeind, Michael Untch, Sibylle Loibl, Dirk Michael Zahm, Hans Tesch, Bernd Gerber, and Andreas Schneeweiss
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Adult ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,Triple Negative Breast Neoplasms ,Neutropenia ,Risk Assessment ,Gastroenterology ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Risk Factors ,Germany ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Anthracyclines ,Chemotherapy-Induced Febrile Neutropenia ,Germ-Line Mutation ,Randomized Controlled Trials as Topic ,BRCA2 Protein ,Chemotherapy ,Taxane ,BRCA1 Protein ,business.industry ,Odds ratio ,Middle Aged ,medicine.disease ,Hematologic Diseases ,Thrombocytopenia ,Neoadjuvant Therapy ,Confidence interval ,Treatment Outcome ,030104 developmental biology ,Oncology ,chemistry ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,Taxoids ,business ,medicine.drug - Abstract
BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities.Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored.Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies.gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.
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- 2021
15. Precursor fractions of neurotensin and enkephalin might point to molecular mechanisms of cancer risk modulation during a lifestyle-intervention in germline BRCA1/2 gene mutation carriers
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Anika Berling-Ernst, Sabine Grill, Maryam Yahiaoui-Doktor, Kerstin Rhiem, Jacqueline Lammert, Janin Schulte, Mirjam Ullrich, Thorsten Schmidt, Christoph Engel, Dimitrios Chronas, Uwe Niederberger, Marion Kiechle, M Basrai, Stephan C. Bischoff, Joachim Struck, Rita K. Schmutzler, and Martin Halle
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Lifestyle intervention ,Oncology ,Cancer Research ,medicine.medical_specialty ,BRCA1/2 mutation carriers ,Population ,Breast Neoplasms ,Disease ,030204 cardiovascular system & hematology ,Gene mutation ,medicine.disease_cause ,Cardiopulmonary fitness ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,education ,Life Style ,Germ-Line Mutation ,Neurotensin ,Nutrition ,education.field_of_study ,Physical activity ,BRCA1 Protein ,business.industry ,Cancer ,Enkephalins ,medicine.disease ,Clinical Trial ,ddc ,Germ Cells ,030220 oncology & carcinogenesis ,Mutation ,Cohort ,Female ,business ,Ovarian cancer ,Carcinogenesis - Abstract
BackgroundGermlineBRCA1/2mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)—involved in tumorigenesis and obesity-related diseases—are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC.MethodsThe stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors.ResultsAt SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L,p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = − 0.435; CI − 0.653 to − 0.151;p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061–0.544;p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: − 37.9,p = 0.097/0.080) in multivariate analysis.ConclusionOur results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.
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- 2021
16. Abstract GS5-02: Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study
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Peter A. Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Sabine Seiler, Wolfgang D. Schmitt, Christoph Uleer, Gabriele Doering, Kerstin Rhiem, Andreas Schneeweiss, Carsten Denkert, Rita K. Schmutzler, Eric Hahnen, Michael Untch, Valentina Nekljudova, Jens-Uwe Blohmer, and Sibylle Loibl
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Cancer Research ,Oncology - Abstract
Background: The GeparOLA study was designed to evaluate the efficacy and safety of the combination of paclitaxel (P) plus olaparib (O) as part of neoadjuvant chemotherapy (NACT) in patients with human epidermal growth factor receptor 2 (HER2)-negative, either hormone receptor (HR)-positive or HR-negative and homologous recombination deficiency (HRD) defined as having a g/tBRCA mutation and/or a high HRD score. Primary analysis showed a pCR rate of 55.1% (90% CI 44.5%-65.3%) with PO and 48.6% (90% CI 34.3%-63.2%) with P plus carboplatinum (Cb). The PO combination could not exclude a pCR rate of ≤55% in the PO arm but was significantly better tolerated. Analysis on the stratified subgroups showed higher pCR rates with PO in the cohorts of patients < 40 years and HR-positive tumors (Fasching Ann Oncol 2020). Here, we report long-term data. Methods: GeparOLA (NCT02789332) was a non-comparative, multicenter, prospective, randomized, open-label, phase II trial. Patients with primary HER2-negative breast cancer, HRD and indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and TNBC or cT1c and Ki-67 >20%) were randomly assigned to receive either P 80 mg/m2 weekly plus O 100 mg twice daily for 12 weeks or P plus Cb area under the curve 2 (AUC2) weekly for 12 weeks, both followed by four cycles of either 2-weekly or 3-weekly epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2. Primary endpoint was pCR (ypT0/is ypN0) rate after NACT with PO followed by EC. Long-term efficacy endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). The time-to-event endpoints analysis is planned with median follow-up of at least 4 years and a follow-up completeness of at least 80%. Results: Between September 2016 and July 2018, 274 patients were screened, of whom 107 were randomized and 106 (PO N=69; PCb N=37) started treatment. The median age was 47.0 years (range 25.0-71.0); 32 patients were aged < 40 years; 36.2% of patients had cT1 tumors and 31.8% were cN-positive; the majority (86.8%) had grade 3 tumors and a Ki-67>20% (89.6%). Seventy-seven patients (72.6%) had TNBC. After a median follow-up of 49.8 months (range 0.1-69.1), 18 (15 in PO; 3 in PCb) iDFS events and 7 (6 in PO; 1 in PCb) deaths were reported. The 4-year survival rates are shown in the table below. iDFS (HR PO to PCb=2.86 [95%CI 0.83-9.9], log-rank p=0.081), DDFS (HR =3.03 [95%CI 0.67-13.67], log-rank p=0.129), and OS (HR=3.27 [95%CI 0.39-27.2], log-rank p=0.244) tended to be inferior with olaparib. Patients without g/tBRCA mutation seem to benefit from the use of carboplatinum (7/30 iDFS/DDFS events in PO; 0/16 in PCb, log-rank p=0.037, HR n.a.). Conclusions: In patients with HER2-negative and HRD breast cancer the use of olaparib instead of carboplatinum although showing comparable pCR rates, tended to result in an overall inferior outcome. This was mainly driven by the patients without a g/tBRCA mutation. In patients with a g/t BRCA mutation no difference between olaparib and carboplatinum was seen. Key words: Olaparib, HER2-negative breast cancer, HRD, survival Funding: The study was financially supported by AstraZeneca Citation Format: Peter A. Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Sabine Seiler, Wolfgang D. Schmitt, Christoph Uleer, Gabriele Doering, Kerstin Rhiem, Andreas Schneeweiss, Carsten Denkert, Rita K. Schmutzler, Eric Hahnen, Michael Untch, Valentina Nekljudova, Jens-Uwe Blohmer, Sibylle Loibl. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-02.
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- 2023
17. Abstract P6-10-03: Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT)
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Bernd Gerber, Claus Hanusch, Andreas Schneeweiss, Ingo Bauerfeind, Fergus J. Couch, Dirk-Michael Zahm, Peter Klare, Bianca Lederer, Jenny Furlanetto, Theresa Link, Christian Jackisch, Michael Untch, Jens Huober, Peter A. Fasching, Kristina Lübbe, Valentina Nekljudova, Kerstin Rhiem, Volker Möbus, Christoph Salat, Rita K. Schmutzler, Sibylle Loibl, Hans Tesch, and Jens-Uwe Blohmer
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Taxane ,business.industry ,medicine.medical_treatment ,Cancer ,Neutropenia ,medicine.disease ,Germline ,Breast cancer ,Internal medicine ,Toxicity ,medicine ,business ,Triple-negative breast cancer - Abstract
Background: BRCA1/2 genes play a central role in DNA repair. Therefore, pts harboring gBRCA1/2m treated with chemotherapy might be at higher risk of acute hematological toxicities due to the lower level of functional BRCA1/2 protein potentially resulting in more toxicity. Published results are discordant, further data are needed. Methods: Pts with early TNBC and known gBRCA1/2m treated with anthracycline-taxane based NACT in the GeparQuinto (n=487), GeparSixto (n=291) and GeparOcto (n=393) studies were included. Primary G-CSF prophylaxis was foreseen only for the iddETC arm in GeparOcto. Primary objective was the rate of neutropenia grade (G)3-4 after cycle 1; secondary objectives were the rate of other hematological toxicities G3-4 and the overall toxicity rate after cycle 1 as well as hematological toxicities in gBRCA1/2 pts during the taxane part of chemotherapy. Results: 209/1171 evaluated pts (17.8%) had a gBRCA1/2m (177 gBRCA1m, 33 gBRCA2m). Median age was 48yrs [21-78]. The rate of neutropenia G3-4 after cycle 1 in gBRCA1/2 wildtype (wt) pts was 35.7% vs 37.4% in gBRCA1/2m (p=0.683), 35.9% in gBRCA1m (p=1.000), 44.8% in gBRCA2m (p=0.330). gBRCA1/2 mutational status did not predict neutropenia G3-4 at univariate (OR=1.08, 95%CI 0.78-1.48 p=0.658) or multivariate analysis adjusted for age, BMI and treatment (OR=1.26, 95%CI 0.87-1.82 p=0.226). The overall rate and the rates of other hematological toxicities are shown in the table. gBRCA1/2 mutational status did also not predict for any other hematological toxicities G3-4 (univariate OR=0.94, 95%CI 0.64-1.40 p=0.773; multivariate OR=0.94, 95%CI 0.62-1.43 p=0.779). gBRCA1/2 mutational status predicted for hematological toxicities G3-4 under taxane treatment (univariate OR=1.94, 95%CI 1.35-2.77 p During taxane treatment, the overall rate of hematological toxicities G3-4 in wt pts was 43.1% (n=270) vs 59.5% (n=91) in gBRCA1/2m, p Conclusions: Overall, gBRCA1/2 mutation is not associated with a significantly higher risk of severe hematological toxicities. Under taxane therapy, pts with gBRCA1/2 demonstrate a higher rate of hematological toxicities G3-4, especially neutropenia, compared to wildtype pts, and should therefore be carefully monitored. Hematological toxicities after cycle 1wildtypegBRCA1/2mp-valuegBRCA1mp-valuegBRCA2mp-valueN%N%N%N%neutropenia G3-432635.77437.40.6836135.91.0001344.80.330febrile neutropenia171.831.41.00010.60.33726.10.130leucopenia G3-424425.83818.20.0212815.80.0041030.30.548anemia G3-420.200.01.00000.01.00000.01.000thrombopenia G3-4111.210.50.70510.60.70400.01.000any hematological toxicities G1-477782.617081.70.76314180.10.4533090.90.344any hematological toxicities G3-442846.38843.60.5337241.90.3171651.60.587 Citation Format: Jenny Furlanetto, Volker Möbus, Andreas Schneeweiss, Kerstin Rhiem, Hans Tesch, Jens-Uwe Blohmer, Kristina Lübbe, Michael Untch, Christoph Salat, Jens Huober, Peter Klare, Rita Schmutzler, Fergus J Couch, Bianca Lederer, Bernd Gerber, Dirk-Michael Zahm, Ingo Bauerfeind, Valentina Nekljudova, Claus Hanusch, Christian Jackisch, Theresa Link, Sibylle Loibl, Peter A Fasching. Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-03.
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- 2020
18. AGO recommendations for the diagnosis and treatment of patients with early breast cancer: update 2022
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Nina Ditsch, Achim Wöcke, Michael Untch, Christian Jackisch, Ute-Susann Albert, Maggie Banys-Paluchowski, Ingo Bauerfeind, Jens-Uwe Blohmer, Wilfried Budach, Peter Dall, Eva Maria Fallenberg, Peter A. Fasching, Tanja N. Fehm, Michael Friedrich, Bernd Gerber, Oleg Gluz, Nadia Harbeck, Jörg Heil, Jens Huober, Hans H. Kreipe, David Krug, Thorsten Kühn, Sherko Kümmel, Cornelia Kolberg-Liedtke, Sibylle Loibl, Diana Lüftner, Michael Patrick Lux, Nicolai Maass, Christoph Mundhenke, Ulrike Nitz, Tjoung-Won Park-Simon, Toralf Reimer, Kerstin Rhiem, Achim Rody, Marcus Schmidt, Andreas Schneeweiss, Florian Schütz, Hans-Peter Sinn, Christine Solbach, Erich-Franz Solomayer, Elmar Stickeler, Christoph Thomssen, Isabell Witzel, Volkmar Müller, Wolfgang Janni, and Marc Thill
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Oncology ,Surgery - Abstract
Introduction: The AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, German Gynecological Oncology Group) Task Force on Diagnosis and Treatment of Breast Cancer as an interdisciplinary team consists of specialists from gynecological oncology, pathology, diagnostic radiology, medical oncology, and radiation oncology with a special focus on breast cancer. Methods: The updated evidence-based treatment recommendation 2022 for early breast cancer (EBC) and metastatic breast cancer of the AGO Task Force has been released. Results and Conclusion: This paper captures the update of EBC.
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- 2022
19. AGO recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer: update 2022
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Marc Thill, Diana Lüftner, Cornelia Kolberg-Liedtke, Ute-Susann Albert, Maggie Banys-Paluchowski, Ingo Bauerfeind, Jens-Uwe Blohmer, Wilfried Budach, Peter Dall, Eva Maria Fallenberg, Peter A. Fasching, Tanja Fehm, Michael Friedrich, Bernd Gerber, Oleg Gluz, Nadia Harbeck, Jörg Heil, Jens Huober, Christian Jackisch, Hans-Heinrich Kreipe, David Krug, Thorsten Kühn, Sherko Kümmel, Sibylle Loibl, Michael Lux, Nicolai Maass, Christoph Mundhenke, Ulrike Nitz, Tjoung-Won Park-Simon, Toralf Reimer, Kerstin Rhiem, Achim Rody, Marcus Schmidt, Andreas Schneeweiss, Florian Schütz, Hans-Peter Sinn, Christine Solbach, Erich-Franz Solomayer, Elmar Stickeler, Christoph Thomssen, Michael Untch, Isabell Witzel, Achim Wöckel, Volkmar Müller, Wolfgang Janni, and Nina Ditsch
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Oncology ,Surgery - Abstract
The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2022 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer.
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- 2022
20. 291 Frequency of pathogenic mutations and prognostic impact of germline gene panel testing in patients with primary epithelial ovarian cancer
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A. du Bois, Kerstin Rhiem, Alexander Traut, P. Harter, Mareike Bommert, Rita K. Schmutzler, Stephanie Schneider, Beyhan Ataseven, and Florian Heitz
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Oncology ,medicine.medical_specialty ,Mutation ,Multivariate analysis ,endocrine system diseases ,business.industry ,Disease ,Debulking ,medicine.disease ,medicine.disease_cause ,Germline ,Germline mutation ,Internal medicine ,Cohort ,medicine ,business ,Ovarian cancer - Abstract
Introduction/Background* The detection of gBRCA1/2 mutations in patients (pts) with epithelial ovarian cancer (EOC) provides information regarding family risk and influences clinical management, e.g. use of PARP inhibitors. The availability of next generation sequencing (NGS) allows for simultaneous sequencing of multiple cancer risk genes including BRCA1/2. Our aim was to evaluate the prevalence and clinical outcome of deleterious germline mutations in EOC patients. Methodology EOC patients treated between 2011 and 2020 at our institution and with germline TruRisk® gene panel testing were included in this retrospective analysis. Based on the genetic test result three cohorts were considered: A) no mutation, B) gBRCA1/2, and C) mutations in other risk genes. Demographic and clinicopathological characteristic were retrieved from the prospective database. To evaluate survival outcome in FIGO III/IV EOC univariate and multivariate logistic regression was performed. Result(s)* In total 702 EOC pts underwent germline panel testing. Median age was 59 years, 74.5% underwent primary debulking surgery, 83.9% were FIGO III/IV, and complete macroscopic resection was achieved in 74.0%. No mutation was detected in 76.6% (n=538), pathogenic gBRCA1/2 mutations in 17.4% (n=122), and mutations in other risk genes in 6.0% (n=42), respectively (tbl.1). Significant differences between the cohorts were detected for age, pervious history of malignancies, personal/familial breast/ovarian cancer history, and histology. For FIGO III/IV patients median PFS was significantly different for cohort A, B, and C with 23, 37, and 34 months (p=0.059/multivariate 0.015), respectively. 3-years-OS was 70%, 83%, and 87% for cohorts A, B, and C (p=0.003), respectively. In multivariate analysis type of surgery (IDS: HR 2.79(1.86-4.19), p 500mL (HR 1.75(1.14-2.68), p=0.010), and residual disease (RD>0mm: HR 2.87(1.99-4.14), p Conclusion* The detection rate of germline mutations in EOC is 23.4%. Our findings underline the necessity to offer germline panel testing in EOC to identify families at risk. Further, our findings underscore the prognostic value of germline mutations towards a better prognosis.
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- 2021
21. Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer
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Esther Pohl-Rescigno, Peter Klare, Gbg, Kristina Lübbe, Michael Untch, Kerstin Rhiem, Carsten Denkert, Jens Huober, Hans Tesch, Andreas Schneeweiss, Sibylle Loibl, Christian Jackisch, Karin Kast, Rita K. Schmutzler, Christine Solbach, Theresa Link, Valentina Nekljudova, L Michel, Peter A. Fasching, Claus Hanusch, Eric Hahnen, Volker Möbus, Ago-B, and Jens-Uwe Blohmer
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Cancer Research ,medicine.medical_specialty ,Paclitaxel ,medicine.medical_treatment ,Triple Negative Breast Neoplasms ,Gastroenterology ,Loading dose ,Polyethylene Glycols ,chemistry.chemical_compound ,Breast cancer ,Trastuzumab ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cyclophosphamide ,Triple-negative breast cancer ,Epirubicin ,Chemotherapy ,business.industry ,medicine.disease ,Survival Analysis ,Carboplatin ,Oncology ,chemistry ,Doxorubicin ,Female ,Pertuzumab ,business ,medicine.drug - Abstract
Background GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points. Patients and methods Patients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles. Results 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6-61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85-1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58-1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08-4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06-10.00], log-rank p = 0.029). Conclusion While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. CLINICALTRIALS. Gov identifier NCT02125344.
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- 2021
22. EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy
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Marieke van de Ven, Tesa M. Severson, Reinhard Büttner, H. Christian Reinhardt, Jos Jonkers, Kerstin Rhiem, J Puppe, Christian Eichler, Birgid Schömig-Markiefka, Carlos Caldas, Peter Bouwman, Chiara S. Brambillasca, Rita K. Schmutzler, Olaf van Tellingen, Wolfram Malter, Gaurav Kumar Pandey, Michael Hauptmann, Luka Ozretić, Peter Mallmann, Philip C. Schouten, Jelle Wesseling, Katarzyna Jóźwiak, Fabinshy Thangarajah, René Bernards, Maarten van Lohuizen, Esther H. Lips, Eric Hahnen, Mark Opdam, and Sabine C. Linn
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0301 basic medicine ,Cisplatin ,Cancer Research ,Chemotherapy ,endocrine system diseases ,Anthracycline ,business.industry ,medicine.medical_treatment ,EZH2 ,macromolecular substances ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,Oncology ,In vivo ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,Immunohistochemistry ,skin and connective tissue diseases ,business ,Survival rate ,medicine.drug - Abstract
Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature (“BRCA1-like”) and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors. Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing. We classified 370 tumors by copy-number profiles as BRCA1-like or non-BRCA1–like and examined its association with EZH2 expression. Additionally, we assessed BRCA1 loss through mutation or promoter methylation status and investigated the predictive value of EZH2 expression in a study population of breast cancer patients treated with adjuvant high-dose platinum-based chemotherapy compared with standard anthracycline-based chemotherapy. To explore whether EZH2 inhibition by GSK126 enhances sensitivity to platinum drugs in EZH2-overexpressing breast cancers we used a Brca1-deficient mouse model. Results: The highest EZH2 expression was found in BRCA1-associated tumors harboring a BRCA1 mutation, BRCA1-promoter methylation or were classified as BRCA1 like. We observed a greater benefit from high-dose platinum-based chemotherapy in BRCA1-like and non-BRCA1–like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in Brca1-deficient mice in comparison with single agents. Conclusions: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1-like status. EZH2 inhibition improves the antitumor effect of platinum drugs in Brca1-deficient breast tumors in vivo.
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- 2019
23. Residual glandular tissue (RGT) in BRCA1/2 germline mutation carriers with unilateral and bilateral prophylactic mastectomies
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Wolfram Malter, David Maintz, Olga Grinstein, Rita K. Schmutzler, Martin Hellmic, Barbara Krug, Kerstin Rhiem, Florian Siedek, and Christina Burke
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Adult ,medicine.medical_specialty ,Neoplasm, Residual ,medicine.medical_treatment ,Breast Neoplasms ,Breast magnetic resonance imaging ,030218 nuclear medicine & medical imaging ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Germline mutation ,medicine ,Humans ,Breast MRI ,skin and connective tissue diseases ,Germ-Line Mutation ,Retrospective Studies ,BRCA2 Protein ,medicine.diagnostic_test ,BRCA1 Protein ,business.industry ,Prophylactic Mastectomy ,Middle Aged ,Fibroglandular Tissue ,Prognosis ,medicine.disease ,Oncology ,030220 oncology & carcinogenesis ,Female ,Surgery ,Radiology ,business ,Ovarian cancer ,Mastectomy ,Follow-Up Studies - Abstract
Prophylactic mastectomy (PME) is increasingly performed in women carrying deleterious BRCA1 and BRCA2 germline mutations. The oncologic risk resulting from residual fibroglandular tissue (RGT) is unknown.All women who had received a mastectomy and at least one postoperative breast MRI, between 2006 and 2016 were extracted from the register of the Center for Hereditary Breast and Ovarian Cancer Cologne (CHBOC). The index MRI was evaluated in terms of basic clinical data and the morphological criteria of RGT. The RGT volume was measured in diameter and was semi-automatically evaluated using software.We identified 169 women carrying BRCA1/2 mutations who underwent prophylactic and curative mastectomy: a total of 338 breasts. RGT was found in 128 of the 338 breasts (37.9%). 68 of the 128 breasts (53.1%) were related to bilateral PME, 37 (28.9%) to unilateral PME and 23 (18.0%) to curative mastectomy. RGT was predominantly unifocal and located in the retroareolar breast region. RGT was observed more often after bilateral PME (p 0.0001). In this subgroup, the nipple-sparing mastectomy dominated (108 of 136, 79.4%), in contrast to 23 standard mastectomies (23 of 94, 24.5%) in the subgroup of curative mastectomy (23%). There was a trend towards higher amounts of RGT in surgical units with fewer mastectomies performed. During follow-up, two breast cancers were detected after bilateral and unilateral PME, respectively.Our results suggest that the indication for surgery and in particular the selected surgical procedure affect the surgical outcome with respect to RGT. Oncological safety should not be neglected, especially in the high-risk group of BRCA1/2 mutation carriers.
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- 2019
24. Breast cancer risk in BRCA1/2 mutation carriers and noncarriers under prospective intensified surveillance
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Barbara Wappenschmidt, Eva Maria Fallenberg, N Herold, Kerstin Rhiem, Denise Horn, Stefanie Pertschy, Karin Kast, Achim Wöckel, Ulrike Siebers-Renelt, Susanne Briest, Marion Kiechle, Walter Just, Christoph Engel, Claus R. Bartram, Markus Loeffler, Dorothee Speiser, Christoph Mundhenke, Karolin Bucksch, AS Vesper, Silke Zachariae, Pauline Wimberger, M Maringa, Nicola Dikow, Jutta Giesecke, Brigitte Schlegelberger, Elena Leinert, Sarah Schott, Eric Hahnen, Ulrich Bick, Rita K. Schmutzler, Anne S. Quante, Simone Reichstein-Gnielinski, Norbert Arnold, Stefanie Weigel, Christine Fischer, Verena Hübbel, Andrea Gehrig, and Tanja Fehm
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Adult ,Heterozygote ,Cancer Research ,medicine.medical_specialty ,Population ,Breast Neoplasms ,Risk Assessment ,Contralateral breast cancer ,03 medical and health sciences ,Brca1 2 mutation ,0302 clinical medicine ,Breast cancer ,Risk Factors ,Germany ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Prospective Studies ,Family history ,Medical History Taking ,skin and connective tissue diseases ,education ,Prospective cohort study ,BRCA2 Protein ,education.field_of_study ,BRCA1 Protein ,business.industry ,Incidence ,Age Factors ,Middle Aged ,medicine.disease ,Oncology ,030220 oncology & carcinogenesis ,Epidemiological Monitoring ,Mutation ,Mutation (genetic algorithm) ,Female ,Ovarian cancer ,business ,Follow-Up Studies - Abstract
Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.
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- 2019
25. High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer
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Dorothee Speiser, Alfons Meindl, Stefanie Weigel, Karl Werner Fritz Schäfer, Irina Lämmer-Skarke, Eva Maria Fallenberg, Thomas Hofmockel, Elena Leinert, Dorothea Rjosk-Dendorfer, Anne S. Quante, Christoph Engel, Barbara Krug, Rita K. Schmutzler, Stephanie Sauer, Kerstin Rhiem, Frederic Dietzel, Walter Heindel, Markus Loeffler, Karin Kast, David Maintz, Ulrich Bick, Anne Hagert-Winkler, Marion Kiechle, Stefanie Pertschy, and Michael Golatta
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Adult ,Risk ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Genes, BRCA2 ,Genes, BRCA1 ,Breast Neoplasms ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Risk groups ,Patient age ,Germany ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Mass Screening ,Public Health Surveillance ,Stage (cooking) ,Early Detection of Cancer ,Aged ,Neoplasm Staging ,medicine.diagnostic_test ,business.industry ,Reproducibility of Results ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Annual Screening ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Hereditary Breast and Ovarian Cancer Syndrome ,Female ,Neoplasm Grading ,business ,Ovarian cancer - Abstract
To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9–93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6–85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6–91.7), p
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- 2019
26. AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2019
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Nina Ditsch, Michael Untch, Marc Thill, Volkmar Müller, Wolfgang Janni, Ute-Susann Albert, Ingo Bauerfeind, Jens Blohmer, Wilfried Budach, Peter Dall, Ingo Diel, Peter A. Fasching, Tanja Fehm, Michael Friedrich, Bernd Gerber, Volker Hanf, Nadia Harbeck, Jens Huober, Christian Jackisch, Cornelia Kolberg-Liedtke, Hans-Heinrich Kreipe, David Krug, Thorsten Kühn, Sherko Kümmel, Sibylle Loibl, Diana Lüftner, Michael Patrick Lux, Nicolai Maass, Volker Möbus, Markus Müller-Schimpfle, Christoph Mundhenke, Ulrike Nitz, Kerstin Rhiem, Achim Rody, Marcus Schmidt, Andreas Schneeweiss, Florian Schütz, Hans-Peter Sinn, Christine Solbach, Erich-Franz Solomayer, Elmar Stickeler, Christoph Thomssen, Frederik Wenz, Isabell Witzel, and Achim Wöckel
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Oncology ,Clinical Information ,Surgery ,ddc:610 - Published
- 2019
27. Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto—GBG 84): A randomised phase III trial
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Michael Untch, Peter Klare, Peter A. Fasching, Christian Jackisch, Valentina Nekljudova, Gunter von Minckwitz, Karin Kast, Sibylle Loibl, Volker Möbus, Hans Tesch, Carsten Denkert, Jörg Thomalla, Jens-Uwe Blohmer, Matthias Frank, Jens Huober, Kerstin Rhiem, Knut Engels, Andreas Schneeweiss, Mahdi Rezai, Sherko Kümmel, Kristina Lübbe, Claus Hanusch, and Barbara Ingold-Heppner
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Adult ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Paclitaxel ,medicine.medical_treatment ,Medizin ,Triple Negative Breast Neoplasms ,Risk Assessment ,Loading dose ,Carboplatin ,Polyethylene Glycols ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Trastuzumab ,Germany ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cyclophosphamide ,Triple-negative breast cancer ,Aged ,Epirubicin ,Chemotherapy ,business.industry ,Middle Aged ,Neoadjuvant Therapy ,Treatment Outcome ,030104 developmental biology ,Tolerability ,chemistry ,Chemotherapy, Adjuvant ,Doxorubicin ,030220 oncology & carcinogenesis ,Female ,Pertuzumab ,business ,medicine.drug - Abstract
Background GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC). Patients and methods Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w for 3 cycles or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344 . Results 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77–1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P Conclusions In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice.
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- 2019
28. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto
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Christian Schem, Julia Reid, A-R Hartman, Kirsten Timms, Christoph Salat, Peter A. Fasching, C. Jackisch, D. M. Zahm, Kerstin Rhiem, Carsten Denkert, Rita K. Schmutzler, Valentina Nekljudova, EP Elkin, Sherko Kümmel, B. Lederer, Mahdi Rezai, Bernd Gerber, Andreas Schneeweiss, S. Loibl, S. Penn, Karsten Weber, G. von Minckwitz, Michael Untch, Stefan Paepke, Eric Hahnen, Sascha D. Braun, J-U Blohmer, and Peter Klare
- Subjects
Bridged-Ring Compounds ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Paclitaxel ,Anthracycline ,medicine.medical_treatment ,Triple Negative Breast Neoplasms ,Disease-Free Survival ,Carboplatin ,Polyethylene Glycols ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Anthracyclines ,Breast ,Mastectomy ,Survival analysis ,Triple-negative breast cancer ,BRCA2 Protein ,Chemotherapy ,Taxane ,BRCA1 Protein ,business.industry ,Hazard ratio ,Recombinational DNA Repair ,Hematology ,Odds ratio ,Middle Aged ,Prognosis ,Survival Analysis ,Neoadjuvant Therapy ,030104 developmental biology ,chemistry ,Doxorubicin ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Mutation ,Female ,Taxoids ,business ,Follow-Up Studies - Abstract
Background In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results A significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059). Conclusions The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
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- 2018
29. Konsensusempfehlung des Deutschen Konsortiums Familiärer Brust- und Eierstockkrebs zum Umgang mit Ergebnissen der Multigenanalyse
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Jan Hauke, Marion Kiechle, Norbert Arnold, Alfons Meindl, Eric Hahnen, Sarah Schott, Karin Kast, Dorothee Speiser, Kerstin Rhiem, Nicola Dikow, Judit Horvath, Christian Sutter, Dieter Niederacher, Beatrix Versmold, Christoph Mundhenke, Nina Ditsch, Bernd Auber, Rita K. Schmutzler, Anke Waha, Olaf Riess, Barbara Wappenschmidt, and Ulrike Faust
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis - Abstract
ZusammenfassungDas Deutsche Konsortium Familiärer Brust- und Eierstockkrebs (GC-HBOC) hat für die Analyse von Risikogenen für das familiäre Mamma- und Ovarialkarzinom ein Multigen-Panel (TruRisk®) etabliert, das derzeit die Kerngene („core genes“) ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51 D und TP53 enthält, sowie weitere Gene, die aus aktuellen Forschungsarbeiten hervorgegangen sind und noch validiert werden müssen. Das syndromassoziierte Gen PTEN befindet sich hinsichtlich seiner Bedeutung in Familien mit prädominantem Brust- und Eierstockkrebs-Phänotyp derzeit ebenfalls in der Evaluation. Ein interdisziplinäres Expertenteam des GC-HBOC hat die verfügbaren Daten zur Risikomodifikation bei Vorliegen einer pathogenen (krankheitsverursachenden) Mutation in diesen Genen basierend auf einer strukturierten Literaturrecherche (Abb. 1S) und im Rahmen eines formalen Konsensusprozesses bewertet. Ziel dieser Arbeit ist es, das individuelle Erkrankungsrisiko besser einschätzen und auf dieser Basis klinische Empfehlungen ableiten zu können. Auf der Grundlage dieser evidenzbasierten Bewertung werden die Ratsuchenden in den Zentren des Deutschen Konsortiums vom Erstgespräch vor Gentest bis zur Inanspruchnahme individueller risikoadaptierter präventiver/therapeutischer Maßnahmen beraten und betreut. Dieser Artikel fasst die konsentierten Inhalte zusammen.
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- 2021
30. Clinical outcome in patients with primary epithelial ovarian cancer and germline BRCA1/2-mutation - real life data
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Philipp Harter, Alexander Traut, Andreas du Bois, Beyhan Ataseven, Harald-Thomas Groeben, Rita K. Schmutzler, Alesina Pier Francesco, Denise Tripon, Florian Heitz, Kerstin Rhiem, Stephanie Schneider, Sebastian Heikaus, Thaïs Baert, and Richard Schwameis
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Adult ,medicine.medical_specialty ,endocrine system diseases ,Adolescent ,Disease ,Carcinoma, Ovarian Epithelial ,Gastroenterology ,Germline ,Young Adult ,Postoperative Complications ,Internal medicine ,medicine ,Humans ,Stage (cooking) ,Germ-Line Mutation ,Aged ,Retrospective Studies ,Aged, 80 and over ,BRCA2 Protein ,Ovarian Neoplasms ,business.industry ,BRCA1 Protein ,Obstetrics and Gynecology ,Postoperative complication ,Histology ,Middle Aged ,Debulking ,Serous fluid ,Treatment Outcome ,Oncology ,Disease Presentation ,Female ,business - Abstract
We evaluated the clinical impact of germline (g)BRCA1/2-mutation on initial disease presentation, surgical implications, surgical morbidity and survival in patients with advanced epithelial ovarian cancer (EOC) undergoing debulking surgery (DS).Data of all consecutive EOC patients with stage III/IV, high-grade serous disease and known gBRCA1/2 status (gBRCA; non-gBRCA), who underwent DS at our department between 01/2011 and 06/2019 were analyzed. Associations between gBRCA-status and severe postoperative complications and survival were analyzed.gBRCA-status was determined in 50.1% (612/1221) of all patients. gBRCA was present in 21.9% (134/612). Significant differences were observed in terms of median age (p = 0.001) and histology (high-grade serous histology gBRCA: 98.5%, non-gBRCA 76.2%; p 0.001). gBRCA-status had no impact on intraoperative disease presentation, surgical complexity or complete resection rate (gBRCA: 74.4%, non-gBRCA: 69.0%; p = 0.274). gBRCA-status was not predictive for severe postoperative complication (gBRCA: 12.0%, non-gBRCA: 19.1%; p = 0.082). Median PFS and OS was 31/22 and 71/53 months in patients with/without gBRCA-mutation, respectively. gBRCA was a significant prognostic factor for PFS (HR 0.57 p 0.001) and for OS (HR 0.64, p = 0.048) after adjusting for established prognostic factors.gBRCA-status had no impact on initial disease presentation, surgical results or postoperative complications. gBRCA patients have a significantly longer PFS but the impact on the long term prognosis is unclear. Complete resection remains the most important prognostic factor in patients with EOC independent of gBRCA-status.
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- 2021
31. AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer : Update 2021
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Marc Thill, Michael Friedrich, Cornelia Kolberg-Liedtke, Ute-Susann Albert, Maggie Banys-Paluchowski, Ingo Bauerfeind, Jens-Uwe Blohmer, Wilfried Budach, Peter Dall, Eva M. Fallenberg, Peter A. Fasching, Tanja Fehm, Bernd Gerber, Oleg Gluz, Nadia Harbeck, Jörg Heil, Jens Huober, Christian Jackisch, Hans-Heinrich Kreipe, David Krug, Thorsten Kühn, Sherko Kümmel, Sibylle Loibl, Diana Lüftner, Michael P. Lux, Nicolai Maass, Christoph Mundhenke, Ulrike Nitz, Tjoung-Won Park-Simon, Toralf Reimer, Kerstin Rhiem, Achim Rody, Marcus Schmidt, Andreas Schneeweiss, Florian Schütz, Hans-Peter Sinn, Christine Solbach, Erich-Franz Solomayer, Elmar Stickeler, Christoph Thomssen, Michael Untch, Isabell Witzel, Achim Wöckel, Volkmar Müller, Wolfgang Janni, and Nina Ditsch
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Oncology ,Medizin ,Surgery ,Review Article - Published
- 2021
32. Survey on physicians' knowledge and training needs in genetic counseling in Germany
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Dominique Stoppa-Lyonnet, Peter Devilee, Kerstin Rhiem, Sylvie Dolbeault, Rita K. Schmutzler, Simone Wesselmann, Viktoria Aue, Julia Dick, Anne Brédart, Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Université Paris Descartes - Paris 5 (UPD5), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Horizon 2020: 634935, and As part of the BRIDGES project, this work was funded by the European Union Horizon 2020 research and innovation program with the grant number No. 634935. It was also co-financed by the Center for Hereditary Breast and Ovarian Cancer at the University Hospital in Cologne, where the survey was conducted.
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medicine.medical_specialty ,Genetic testing ,Genetic counseling ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,medicine ,030212 general & internal medicine ,Hereditary breast cancer ,BRCA2 mutations ,medicine.diagnostic_test ,business.industry ,Cancer ,medicine.disease ,BRCA1 ,3. Good health ,Test (assessment) ,Oncology ,BRCA1/BRCA2 mutations ,030220 oncology & carcinogenesis ,Family medicine ,Surgery ,business ,Risk assessment ,Mastectomy ,Research Article - Abstract
Background: In recent years, germline testing of women with a risk of developing breast and ovarian cancer has increased rapidly. This is due to lower costs for new high-throughput sequencing technologies and the manifold preventive and therapeutic options for germline mutation carriers. The growing demand for genetic counseling meets a shortfall of counselors and illustrates the need to involve the treating clinicians in the genetic testing process. This survey was undertaken to assess their state of knowledge and training needs in the field of genetic counseling and testing. Methods: A cross-sectional survey within the European Bridges Study (Breast Cancer Risk after Diagnostic Gene Sequencing) was conducted among physician members (n = 111) of the German Cancer Society who were primarily gynecologists. It was designed to examine their experience in genetic counseling and testing. Results: Overall, the study revealed a need for training in risk communication and clinical recommendations for persons at risk. One-third of respondents communicated only relative disease risks (31.5%) instead of absolute disease risks in manageable time spans. Moreover, almost one-third of the respondents (31.2%) communicated bilateral and contralateral risk-reducing mastectomy as an option for healthy women and unilateral-diseased breast cancer patients without mutations in high-risk genes (e.g. BRCA1 or BRCA2). Most respondents expressed training needs in the field of risk assessment models, the clinical interpretation of genetic test results, and the decision-making process. Conclusion: The survey demonstrates a gap of genetic and risk literacy in a relevant proportion of physicians and the need for appropriate training concepts.
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- 2021
33. AGO Recommendations for the diagnosis and treatment of patients with early breast cancer: update 2021
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Nina Ditsch, Cornelia Kolberg-Liedtke, Michael Friedrich, Christian Jackisch, Ute-Susann Albert, Maggie Banys-Paluchowski, Ingo Bauerfeind, Jens-Uwe Blohmer, Wilfried Budach, Peter Dall, Eva M. Fallenberg, Peter A. Fasching, Tanja Fehm, Bernd Gerber, Oleg Gluz, Nadia Harbeck, Jörg Heil, Jens Huober, Hans-Heinrich Kreipe, David Krug, Thorsten Kühn, Sherko Kümmel, Sibylle Loibl, Diana Lüftner, Michael P. Lux, Nicolai Maass, Christoph Mundhenke, Ulrike Nitz, Tjoung-Won Park-Simon, Toralf Reimer, Kerstin Rhiem, Achim Rody, Marcus Schmidt, Andreas Schneeweiss, Florian Schütz, Hans-Peter Sinn, Christine Solbach, Erich-Franz Solomayer, Elmar Stickeler, Christoph Thomssen, Michael Untch, Isabell Witzel, Achim Wöckel, Volkmar Müller, Wolfgang Janni, and Marc Thill
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Oncology ,Medizin ,Surgery ,Review Article ,ddc:610 - Abstract
Weitere Verfasser:innen aus Einrichtungen außerhalb der Universität Duisburg-Essen sind nicht aufgeführt.
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- 2021
34. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study)
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Sabine Schmatloch, Sabine Seiler, G. Doering, Rita K. Schmutzler, Andrea Stefek, Eric Hahnen, C. Jackisch, S. Loibl, Arbeitsgemeinschaft Gynäkologische Onkologie Breast, Fenja Seither, Wolfgang D. Schmitt, Nicole Burchardi, J Huober, J-U Blohmer, Knut Engels, Peter Klare, PA Fasching, Carsten Denkert, Theresa Link, Michael Untch, Andreas Schneeweiss, Claus Hanusch, Jan Hauke, Kerstin Rhiem, and Christoph Uleer
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0301 basic medicine ,Adult ,medicine.medical_specialty ,Combination therapy ,Paclitaxel ,Receptor, ErbB-2 ,medicine.medical_treatment ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,Gastroenterology ,Piperazines ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Homologous Recombination ,Cyclophosphamide ,Neoadjuvant therapy ,Aged ,business.industry ,Area under the curve ,Hematology ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,030104 developmental biology ,Treatment Outcome ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,PARP inhibitor ,Phthalazines ,business ,Epirubicin ,medicine.drug - Abstract
Background The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA ( ClinicalTrials.gov , NCT02789332 ) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. Patients and methods Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR−) and age ( Results A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients Conclusion GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.
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- 2020
35. AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2020
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Nina Ditsch, Michael Untch, Cornelia Kolberg-Liedtke, Christian Jackisch, David Krug, Michael Friedrich, Wolfgang Janni, Volkmar Müller, Ute-Susann Albert, Malgorzata Banys-Paluchowski, Ingo Bauerfeind, Jens-Uwe Blohmer, Wilfried Budach, Peter Dall, Ingo Diel, Eva Maria Fallenberg, Peter A. Fasching, Tanja Fehm, Bernd Gerber, Oleg Gluz, Volker Hanf, Nadia Harbeck, Jörg Heil, Jens Huober, Hans H. Kreipe, Thorsten Kühn, Sherko Kümmel, Sibylle Loibl, Diana Lüftner, Michael Lux, Nicolai Maass, Volker Moebus, Christoph Mundhenke, Tjoung-Won Park-Simon, Toralf Reimer, Kerstin Rhiem, Achim Rody, Marcus Schmidt, Andreas Schneeweiss, Chistine Solbach, Erich-Franz Solomayer, Elmar Stickeler, Christoph Thomssen, Isabell Witzel, Achim Wöckel, and Marc Thill
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medicine.medical_specialty ,business.industry ,General surgery ,medicine.medical_treatment ,Locally advanced ,MEDLINE ,medicine.disease ,Primary tumor ,Metastatic breast cancer ,Systemic therapy ,Surgery ,Targeted therapy ,Breast cancer ,Oncology ,Clinical Information ,Medicine ,ddc:610 ,business ,Scientific validity - Abstract
Every year the Breast Committee of the Arbeitsgemeinschaft Gynakologische Onkologie (German Gynecological Oncology Group, AGO), a group of gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiologic diagnostics, medical oncology, and radiation oncology, prepares and updates evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. Every update is performed according to a documented rule-fixed algorithm, by thoroughly reviewing and scoring the recent publications for their scientific validity and clinical relevance. This current publication presents the 2019 update on the recommendations for metastatic breast cancer.
- Published
- 2020
36. Cost-Effectiveness of Targeted Genetic Testing for Breast and Ovarian Cancer: A Systematic Review
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Dirk Müller, Marion Danner, Andreas Koldehoff, Stephanie Stock, Daniele Civello, and Kerstin Rhiem
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Oncology ,medicine.medical_specialty ,Cost effectiveness ,Cost-Benefit Analysis ,MEDLINE ,Breast Neoplasms ,Cascade screening ,03 medical and health sciences ,0302 clinical medicine ,Centre for Reviews and Dissemination ,Breast cancer ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Genetic Testing ,health care economics and organizations ,Genetic testing ,BRCA2 Protein ,Ovarian Neoplasms ,medicine.diagnostic_test ,business.industry ,BRCA1 Protein ,030503 health policy & services ,Health Policy ,Public Health, Environmental and Occupational Health ,Cancer ,medicine.disease ,Female ,0305 other medical science ,Ovarian cancer ,business - Abstract
Background Targeted genetic testing is a tool to identify women at increased risk of gynaecological cancer. Objective This systematic review evaluates the results and quality of cost-effectiveness modeling studies that assessed targeted genetic-based screen-and-treat strategies to prevent breast and ovarian cancer. Methods Using MEDLINE and databases of the Centre for Reviews and Dissemination, we searched for health economic modeling evaluations of targeted genetic-based screen-and-treat strategies to prevent inheritable breast and ovarian cancer (until August 2020). The incremental cost-effectiveness ratios (ICERs) were compared. Methodological variations were addressed by evaluating the model conceptualizations, the modeling techniques, parameter estimation and uncertainty, and transparency and validation of the models. Additionally, the reporting quality of each study was assessed. Results Eighteen studies met our inclusion criteria. From a payer perspective, the ICERs of (1) BRCA screening for high-risk women without cancer ranged from dominating the no test strategy to an ICER of $21 700/quality-adjusted life years (QALY). In studies that evaluated (2) BRCA cascade screening (ie, screening of women with cancer plus their unaffected relatives) compared with no test, the ICERs were between $6500/QALY and $50 200/QALY. Compared with BRCA alone, (3) multigene testing in women without cancer had an ICER of $51 800/QALY (one study), while for (4) multigene-cascade screening the ICERs were $15 600/QALY, $56.500/QALY, and $69 600/QALY for women in the United Kingdom, Norway, and the United States, respectively (2 studies). More recently published studies showed a higher methodological and reporting quality. Conclusions Targeted BRCA or multiple gene screening is likely to be cost-effective. Methodological variations could be decreased by the development of a reference model, which may serve as a tool for validation of present and future cost-effectiveness models.
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- 2020
37. Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer: A Secondary Analysis of the GeparOcto Randomized Clinical Trial
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Kristina Lübbe, Valentina Nekljudova, Esther Pohl-Rescigno, Christian Jackisch, Nana Weber-Lassalle, Kerstin Rhiem, Michael Untch, Holger Thiele, Jenny Furlanetto, Volker Möbus, Corinna Ernst, Bianca Lederer, Claus Hanusch, Peter A. Fasching, Andreas Schneeweiss, Jan Hauke, Mohamad Kayali, Volkmar Müller, Peter Nürnberg, Sibylle Loibl, Hans Tesch, Rita K. Schmutzler, Eric Hahnen, Janine Altmüller, and Carsten Denkert
- Subjects
Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Breast Neoplasms ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Breast cancer ,Randomized controlled trial ,law ,Internal medicine ,Medicine ,Humans ,030212 general & internal medicine ,Prospective cohort study ,Triple-negative breast cancer ,Germ-Line Mutation ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Brief Report ,Odds ratio ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Carboplatin ,chemistry ,030220 oncology & carcinogenesis ,Female ,business ,Epirubicin ,medicine.drug - Abstract
IMPORTANCE: The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome. OBJECTIVE: To determine treatment outcome for BC according to germline variant status. DESIGN, SETTING, AND PARTICIPANTS: This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018. MAIN OUTCOMES AND MEASURES: Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. RESULTS: In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor–positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02). CONCLUSIONS AND RELEVANCE: Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor–positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02125344
- Published
- 2020
38. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness
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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
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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.
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- 2020
39. Pathological Response in the Breast and Axillary Lymph Nodes after Neoadjuvant Systemic Treatment in Patients with Initially Node-Positive Breast Cancer Correlates with Disease Free Survival: An Exploratory Analysis of the GeparOcto Trial
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Bernd Gerber, Andreas Schneeweiss, Volker Möbus, Michael Golatta, Hans Tesch, David Krug, Claus Hanusch, Carsten Denkert, Kristina Lübbe, Jörg Heil, Jens Huober, Beyhan Ataseven, Peter Klare, Markus Hahn, Michael Untch, Karin Kast, Christian Jackisch, Jörg Thomalla, Fenja Seither, Jens-Uwe Blohmer, Kerstin Rhiem, Peter A. Fasching, Valentina Nekljudova, Sibylle Loibl, and Thorsten Kühn
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Cancer Research ,breast cancer ,Oncology ,pathological complete response ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,neoadjuvant therapy ,axillary surgery ,lymph node ,prognosis ,ddc:610 ,RC254-282 - Abstract
Simple Summary The extent of axillary surgery has been reduced in recent years to minimize side effects. However, a negative impact of reduced surgery on outcome must be avoided. We investigated for whom the extent of surgery can be safely reduced by examining early-stage breast cancer patients converting from lymph node (LN)-positive to LN-negative disease after neoadjuvant systemic treatment (NAST). Of 242 initially LN-positive patients treated within the GeparOcto trial, 54.5% were classified as LN-negative after NAST, 31.8% as LN-positive, and for 13.6% data were missing. Overall, 92.1% of patients underwent complete axillary LN dissection, with 6.6% undergoing sentinel LN dissection only. At surgery, 55.4% of patients had no signs of cancer in the LN, 45.0% had no signs of cancer in the breast (of those 8.3% had involved LN), and 41.3% had no signs of cancer at all. Patients with involved LN still had a bad prognosis. Conversion from LN-positive to LN-negative after NAST is of highest prognostic value. Surgical axillary staging after NAST is essential in these patients to offer tailored treatment. Abstract Background: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS). Methods: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial. Results: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23–0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor. Conclusions: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.
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- 2022
40. A tandem duplication of BRCA1 exons 1–19 through DHX8 exon 2 in four families with hereditary breast and ovarian cancer syndrome
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Brigitte Pabst, Chen Du, C Scholz, Han Cao, Kerstin Rhiem, Rita K. Schmutzler, Barbara Wappenschmidt, Dorothea Mark, Beatrix Böckmann, Doris Steinemann, Saki Chan, Susanne Morlot, Bernd Auber, Thomas Illig, and Brigitte Schlegelberger
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Adult ,0301 basic medicine ,Cancer Research ,DNA Copy Number Variations ,Genes, BRCA1 ,Biology ,DEAD-box RNA Helicases ,Structural variation ,03 medical and health sciences ,Exon ,Gene Duplication ,Gene duplication ,Humans ,Copy-number variation ,Gene ,Genetics ,Intron ,High-Throughput Nucleotide Sequencing ,Exons ,Penetrance ,030104 developmental biology ,Oncology ,Hereditary Breast and Ovarian Cancer Syndrome ,Female ,RNA Splicing Factors ,Tandem exon duplication - Abstract
The purpose of this study is to characterize a novel structural variant, a large duplication involving exons 1–19 of the BRCA1 gene in four independent families, and to provide diagnostically valuable information including the position of the breakpoints as well as clues to its clinical significance. The duplication of exons 1–19 of the BRCA1 gene was initially detected by routine laboratory testing including MLPA analysis and next generation sequencing. For detailed characterization we performed array-comparative genome hybridization analysis, fluorescent in situ hybridization, next generation mapping, and long-distance PCR for break-point sequencing. Our data revealed a tandem duplication on chromosome 17 that encompassed 357 kb and included exons 1–19 of the BRCA1 gene and the genes NBR2, NBR1, TMEM106A, LOC100130581, ARL4D, MIR2117 up to parts of the DHX8 gene. This structural variant appeared as a tandem duplication with breakpoints in intron 19 of the BRCA1 gene and in intron 3 of the DHX8 gene (HGVS:chr17(hg19):g.41210776_41568516dup). Segregation analysis indicated that this structural rearrangement is phased in trans with a known pathogenic exon deletion of the BRCA1 gene in one family. The copy number variation initially recognized as duplication of exon 1–19 of the BRCA1 gene by MLPA analysis is a structural variation with breakpoints in the BRCA1 and DHX8 genes. Although currently to be classified as a variant of unknown significance, our family data indicates that this duplication may be a benign variation or at least of markedly reduced penetrance since it occurs in trans with another known fully pathogenic variant in the BRCA1 gene.
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- 2018
41. Cancer surveillance and distress among adult pathogenic TP53 germline variant carriers in Germany: A multicenter feasibility and acceptance survey
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Kerstin Rhiem, Nicola Dikow, Nina Ditsch, Sarah Schott, Imad Maatouk, Julia Vogel, Christian P. Kratz, Dirk Jäger, Stefan Fröhling, Christian Sutter, Dorothee Speiser, Marion Kiechle, Stephan Seitz, Karin Kast, Markus W. Haun, Friedrich W. Cremer, Nathalie Rippinger, Rita K. Schmutzler, Christine Fischer, Andrea Hahne, Sabine Grill, Huu P. Nguyen, Simone Hettmer, and Hanno Glimm
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Coping (psychology) ,Heterozygote ,media_common.quotation_subject ,Li-Fraumeni Syndrome ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Interquartile range ,Germany ,Neoplasms ,Medicine ,Humans ,Genetic Predisposition to Disease ,030212 general & internal medicine ,Genetic Testing ,ddc:610 ,Germ-Line Mutation ,Genetic testing ,media_common ,medicine.diagnostic_test ,business.industry ,Middle Aged ,medicine.disease ,ddc ,Distress ,Oncology ,Li–Fraumeni syndrome ,030220 oncology & carcinogenesis ,Family medicine ,Population study ,Female ,Worry ,Tumor Suppressor Protein p53 ,business ,Psychosocial - Abstract
Background Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program. Methods Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12. Results Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively). Conclusions Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping.
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- 2019
42. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer
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Christoph Engel, Ellen Honisch, Walter Just, Eva Groß, Nana Weber-Lassalle, Dieter Niederacher, Juliane Ramser, Lisa Richters, Kristina Klaschik, Konrad Platzer, Peter Nürnberg, Guido Neidhardt, Clemens R. Müller, Norbert Arnold, Britta Blümcke, Christopher Schroeder, Corinna Ernst, Barbara Wappenschmidt, Andrea Gehrig, Gunnar Schmidt, Julika Borde, Bernd Auber, Holger Thiele, Janine Altmüller, Alfons Meindl, Konstantin Weber-Lassalle, Karl Hackmann, Bernd Dworniczak, Christian Kubisch, Anne-Karin Kahlert, Eric Hahnen, Kerstin Rhiem, Judit Horvath, Jan Hauke, Shan Wang-Gohrke, Alexander E Volk, and Rita K. Schmutzler
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Adult ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Breast Neoplasms ,Gene mutation ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Germline mutation ,Loss of Function Mutation ,Risk Factors ,Ovarian cancer ,Internal medicine ,Humans ,Medicine ,Missense mutation ,Genetic Predisposition to Disease ,ddc:610 ,Family history ,Germline mutations ,Genetic Association Studies ,Germ-Line Mutation ,Aged ,Ovarian Neoplasms ,business.industry ,BRIP1 ,Odds ratio ,Middle Aged ,BRIP1 gene ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Fanconi Anemia Complementation Group Proteins ,Pedigree ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,RNA Helicases ,Research Article - Abstract
Background Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. Methods To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. Results BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P
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- 2018
43. 1506MO Incorporating genetic and non-genetic risk factors in breast cancer risk prediction for healthy women with non-informative genetic test result
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Rita K. Schmutzler, Eric Hahnen, Anne Brédart, C. J. van Asperen, C. Ernst, Inge M. M. Lakeman, B. Blümcke, R. Remy, Peter Devilee, Kerstin Rhiem, J. Dick, Anja Tüchler, and Dominique Stoppa-Lyonnet
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Oncology ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,Medicine ,Hematology ,Genetic risk ,business ,medicine.disease ,Test (assessment) - Published
- 2021
44. Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC)
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Michael Untch, Claus Hanusch, Carsten Denkert, Christian Jackisch, Nicole Burchardi, Christine Solbach, Jenny Furlanetto, Peter Staib, Andreas Schneeweiss, Peter A. Fasching, Jens Uwe Blohmer, Theresa Link, Sibylle Loibl, Jens Huober, Dirk Michael Zahm, Julia Rey, Michael Braun, Kerstin Rhiem, and Jörg Thomalla
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Taxane ,Durvalumab ,Anthracycline ,business.industry ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Internal medicine ,medicine ,In patient ,business ,Triple-negative breast cancer - Abstract
506 Background: The GeparNuevo trial investigated the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor (CPI), to standard neoadjuvant chemotherapy (NACT) in patients with early TNBC. Durvalumab increased the pathological complete response (pCR) rate particularly in patients treated with durvalumab alone before start of chemotherapy (Loibl et al. Ann Oncol 2019). Methods: GeparNuevo randomized patients with cT1b-cT4a-d tumors and centrally confirmed TNBC to durvalumab (D) 1.5 g i.v. or placebo every 4 weeks. D/placebo monotherapy (0.75 g i.v.) was given for the first 2 weeks (window phase), followed by D/placebo plus nab-paclitaxel 125 mg/m² weekly for 12 weeks, followed by D/placebo plus epirubicin/cyclophosphamide (EC) q2 weeks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocytes (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). The primary objective was pCR (ypT0 ypN0). Secondary time-to-event endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Results: A total of 174 patients were enrolled between June 2016 and September 2017. The pCR rate with durvalumab was 53.4% versus placebo 44.2% (OR 1.45, 95% CI 0.80–2.63, unadjusted Wald p = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR 2.22, 95% CI 1.06–4.64, p = 0.035; interaction p = 0.048). After a median follow-up of 42.2 months, 34 events occurred in 174 patients. 3-year iDFS in pCR vs non pCR was 92.0% vs 71.9% (log-rank p = 0.002). 3-year iDFS was 84.9% with durvalumab vs 76.9% with placebo (HR 0.54, 95%CI 0.27-1.09, stratified log-rank p = 0.0559); 3-year DDFS 91.4% vs 79.5% (HR 0.37, 95%CI 0.15-0.87, p = 0.0148); 3-year OS 95.1% vs 83.1% (HR 0.26, 95%CI 0.09-0.79, p = 0.0076). No difference was seen in iDFS, DDFS and OS between the window and no window cohort. Conclusions: Durvalumab added to neoadjuvant chemotherapy in TNBC significantly improved long-term outcome despite a small pCR increase and no continuation after surgery. It needs to be questioned whether adjuvant therapy with CPI is needed at all. Clinical trial information: NCT02685059.
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- 2021
45. pCR rates in patients with bilateral breast cancer after neoadjuvant anthracycline-taxane based-chemotherapy – A retrospective pooled analysis of individual patients data of four German neoadjuvant trials
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Jens-Uwe Blohmer, Claus Hanusch, Bianca Lederer, Mattea Reinisch, Valentina Nekljudova, Jens Huober, Gunter von Minckwitz, Michael Untch, Kerstin Rhiem, Christian Jackisch, Andreas Schneeweiss, Sibylle Loibl, Carsten Denkert, and Sherko Kümmel
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Adult ,Bridged-Ring Compounds ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Anthracycline ,Axillary lymph nodes ,medicine.medical_treatment ,Medizin ,Breast Neoplasms ,Disease-Free Survival ,Neoplasms, Multiple Primary ,Lesion ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Germany ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Anthracyclines ,Prospective Studies ,Pathological ,Aged ,Retrospective Studies ,Aged, 80 and over ,Clinical Trials as Topic ,Chemotherapy ,Taxane ,business.industry ,General Medicine ,Middle Aged ,Bilateral breast cancer ,Neoadjuvant Therapy ,Tumor Burden ,Surgery ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Chemotherapy, Adjuvant ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Female ,Taxoids ,medicine.symptom ,business - Abstract
Purpose Patients with bilateral breast cancer (BBC) are usually excluded from participating in clinical trials and little is known about the response and outcome of BBC to neoadjuvant chemotherapy compared to unilateral BC (UBC). Methods We prospectively captured the information on patients with BBC in our database treated within four neoadjuvant chemotherapy trials and collected retrospectively the rate of pathological complete response (pCR) defined as ypT0 ypN0, ypT0/is ypN0, ypT0 ypNX, clinical and histologic parameters. Synchronous carcinoma in the contralateral breast was considered as the non-indicator lesion. Patients with UBC only treated within the same neoadjuvant trials performed the control group. Results From the 6727 patients treated within 4 German neoadjuvant trials 119 (1.8%) patients have been identified with the diagnosis of BBC. The pCR rate (ypT0 ypN0) was 12.6% in the non-indicator lesion group versus 10.9% the indicator lesion group versus 20.9% for patients with unilateral disease (p = 0.003). There were more advanced tumor stages and positive axillary lymph nodes in the indicator lesion than in the nonindicator lesion or in UBC. In 52.5% the molecular subtype was identical between indicator and non-indicator lesion with more triple negative and HER2 positive BC in the group of UBC. The disease free survival rate (DFS) was 25.8% for patients with UBC versus 39.6% for patients with BBC. Conclusion The selection for the indicator lesion was based on tumor size, nodal status and inclusion criteria. Patients with BBC patients had a lower pCR rate and a lower DFS.
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- 2017
46. Germline Mutations in Triple-Negative Breast Cancer
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Christoph Engel, Eric Hahnen, Jan Hauke, Kerstin Rhiem, Guido Neidhardt, and Rita K. Schmutzler
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,PALB2 ,Cancer ,Review Article ,Disease ,medicine.disease ,Germline ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Germline mutation ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cancer research ,Surgery ,skin and connective tissue diseases ,business ,Ovarian cancer ,Triple-negative breast cancer - Abstract
Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline BRCA1/2 mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased BRCA1/2 mutation probability, which is up to 40% when both risk factors are considered. Apart from BRCA1/2, the rarely mutated breast cancer predisposition genes PALB2 and FANCM have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing BRCA1/2 mutation carriers are discussed.
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- 2017
47. AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2019
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Marc Thill, Christian Jackisch, Wolfgang Janni, Volkmar Müller, Ute-Susann Albert, Ingo Bauerfeind, Jens Blohmer, Wilfried Budach, Peter Dall, Ingo Diel, Peter A. Fasching, Tanja Fehm, Michael Friedrich, Bernd Gerber, Volker Hanf, Nadia Harbeck, Jens Huober, Cornelia Kolberg-Liedtke, Hans-Heinrich Kreipe, David Krug, Thorsten Kühn, Sherko Kümmel, Sibylle Loibl, Diana Lüftner, Michael Patrick Lux, Nicolai Maass, Volker Möbus, Markus Müller-Schimpfle, Christoph Mundhenke, Ulrike Nitz, Kerstin Rhiem, Achim Rody, Marcus Schmidt, Andreas Schneeweiss, Florian Schütz, Hans-Peter Sinn, Christine Solbach, Erich-Franz Solomayer, Elmar Stickeler, Christoph Thomssen, Michael Untch, Frederik Wenz, Isabell Witzel, Achim Wöckel, and Nina Ditsch
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Oncology ,Clinical Information ,Surgery ,ddc:610 - Abstract
Every year the Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO), a group of gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiologic diagnostics, medical oncology, and radiation oncology, prepares and updates evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. Every update is performed according to a documented rule-fixed algorithm, by thoroughly reviewing and scoring the recent publications for their scientific validity and clinical relevance. This current publication presents the 2019 update on the recommendations for metastatic breast cancer.
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- 2019
48. NAB-Paclitaxel Improves Disease-Free Survival in Early Breast Cancer: GBG 69-GeparSepto
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Bahriye Aktas, Christian Schem, Jens Huober, Jenny Furlanetto, John Hackmann, Valentina Nekljudova, Hermann Wiebringhaus, Carsten Denkert, Michael Untch, Gunter von Minckwitz, Wolfgang D. Schmitt, Marianne Just, Kerstin Rhiem, Claus Hanusch, Christian Jackisch, Peter A. Fasching, Sibylle Loibl, Jens-Uwe Blohmer, Sherko Kümmel, Bernd Gerber, Andreas Schneeweiss, Mathias Warm, and Sabine Schmatloch
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Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Disease free survival ,Paclitaxel ,medicine.medical_treatment ,Breast Neoplasms ,Disease-Free Survival ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Trastuzumab ,Internal medicine ,Albumins ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Cyclophosphamide ,Nab-paclitaxel ,Early breast cancer ,Pathologic Complete Remission ,Aged ,Epirubicin ,030219 obstetrics & reproductive medicine ,business.industry ,Middle Aged ,Clinical trial ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,business ,Adjuvant ,medicine.drug - Abstract
PURPOSE The GeparSepto trial demonstrated that weekly nanoparticle albumin-bound (NAB)–paclitaxel significantly improves the pathologic complete remission rate compared with weekly solvent-based (sb) paclitaxel followed by epirubicin plus cyclophosphamide as neoadjuvant treatment in patients with primary breast cancer (BC). Here, we report data on long-term outcomes. METHODS Patients with histologically confirmed primary BC were randomly assigned in a 1:1 ratio to 12 times weekly NAB-paclitaxel 150 mg/m2 (after study amendment, 125 mg/m2) or weekly sb-paclitaxel 80 mg/m2 followed in both arms by four times epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks. Patients with human epidermal growth factor receptor 2 (HER2)-positive BC received dual antibody treatment with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) concurrently to chemotherapy and continued for 1 year. RESULTS A total of 1,206 patients started treatment, 606 with NAB-paclitaxel and 600 with sb-paclitaxel. After a median follow-up of 49.6 months (range, 0.5 to 64.0 months), 243 invasive disease–free survival (iDFS) events were reported (143 in the sb-paclitaxel and 100 in the NAB-paclitaxel arm). At 4 years, overall patients treated with NAB-paclitaxel had a significantly better iDFS compared with sb-paclitaxel (84.0% v 76.3%; hazard ratio, 0.66; 95% CI, 0.51 to 0.86; P = .002), whereas overall survival did not significantly differ between the two treatment arms (89.7% v 87.2%, respectively; hazard ratio, 0.82; 95% CI, 0.59 to 1.16; P = .260). Long-term follow-up of the treatment-related peripheral sensory neuropathy (PSN) showed a significant decrease of the median time to resolve PSN after NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2. CONCLUSION The significantly higher pathologic complete response rate with NAB-paclitaxel translated into a significantly improved iDFS in patients with early BC as compared with sb-paclitaxel. PSN improved much faster under NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2.
- Published
- 2019
49. An international survey of surveillance schemes for unaffected BRCA1 and BRCA2 mutation carriers
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Yael Laitman, Johanna Rantala, Ava Kwong, Gillian Mitchell, Alex Teulé, Nicola K. Poplawski, Angel Izquierdo, Shani Paluch-Shimon, Rita K. Schmutzler, Brita Arver, Beth Y. Karlan, Nadine Tung, Jong Won Lee, Saundra S. Buys, Anna Jakubowska, Kerstin Rhiem, Jenny Lester, Andrew K. Godwin, Banu Arun, Jan Lubinski, Nalven Tessa, Katherine L. Tucker, Mark E. Robson, Christian F. Singer, Marc Tischkowitz, Joan Brunet, Miri Sklair-Levy, Tamar Perri, Kathleen Claes, Tom Van Maerken, Eitan Friedman, Caroline Seynaeve, Sung-Won Kim, Luigina Bonelli, Anne-Marie Gerdes, Dana Madorsky-Feldman, Susan M. Domchek, Liliana Varesco, and Medical Oncology
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Adult ,Cancer Research ,medicine.medical_specialty ,Breast imaging ,Cost effectiveness ,Oncology and Carcinogenesis ,Clinical Sciences ,Breast Neoplasms ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Breast cancer ,Surveys and Questionnaires ,medicine ,Mammography ,High-risk women ,Humans ,Oncology & Carcinogenesis ,030212 general & internal medicine ,Prospective Studies ,Young adult ,Risk-reducing surgery ,skin and connective tissue diseases ,Prospective cohort study ,Gynecology ,BRCA2 Protein ,Ovarian Neoplasms ,Evidence-Based Medicine ,medicine.diagnostic_test ,Obstetrics ,business.industry ,BRCA1 Protein ,BRCA1/BRCA2 mutation carriers ,Prophylactic Mastectomy ,Early detection ,Prophylactic Surgical Procedures ,medicine.disease ,Magnetic Resonance Imaging ,Surveillance schemes ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Practice Guidelines as Topic ,Female ,business ,Ovarian cancer - Abstract
Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e-mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed.
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- 2016
50. Influence of denosumab on disseminated tumor cells (DTC) in the bone marrow of breast cancer (BC) patients with neoadjuvant treatment: A GeparX translational substudy
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Eike Simon, Christine Solbach, A Petzold, C Meisel, Petra Krabisch, Tanja Fehm, Oliver J. Stoetzer, Hans Tesch, Cristin Kühn, Sherko Kümmel, Kerstin Rhiem, Jens Uwe Blohmer, Jan Dominik Kuhlmann, Sibylle Loibl, Theresa Link, Pauline Wimberger, Valentina Nekljudova, Carsten Denkert, Bruno Valentin Sinn, and Marianne Just
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Oncology ,Cancer Research ,medicine.medical_specialty ,Prognostic factor ,business.industry ,Tumor cells ,macromolecular substances ,medicine.disease ,medicine.anatomical_structure ,Denosumab ,Breast cancer ,Neoadjuvant treatment ,Internal medicine ,medicine ,Bone marrow ,business ,medicine.drug - Abstract
580 Background: DTCs in the bone marrow are observed in up to 30% at primary diagnosis of BC and their presence is an independent prognostic factor for reduced survival. It was shown that antiresorptive therapy eradicates DTCs and improves prognosis in DTC-positive BC patients (pts). In the GeparX phase III prospective randomized trial, denosumab (a monoclonal IgG2-anti-RANKL-antibody) was investigated as add-on treatment to neoadjuvant chemotherapy (NACT) with two different nab-paclitaxel schedules in early high-risk primary BC. In a translational substudy, we analyzed for the first time the influence of short-term denosumab treatment (24 weeks) on the presence of DTCs. Methods: A total of 167 pts from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive pts were re-analyzed for DTCs after NACT±Denosumab. Results: Overall, 60/167 pts (35.9%) treated with NACT±Denosumab had a pathological complete response (pCR; 55.4% in TNBC, 43.3% in HER2+, 15.3% in HR+/HER2-). At baseline, 43/167 pts (25.7%) were DTC-positive and 41 of those were available for re-analysis of DTCs after NACT±Denosumab. DTC eradication was observed in 77.8% after NACT+Denosumab and in 69.6% after NACT alone (p = 0.726). Due to the limited number of pts eligible for DTC-re-analysis after NACT, a subtype specific analysis for the effect of denosumab was not possible. There was no significant association between pCR and i) the presence of DTCs at baseline (37.1% DTC-negative vs 32.6% positive, p = 0.71) or ii) the eradication of DTCs after NACT±Denosumab (36.7% vs 27.3%, p = 0.72). Notably, in TNBC, we observed a tendency that DTC-positivity at baseline or DTC-persistence after NACT could be associated with reduced pCR rate (40.0% in DTC-positive vs. 66.7% in DTC-negative pts, p = 0.16; 25% in DTC-persistent pts vs. 50% in DTC-eradicated pts, p = 0.59). Conclusions: Denosumab in addition to NACT does not improve pCR, but the suspected effect of denosumab on DTC eradication should be further analyzed in TNBC. Key words: GeparX trial, denosumab, disseminated tumor cells, bone marrow, neoadjuvant chemotherapy. Funding: GeparX and DTC substudy were financially supported by Amgen and Celgene. Clinical trial information: NCT02682693 .
- Published
- 2020
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