PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS:MK-2206graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
RCT Entities:
PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by humanepidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS:MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
Authors: Hope S Rugo; Olufunmilayo I Olopade; Angela DeMichele; Christina Yau; Laura J van 't Veer; Meredith B Buxton; Michael Hogarth; Nola M Hylton; Melissa Paoloni; Jane Perlmutter; W Fraser Symmans; Douglas Yee; A Jo Chien; Anne M Wallace; Henry G Kaplan; Judy C Boughey; Tufia C Haddad; Kathy S Albain; Minetta C Liu; Claudine Isaacs; Qamar J Khan; Julie E Lang; Rebecca K Viscusi; Lajos Pusztai; Stacy L Moulder; Stephen Y Chui; Kathleen A Kemmer; Anthony D Elias; Kirsten K Edmiston; David M Euhus; Barbara B Haley; Rita Nanda; Donald W Northfelt; Debasish Tripathy; William C Wood; Cheryl Ewing; Richard Schwab; Julia Lyandres; Sarah E Davis; Gillian L Hirst; Ashish Sanil; Donald A Berry; Laura J Esserman Journal: N Engl J Med Date: 2016-07-07 Impact factor: 91.245
Authors: José Baselga; Javier Cortés; Seock-Ah Im; Emma Clark; Graham Ross; Astrid Kiermaier; Sandra M Swain Journal: J Clin Oncol Date: 2014-10-20 Impact factor: 44.544
Authors: Fatima Cardoso; Laura J van't Veer; Jan Bogaerts; Leen Slaets; Giuseppe Viale; Suzette Delaloge; Jean-Yves Pierga; Etienne Brain; Sylvain Causeret; Mauro DeLorenzi; Annuska M Glas; Vassilis Golfinopoulos; Theodora Goulioti; Susan Knox; Erika Matos; Bart Meulemans; Peter A Neijenhuis; Ulrike Nitz; Rodolfo Passalacqua; Peter Ravdin; Isabel T Rubio; Mahasti Saghatchian; Tineke J Smilde; Christos Sotiriou; Lisette Stork; Carolyn Straehle; Geraldine Thomas; Alastair M Thompson; Jacobus M van der Hoeven; Peter Vuylsteke; René Bernards; Konstantinos Tryfonidis; Emiel Rutgers; Martine Piccart Journal: N Engl J Med Date: 2016-08-25 Impact factor: 91.245
Authors: Gunter von Minckwitz; Marion Procter; Evandro de Azambuja; Dimitrios Zardavas; Mark Benyunes; Giuseppe Viale; Thomas Suter; Amal Arahmani; Nathalie Rouchet; Emma Clark; Adam Knott; Istvan Lang; Christelle Levy; Denise A Yardley; Jose Bines; Richard D Gelber; Martine Piccart; Jose Baselga Journal: N Engl J Med Date: 2017-06-05 Impact factor: 91.245
Authors: W Fraser Symmans; Florentia Peintinger; Christos Hatzis; Radhika Rajan; Henry Kuerer; Vicente Valero; Lina Assad; Anna Poniecka; Bryan Hennessy; Marjorie Green; Aman U Buzdar; S Eva Singletary; Gabriel N Hortobagyi; Lajos Pusztai Journal: J Clin Oncol Date: 2007-09-04 Impact factor: 44.544
Authors: Cynthia X Ma; Vera Suman; Matthew P Goetz; Donald Northfelt; Mark E Burkard; Foluso Ademuyiwa; Michael Naughton; Julie Margenthaler; Rebecca Aft; Richard Gray; Amye Tevaarwerk; Lee Wilke; Tufia Haddad; Timothy Moynihan; Charles Loprinzi; Tina Hieken; Erica K Barnell; Zachary L Skidmore; Yan-Yang Feng; Kilannin Krysiak; Jeremy Hoog; Zhanfang Guo; Leslie Nehring; Kari B Wisinski; Elaine Mardis; Ian S Hagemann; Kiran Vij; Souzan Sanati; Hussam Al-Kateb; Obi L Griffith; Malachi Griffith; Laurence Doyle; Charles Erlichman; Matthew J Ellis Journal: Clin Cancer Res Date: 2017-09-05 Impact factor: 13.801
Authors: Gunter von Minckwitz; Chiun-Sheng Huang; Max S Mano; Sibylle Loibl; Eleftherios P Mamounas; Michael Untch; Norman Wolmark; Priya Rastogi; Andreas Schneeweiss; Andres Redondo; Hans H Fischer; William Jacot; Alison K Conlin; Claudia Arce-Salinas; Irene L Wapnir; Christian Jackisch; Michael P DiGiovanna; Peter A Fasching; John P Crown; Pia Wülfing; Zhimin Shao; Elena Rota Caremoli; Haiyan Wu; Lisa H Lam; David Tesarowski; Melanie Smitt; Hannah Douthwaite; Stina M Singel; Charles E Geyer Journal: N Engl J Med Date: 2018-12-05 Impact factor: 176.079
Authors: Clifford Hudis; Charles Swanton; Yelena Y Janjigian; Ray Lee; Stephanie Sutherland; Robert Lehman; Sarat Chandarlapaty; Nicola Hamilton; Devika Gajria; James Knowles; Jigna Shah; Keith Shannon; Ernestina Tetteh; Daniel M Sullivan; Carolina Moreno; Li Yan; Hyo Sook Han Journal: Breast Cancer Res Date: 2013-11-19 Impact factor: 6.466
Authors: Daphne Gschwantler-Kaulich; Yen Y Tan; Eva-Maria Fuchs; Gernot Hudelist; Wolfgang J Köstler; Angelika Reiner; Carmen Leser; Mohamed Salama; Johannes Attems; Christine Deutschmann; Christoph C Zielinski; Christian F Singer Journal: PLoS One Date: 2017-03-02 Impact factor: 3.240
Authors: Douglas Yee; Angela M DeMichele; Christina Yau; Claudine Isaacs; W Fraser Symmans; Kathy S Albain; Yunn-Yi Chen; Gregor Krings; Shi Wei; Shuko Harada; Brian Datnow; Oluwole Fadare; Molly Klein; Stefan Pambuccian; Beiyun Chen; Kathi Adamson; Sharon Sams; Paulette Mhawech-Fauceglia; Anthony Magliocco; Mike Feldman; Mara Rendi; Husain Sattar; Jay Zeck; Idris T Ocal; Ossama Tawfik; Lauren Grasso LeBeau; Sunati Sahoo; Tuyethoa Vinh; A Jo Chien; Andres Forero-Torres; Erica Stringer-Reasor; Anne M Wallace; Lajos Pusztai; Judy C Boughey; Erin D Ellis; Anthony D Elias; Janice Lu; Julie E Lang; Hyo S Han; Amy S Clark; Rita Nanda; Donald W Northfelt; Qamar J Khan; Rebecca K Viscusi; David M Euhus; Kirsten K Edmiston; Stephen Y Chui; Kathleen Kemmer; John W Park; Minetta C Liu; Olufunmilayo Olopade; Brian Leyland-Jones; Debasish Tripathy; Stacy L Moulder; Hope S Rugo; Richard Schwab; Shelly Lo; Teresa Helsten; Heather Beckwith; Patricia Haugen; Nola M Hylton; Laura J Van't Veer; Jane Perlmutter; Michelle E Melisko; Amy Wilson; Garry Peterson; Adam L Asare; Meredith B Buxton; Melissa Paoloni; Julia L Clennell; Gillian L Hirst; Ruby Singhrao; Katherine Steeg; Jeffrey B Matthews; Smita M Asare; Ashish Sanil; Scott M Berry; Laura J Esserman; Donald A Berry Journal: JAMA Oncol Date: 2020-09-01 Impact factor: 31.777
Authors: Denise M Wolf; Christina Yau; Julia Wulfkuhle; Lamorna Brown-Swigart; Rosa I Gallagher; Pei Rong Evelyn Lee; Zelos Zhu; Mark J Magbanua; Rosalyn Sayaman; Nicholas O'Grady; Amrita Basu; Amy Delson; Jean Philippe Coppé; Ruixiao Lu; Jerome Braun; Smita M Asare; Laura Sit; Jeffrey B Matthews; Jane Perlmutter; Nola Hylton; Minetta C Liu; Paula Pohlmann; W Fraser Symmans; Hope S Rugo; Claudine Isaacs; Angela M DeMichele; Douglas Yee; Donald A Berry; Lajos Pusztai; Emanuel F Petricoin; Gillian L Hirst; Laura J Esserman; Laura J van 't Veer Journal: Cancer Cell Date: 2022-05-26 Impact factor: 38.585
Authors: Chengyue Wu; Guillermo Lorenzo; David A Hormuth; Ernesto A B F Lima; Kalina P Slavkova; Julie C DiCarlo; John Virostko; Caleb M Phillips; Debra Patt; Caroline Chung; Thomas E Yankeelov Journal: Biophys Rev (Melville) Date: 2022-05-17
Authors: Minkyu Kim; Jisoo Park; Mehdi Bouhaddou; Kyumin Kim; Ajda Rojc; Maya Modak; Margaret Soucheray; Michael J McGregor; Patrick O'Leary; Denise Wolf; Erica Stevenson; Tzeh Keong Foo; Dominique Mitchell; Kari A Herrington; Denise P Muñoz; Beril Tutuncuoglu; Kuei-Ho Chen; Fan Zheng; Jason F Kreisberg; Morgan E Diolaiti; John D Gordan; Jean-Philippe Coppé; Danielle L Swaney; Bing Xia; Laura van 't Veer; Alan Ashworth; Trey Ideker; Nevan J Krogan Journal: Science Date: 2021-10-01 Impact factor: 63.714
Authors: Denise M Wolf; Christina Yau; Julia Wulfkuhle; Lamorna Brown-Swigart; Rosa I Gallagher; Mark Jesus M Magbanua; Nick O'Grady; Gillian Hirst; Smita Asare; Debu Tripathy; Don Berry; Laura Esserman; A Jo Chien; Emanuel F Petricoin; Laura van 't Veer Journal: NPJ Breast Cancer Date: 2020-10-02