PURPOSE: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. PATIENTS AND METHODS: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. CONCLUSION: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. CLINICAL TRIAL: (NCT01305941).
PURPOSE:HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. PATIENTS AND METHODS: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. CONCLUSION: While intracranial RR to ETV was low in HER2 + BCBMpatients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. CLINICAL TRIAL: (NCT01305941).
Entities:
Keywords:
Brain metastases; Breast cancer; Metastases; PI3K, MEK; Targeted therapy
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Priscilla K Brastianos; Scott L Carter; Gad Getz; William C Hahn; Sandro Santagata; Daniel P Cahill; Amaro Taylor-Weiner; Robert T Jones; Eliezer M Van Allen; Michael S Lawrence; Peleg M Horowitz; Kristian Cibulskis; Keith L Ligon; Josep Tabernero; Joan Seoane; Elena Martinez-Saez; William T Curry; Ian F Dunn; Sun Ha Paek; Sung-Hye Park; Aaron McKenna; Aaron Chevalier; Mara Rosenberg; Frederick G Barker; Corey M Gill; Paul Van Hummelen; Aaron R Thorner; Bruce E Johnson; Mai P Hoang; Toni K Choueiri; Sabina Signoretti; Carrie Sougnez; Michael S Rabin; Nancy U Lin; Eric P Winer; Anat Stemmer-Rachamimov; Matthew Meyerson; Levi Garraway; Stacey Gabriel; Eric S Lander; Rameen Beroukhim; Tracy T Batchelor; Jose Baselga; David N Louis Journal: Cancer Discov Date: 2015-09-26 Impact factor: 39.397
Authors: Anna Brunn; Manuel Montesinos-Rongen; Andreas Strack; Guido Reifenberger; Christian Mawrin; Carlo Schaller; Martina Deckert Journal: Acta Neuropathol Date: 2007-07-20 Impact factor: 17.088
Authors: Rebekah Baskin; Nicholas T Woods; Gustavo Mendoza-Fandiño; Peter Forsyth; Kathleen M Egan; Alvaro N A Monteiro Journal: Sci Rep Date: 2015-11-27 Impact factor: 4.379
Authors: Michelle E Melisko; Michael Assefa; Jimmy Hwang; Amy DeLuca; John W Park; Hope S Rugo Journal: Breast Cancer Res Treat Date: 2019-06-06 Impact factor: 4.872
Authors: Brunilde Gril; Debbie Wei; Alexandra S Zimmer; Christina Robinson; Imran Khan; Simone Difilippantonio; Michael G Overstreet; Patricia S Steeg Journal: Neuro Oncol Date: 2020-11-26 Impact factor: 12.300
Authors: Franziska M Ippen; Christopher A Alvarez-Breckenridge; Benjamin M Kuter; Alexandria L Fink; Ivanna V Bihun; Matthew Lastrapes; Tristan Penson; Stephen P Schmidt; Gregory R Wojtkiewicz; Jianfang Ning; Megha Subramanian; Anita Giobbie-Hurder; Maria Martinez-Lage; Scott L Carter; Daniel P Cahill; Hiroaki Wakimoto; Priscilla K Brastianos Journal: Clin Cancer Res Date: 2019-02-22 Impact factor: 12.531
Authors: Daisuke Yamashita; Mutsuko Minata; Ahmed N Ibrahim; Shinobu Yamaguchi; Vito Coviello; Joshua D Bernstock; Shuko Harada; Richard A Cerione; Bakhos A Tannous; Concettina La Motta; Ichiro Nakano Journal: Mol Cancer Ther Date: 2020-03-03 Impact factor: 6.261
Authors: Jawad Fares; Deepak Kanojia; Alex Cordero; Aida Rashidi; Jason Miska; Charles W Schwartz; Solomiia Savchuk; Atique U Ahmed; Irina V Balyasnikova; Massimo Cristofanilli; William J Gradishar; Maciej S Lesniak Journal: Neurooncol Pract Date: 2019-02-11