Ontology highlight
ABSTRACT: 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).
SUBMITTER: Van Swearingen AED
PROVIDER: S-EPMC6779035 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
Van Swearingen Amanda E D AED Siegel Marni B MB Deal Allison M AM Sambade Maria J MJ Hoyle Alan A Hayes D Neil DN Jo Heejoon H Little Paul P Dees Elizabeth Claire EC Muss Hyman H Jolly Trevor T Zagar Timothy M TM Patel Nirali N Miller C Ryan CR Parker Joel S JS Smith J Keith JK Fisher Julie J Shah Nikita N Nabell Lisle L Nanda Rita R Dillon Patrick P Abramson Vandana V Carey Lisa A LA Anders Carey K CK
Breast cancer research and treatment 20180625 3
<h4>Purpose</h4>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.<h4>Patients and methods</h4>Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate ...[more]