Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer
| Autor: | Justin M. Balko, Qiong Xu, Carlos R. Gil Del Alcazar, Yu Wang, Aditya Bardia, Vivian W. Wang, Rebecca Gelman, Hao Guo, Daniel G. Stover, Beth Overmoyer, Yaomin Xu, Maxwell R. Lloyd, Nan Lin, Eric P. Winer, Franziska Michor, Sara M. Tolaney, Kornelia Polyak, Jane E. Brock |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Ruxolitinib Phases of clinical research Inflammatory breast cancer lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine Breast cancer Internal medicine medicine Clinical endpoint Pharmacology (medical) Radiology Nuclear Medicine and imaging Triple-negative breast cancer business.industry Cancer medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Metastatic breast cancer 030104 developmental biology 030220 oncology & carcinogenesis business medicine.drug |
| Zdroj: | npj Breast Cancer, Vol 4, Iss 1, Pp 1-9 (2018) NPJ Breast Cancer |
| ISSN: | 2374-4677 |
| Popis: | Preclinical data support a role for the IL-6/JAK2/STAT3 signaling pathway in breast cancer. Ruxolitinib is an orally bioavailable receptor tyrosine inhibitor targeting JAK1 and JAK2. We evaluated the safety and efficacy of ruxolitinib in patients with metastatic breast cancer. This was a non-randomized phase II study enrolling patients with refractory, metastatic triple-negative breast cancer. The primary endpoint was objective response by RECIST 1.1. The study was designed to enroll patients whose archival tumor tissue was pSTAT3-positive (T-score >5) by central immunohistochemistry. pSTAT3 staining was available from 171 of 217 consented patients and pSTAT3 T-score was positive in 67/171 (39.2%) tumors, suggesting that JAK–STAT activation is frequent. Twenty-three patients including one patient with inflammatory breast cancer were enrolled. Ruxolitinib was well-tolerated with infrequent grade 3 or higher toxicities with fatigue as the most common toxicity. Among 21 patients who received at least one dose of protocol therapy, no objective responses were observed and the study was closed to further accrual. Pharmacodynamic analyses of baseline vs. cycle 2 biopsies suggest on-target activity, including a significant decrease in the proportion of pSTAT3+ cells in three patients with paired biopsies and downregulation of JAK–STAT target genes and signatures via transcriptional analyses of 11 total baseline and four metastatic biopsies. Immuno-FISH analyses demonstrate intratumoral heterogeneity of pSTAT3 and JAK2 amplification. Ruxolitinib, as a single agent, did not meet the primary efficacy endpoint in this refractory patient population despite evidence of on-target activity. Clinical trial: JAK inhibitor not effective for triple-negative breast cancer A drug that blocks the Janus tyrosine kinase (JAK) pathway offered no clinical benefit to women with triple-negative breast cancer. Ruxolitinib is an inhibitor of JAK1 and JAK2 that is approved to treat certain rare cancers of the blood and bone marrow, and there’s a good scientific evidence to think it might have anti-tumor effects against breast cancer as well. So a team led by N.U.L. from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, conducted a small phase II trial to evaluate ruxolitinib in women with refractory, metastatic, triple-negative disease whose tumors tested positive for high expression of pSTAT3, a protein in the same signaling pathway as JAK. Yet, despite the fact that pSTAT3 levels went down among the 21 women who received the drug, not a single one responded to the therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|