Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer
Abstract Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective i...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-11-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-022-00487-x |
| _version_ | 1827616635737866240 |
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| author | Igor Makhlin Nicholas P. McAndrew E. Paul Wileyto Amy S. Clark Robin Holmes Lisa N. Bottalico Clementina Mesaros Ian A. Blair Grace R. Jeschke Kevin R. Fox Susan M. Domchek Jennifer M. Matro Angela R. Bradbury Michael D. Feldman Elizabeth O. Hexner Jacqueline F. Bromberg Angela DeMichele |
| author_facet | Igor Makhlin Nicholas P. McAndrew E. Paul Wileyto Amy S. Clark Robin Holmes Lisa N. Bottalico Clementina Mesaros Ian A. Blair Grace R. Jeschke Kevin R. Fox Susan M. Domchek Jennifer M. Matro Angela R. Bradbury Michael D. Feldman Elizabeth O. Hexner Jacqueline F. Bromberg Angela DeMichele |
| author_sort | Igor Makhlin |
| collection | DOAJ |
| description | Abstract Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4–45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6–3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC. |
| first_indexed | 2024-03-09T09:30:04Z |
| format | Article |
| id | doaj.art-735547286a764f31ad3de14024a4e997 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-09T09:30:04Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-735547286a764f31ad3de14024a4e9972023-12-02T04:05:21ZengNature Portfolionpj Breast Cancer2374-46772022-11-01811910.1038/s41523-022-00487-xRuxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancerIgor Makhlin0Nicholas P. McAndrew1E. Paul Wileyto2Amy S. Clark3Robin Holmes4Lisa N. Bottalico5Clementina Mesaros6Ian A. Blair7Grace R. Jeschke8Kevin R. Fox9Susan M. Domchek10Jennifer M. Matro11Angela R. Bradbury12Michael D. Feldman13Elizabeth O. Hexner14Jacqueline F. Bromberg15Angela DeMichele16Division of Hematology/Oncology, University of Pennsylvania, Perelman School of MedicineDivision of Hematology/Oncology, UCLA David Geffen School of MedicineCenter for Clinical Epidemiology and Biostatistics, University of PennsylvaniaDivision of Hematology/Oncology, University of Pennsylvania, Perelman School of MedicineUniversity of Pennsylvania, Abramson Cancer CenterDepartment of Systems Pharmacology and Translational Therapeutics, University of PennsylvaniaCenter for Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of PennsylvaniaDepartment of Systems Pharmacology and Translational Therapeutics, University of PennsylvaniaGeorgetown UniversityDivision of Hematology/Oncology, University of Pennsylvania, Perelman School of MedicineDivision of Hematology/Oncology, University of Pennsylvania, Perelman School of MedicineDivision of Hematology/Oncology, UC San DiegoDivision of Hematology/Oncology, University of Pennsylvania, Perelman School of MedicineDepartment of Pathology, Perelman School of Medicine, University of PennsylvaniaDivision of Hematology/Oncology, University of Pennsylvania, Perelman School of MedicineMemorial Sloan Kettering Cancer CenterDivision of Hematology/Oncology, University of Pennsylvania, Perelman School of MedicineAbstract Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4–45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6–3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.https://doi.org/10.1038/s41523-022-00487-x |
| spellingShingle | Igor Makhlin Nicholas P. McAndrew E. Paul Wileyto Amy S. Clark Robin Holmes Lisa N. Bottalico Clementina Mesaros Ian A. Blair Grace R. Jeschke Kevin R. Fox Susan M. Domchek Jennifer M. Matro Angela R. Bradbury Michael D. Feldman Elizabeth O. Hexner Jacqueline F. Bromberg Angela DeMichele Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer npj Breast Cancer |
| title | Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer |
| title_full | Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer |
| title_fullStr | Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer |
| title_full_unstemmed | Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer |
| title_short | Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer |
| title_sort | ruxolitinib and exemestane for estrogen receptor positive aromatase inhibitor resistant advanced breast cancer |
| url | https://doi.org/10.1038/s41523-022-00487-x |
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