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 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.

High expression of STAT3 within the tumour‐associated stroma predicts poor outcome in breast cancer patients

“…In four TNBC cell lines, inhibiting STAT3 using LLY17 reduced cell migration, growth and increased susceptibility to apoptosis in vitro 29 . In ER‐positive breast cancer, there are studies looking at JAK inhibitors such as ruxolitinib to treat systemic inflammation 30 . Further research is needed to validate these findings with an approach using more recapitulative models of patient disease such as patient‐derived organoids and co‐cultures with CAFs.…”

Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics

“…However, the impact on tumor growth was minimal [138]. When inflammatory biomarkers were examined, no difference were found in the changes in IL-6 and CRP from baseline through treatment between responders and non-responders to therapy [138]. This demonstrates some of the challenges with re-capitulating preclinical study findings in human clinical trials.…”

“…Other investigators discovered associations of high serum IL-6 levels with poor response to therapy, including resistance to chemotherapy and endocrine therapy, providing the rationale for combination treatment of breast cancer therapy with Ruxolitinib [135][136][137]. Most recently, combination treatment with aromatase inhibitor in aromatase inhibitor refractory hormone receptor-positive metastatic breast cancer in 21 patients demonstrated on-target inhibition of STAT3 phosphorylation [138]. However, the impact on tumor growth was minimal [138].…”

“…Most recently, combination treatment with aromatase inhibitor in aromatase inhibitor refractory hormone receptor-positive metastatic breast cancer in 21 patients demonstrated on-target inhibition of STAT3 phosphorylation [138]. However, the impact on tumor growth was minimal [138]. When inflammatory biomarkers were examined, no difference were found in the changes in IL-6 and CRP from baseline through treatment between responders and non-responders to therapy [138].…”