Khandan Keyomarsi: Hydroxychloroquine to Enhance Palbociclib and Letrozole Efficacy in ER+/HER2 – Metastatic Breast Cancer
Khandan Keyomarsi, Professor in the Department of Experimental Radiation Oncology in the Division of Radiation Oncology at The University of Texas MD Anderson Cancer Center, recently shared an article she and her colleagues authored on LinkedIn:
“We are thrilled to announce the publication of our bench-to-clinic translational study, entitled “Phase I Trial of Hydroxychloroquine to Enhance Palbociclib and Letrozole Efficacy in ER+/HER2− Metastatic Breast Cancer,” in NPJ Breast Cancer. This work bridges preclinical discoveries with clinical application, exploring the integration of hydroxychloroquine (HCQ) with continuous low-dose palbociclib and letrozole to address resistance mechanisms in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2− MBC).
Building on our preclinical findings that low-dose palbociclib activates protective autophagy while HCQ inhibits this pathway to enhance therapeutic outcomes, we conducted this Phase I trial (NCT03774472) to evaluate safety, tolerability, and preliminary efficacy.
The trial enrolled 14 patients and established the recommended Phase II dose (RP2D) as HCQ 800 mg/day in combination with continuous palbociclib (75 mg/day) and letrozole (2.5 mg/day). The regimen demonstrated an excellent safety profile with no dose-limiting toxicities and manageable adverse events. Clinically, two patients achieved partial responses, and 11 of 12 evaluable participants experienced stable disease. Biomarker analyses revealed reductions in Ki67 and Rb levels, alongside increases in autophagy markers (p62, LAMP1), highlighting the mechanistic underpinnings of this therapeutic combination.
These findings underscore the potential of autophagy inhibition to enhance CDK4/6 inhibitor efficacy, paving the way for innovative treatment strategies. We are excited to advance to a Phase II trial, aiming to confirm these results and further refine biomarker-driven patient selection, with the potential to transform the management of HR+/HER2− MBC.”
Authors: Akshara Singareeka Raghavendra et al.
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