Abstract 5333: CDK4/6 inhibitors in patients with bone-only metastatic breast cancer, the role of immune microenvironment
Authors: Mahta Mardani, Suleyman Noordeen, Katherine Clifton, Cynthia Ma, Jingyu Xiang, Jingqin Luo, Takayuki Kobayashi, Jing Xi, Nusayba Bagegni, Foluso Ademuyiwa, Rama Suresh, Ashley Frith, Andrew A. Davis, Ron Bose, Lindsay Peterson, Shana Thomas, Yu Tao, Kaylee O’Donnell, Netra Navadkar, Kristin Kwakwa, Will Mattock, Thomas Walsh, Yalin Xu, Deborah J. Veis, Xinming Su, Katherine Weilbaecher
Journal: Cancer Research (2025)

Abstract Background: CDK4/6 inhibitors (CDK4/6i) have revolutionized HR+ metastatic breast cancer treatment. Trials like PALOMA, MONALEESA, and MONARCH showed improved progression-free survival (PFS) with endocrine therapy (ET), establishing it as first-line treatment. Bone metastases are common in HR+ breast cancer, with 40% of patients having bone-only disease (BoD), which has a distinct course and better prognosis. However, CDK4/6i trials showed less significant PFS benefits in BoD subgroups. This study explores BoD survival outcomes and CDK4/6i efficacy. Methods: Patients with HR+, HER2- metastatic breast cancer from a retrospective study at Washington University School of Medicine were included. All the patients received CDK4/6i in the first- or second-line settings from June 2014 to March 2020. Outcomes were collected through June 2023. The Kaplan-Meier with log-rank test and multivariable Cox model were used for survival analysis. We used murine triple negative 4T1 and ER+ luminal B PyMT Bo1 breast tumor cell line-derived models in immunocompetent mice. Results: We included 167 female patients (131 first, 36 second line) treated with palbociclib plus ET for at least two months. Median age was 62 years (28-87), and 70 (41%) were in the BoD group. Median PFS was significantly shorter in the BoD group compared to the BV (Visceral +/- Bone) group (16.8 vs. 25 months, p=0.04). Multivariate analysis, adjusted for age and race, showed BoD had an HR of 1.65 (95% CI: 1.05-2.68) for PFS.The results of preclinical models showed that single-agent ribociclib decreased the primary mammary gland tumor burden. This effect was abolished when CD8+ T-cells were depleted. However, in the bone colonization model, ribociclib had a nonsignificant effect on bone tumor burden despite decreases in tumoral Ki-67. Arg1+ immune suppressive macrophages were significantly decreased in primary tumors but not in bone tumors after ribociclib administration, suggesting a relative treatment resistance and immune suppression in the bone tumors. Next, we analyzed baseline bone biopsies from 44 patients, categorized as responders (PFS &amp;gt;1 year) or non-responders (PFS &amp;lt;6 months). Ki67 expression was not different between groups but was decreased in 4 patients with paired pre-and post-treatment biopsies. Using Hyperion imaging mass cytometry, we profiled a patient’s bone tumor before and after Palbociclib; we found increased PD-L1, CD8+ T-cells, and CD206+ myeloid cells post-treatment. Immune profiling for all 44 patients is ongoing, with future efforts to understand different immune cell populations’ role in CDK4/6i response and identify targets to enhance their effects in bone metastases. Conclusion: Our retrospective study and preclinical data suggest CDK4/6i may be less effective in the bone microenvironment, underscoring the need for research into the role of the bone tumor immune microenvironment in treatment response. Citation Format: Mahta Mardani, Suleyman Noordeen, Katherine Clifton, Cynthia Ma, Jingyu Xiang, Jingqin Luo, Takayuki Kobayashi, Jing Xi, Nusayba Bagegni, Foluso Ademuyiwa, Rama Suresh, Ashley Frith, Andrew A. Davis, Ron Bose, Lindsay Peterson, Shana Thomas, Yu Tao, Kaylee O’Donnell, Netra Navadkar, Kristin Kwakwa, Will Mattock, Thomas Walsh, Yalin Xu, Deborah J. Veis, Xinming Su, Katherine Weilbaecher. CDK4/6 inhibitors in patients with bone-only metastatic breast cancer, the role of immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5333.