Abstract P4-01-24: Common determinants of CDK4/6 inhibitor-based therapy in metastatic HR+/HER2- breast cancer

Abstract CDK4/6 inhibitors in combination with endocrine therapy are widely used to treat HR+/HER2- metastatic breast cancer. Generally, CDK4/6 inhibitors lead to a doubling of progression-free survival compared to single agent endocrine therapy. Despite a known mechanism of action, features that define the duration of response to CDK4/6 inhibitors with either aromatase inhibitors or fulvestrant remain lacking. Over 300 patients receiving standard-of-care CDK4/6 inhibitor combination therapy for metastatic disease were enrolled in an ongoing observational study (NCT04526587) and an IRB-approved retrospective analysis. Clinical, pathological, and gene expression data were employed to define determinants for the duration of progression-free survival (PFS). Visceral disease (HR 1.55, p=0.0013), prior endocrine therapy (HR 2.34, p<0.001), and the type of endocrine therapy (HR 2.16, p<0.001) were associated with duration of progression-free survival. Multiple gene expression signatures associated with prognosis of HR+/HER2- breast cancer were evaluated for association with PFS with variable statistical significance. Random survival forest was applied to combined prognostic signatures and clinical variables to identify independent features associated PFS. The resultant final model resulted in robust association with PFS (HR: 6.9, p<e-10) using all samples, as well as selectively in a validation subset (HR: 2.2, p<e-04). This tool was effective at predicting intrinsic resistance in metastatic and neoadjuvant samples. Additionally, the mortality predicted by this model tracked with the median PFS observed in PALOMA-2/3 and PEARL studies. Interrogating significant genes across all studies indicate common enrichment of genes associated with cell cycle and estrogen receptor signaling. These findings indicate that there are common features from real-world use of CDK4/6 inhibitors and clinical studies that could be used to infer time-to progression. Citation Format: Erik Knudsen, Agnieszka K. Witkiewicz, Jianxin Wang, Emily Schultz, Thomas N. O'Connor, Ellis Levine. Common determinants of CDK4/6 inhibitor-based therapy in metastatic HR+/HER2- breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-01-24.