Abstract 5341: Duration of CDK4/6 inhibitor (CDKi) treatment in metastatic HR+ HER2- breast cancer (mHRBC) is associated with changes in AKT pathway protein expression

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Abstract Background: First-line CDKi and endocrine therapy has improved survival for patients with mHRBC. Upon CDKi progression, the optimal treatment strategy for mHRBC without a targetable mutation in PIK3CA, AKT, PTEN or ESR1 is unclear. The CAPItello-291 trial showed that targeting the PIK3CA pathway after CDKi improved progression-free survival, including mHRBC without identifiable genomic alterations in PIK3CA, AKT or PTEN. Protein expression analysis may identify whether signaling pathways such as PIK3CA/AKT are upregulated after CDKi and proffer rational targets even without genomic alterations. We used digital spatial profiling (DSP) to perform protein expression analysis of oncogenic pathways on mHRBC samples collected from patients before and after CDKi treatment. Methods: Patients with mHRBC treated with a CDKi between 2015 and 2022 with available archival tissue were included in this study. Samples were obtained <2.5 years prior to CDKi start and <1 year after CDKi discontinuation. The sample cohort included 6 paired biopsies, which enable direct assessment of CDKi changes. A single FFPE slide per sample was stained with an 82-protein cocktail of antibodies conjugated to UV-photocleavable DNA barcodes and analyzed using the NanoString GeoMx platform. For each sample, three 660-micron regions of interest (ROI) were selected to maximize tumor cell content and avoid necrosis or sectioning artifacts. Protein expression data was normalized by geometric mean, ROI expression was averaged per patient, and means comparisons were made between groups. This study was approved by the OHSU Institutional Review Board Results: Thirty-five samples from 29 patients were analyzed (23 pre-CDKi, 12 post-CDKi). AKT and INPP4B expression was greater post-CDKi in patients treated for >6 months compared to those treated for ≤6 months (AKT, >6 months: 2254, ≤6 months: 1194, p = 0.032; INPP4B, >6 months: 1135, ≤6 months: 390, p=0.032). BCL-2 expression was greater and Ki-67 expression was lower post-CDKi in patients treated for >6 months compared to those treated ≤ 6 months (BCL-2, >6 months: 1547, ≤6 months: 563, p=0.016; Ki-67, >6 months: 421, ≤ 6 months 1807, p=0.016). Conclusion: Patients treated with CDKi for longer durations had increased expression of PIK3CA/AKT pathway proteins; suggesting that the pathway could become upregulated during CDKi treatment. Higher BCL-2 expression is associated with reduced apoptosis, and lower Ki-67 expression is associated with slower proliferation rates. Whether these observations are a result of CDKi treatment or are related to indolent tumor behavior merits further study. Future studies will evaluate RNA sequencing and multiplex immunohistochemistry of immune microenvironment on samples from the same cohort to more deeply characterize the effects of CDKi on mHRBC tumors. Citation Format: Brie Chun, Allison Creason, Shaun M. Goodyear, Laura Heiser, Zahi Mitri. Duration of CDK4/6 inhibitor (CDKi) treatment in metastatic HR+ HER2- breast cancer (mHRBC) is associated with changes in AKT pathway protein expression [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 5341.

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