Abstract PS1-08-18: The significance of HER2 Low status on clinical outcomes of breast cancer patients with metastatic hormone-receptor positive tumors treated in the CDK4/6 inhibitor era

Abstract Background: HER2-low (IHC 1+ or 2+/ISH-) is a relatively new sub-type in breast cancer (BC) classification, describing tumors without HER2-oncogene overexpression but rather lower levels of HER2. We describe the characteristics and clinical outcomes of patients with hormone-receptor positive (HR+) metastatic BC (mBC) with HER2-low and HER2 IHC 0 tumors, treated with CDK4/6 inhibitors (CDK4/6i) prior to inclusion of trastuzumab-deruxtecan in the national formulary, in a 2.8-million-member Health Maintenance Organization (HMO). Methods: Patients aged >=18 years who initiated endocrine treatment with-CDK4/6i combination between 1st January 2018 to 31st December 2022 for mBC were identified in this retrospective cohort study with follow up until 31st December 2023. Patients were classified into HER2 IHC 0 and HER2-low, based on deidentified data extraction. Kaplan-Meier analysis was used to describe time-on-treatment (TOT, as a surrogate for progression-free-survival) and overall survival (OS). Results: A total of 1,067 patients were identified with a median age of 63 years, 60.7% were HER2-low, 31.4% were HER2 IHC 0 and 7.9% with missing data A total of 705 patients received first-line CDK4/6i with an aromatase inhibitor (AI) and 362 received CDK4/6i with fulvestrant (F). Median follow-up periods were 27.6 months and 23.0 months, respectively. For the group of patients receiving first-line CDK4/6i & AI, median TOT was 27.0 (95%CI: 23.5-34.4) and 22.6 (95%CI: 17.5,32.7) months for patients with HER2-low and HER2 IHC 0 respectively, and median OS was 67.0 (95%CI: 58.0, NR) months and 52.4 (95%CI: 47.4, NR) months, respectively (P=0.056). For the group of patients receiving CDK4/6i & F, median TOT was 11.6 months (95%CI: 10.0, 14.1), and median OS was 36.4 months (95%CI: 31.1, 40.3), and did not differ between groups. For all patients, a total of 523 patients (49%) received at least one subsequent line after CDK4/6i initial treatment and 346 (32.4%) continued to a further line, with TOT around 4 months. Conclusion: This study shows that HR+/HER2- metastatic breast cancer is a mixed population of IHC scores, with 60-65% of cases being HER2-low. The limited real-world TOT duration at post-CDK4/6i progression highlights a critical unmet need for new and more efficacious treatments for patients progressing on this modern endocrine-biologic regimen. In this real-world analysis, first-line CDK4/6i & AI treatment showed numerically higher OS by 14.6 months in HER2-low patients compared to HER2 IHC 0 tumors whereas in patients who received CDK4/6i&F at more advanced setting of their metastatic disease, OS did not differ by HER2 status. Those results stand in line with recent retrospective analysis of PALOMA-2 and PALOMA-3 trials, where HER2-low patients showed higher benefit from CDK4/6i in the 1st line setting compared with HER2 IHC 0, whereas in later treatment-lines adding CDK4/6i to endocrine therapy benefited all patients similarly. Additional studies are encouraged to support this retrospective observation. Citation Format: S. Sharman Moser, B. Horowitz, R. Ginsburg, G. Luria, I. Livnat, M. Hoshen, S. Gazit, N. Siegelmann-Danieli. The significance of HER2 Low status on clinical outcomes of breast cancer patients with metastatic hormone-receptor positive tumors treated in the CDK4/6 inhibitor era [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-18.