Abstract PS3-08-25: Integrated Prognostic and Chemotherapy Sensitivity Assessment Using Multiple Gene Assays in ER-positive, HER2-negative Early Breast Cancer

Abstract Background: To assess recurrence risk in ER-positive, HER2-negative early breast cancer, multigene assays (MGAs) are useful in addition to clinicopathological factors. In Japan, Curebest™ 95GC was developed in 2011 and introduced clinically in 2013. Oncotype DX® was added to national health insurance in 2023. While adjuvant chemotherapy is often considered for patients classified as high-risk by any MGA, treatment decisions can be complex. Furthermore, breast cancers identified as high-risk by MGAs often exhibit higher pathological complete response (pCR) rates, suggesting increased sensitivity to chemotherapy. This study aimed to evaluate MGAs from two perspectives—prognostic prediction and NAC sensitivity—to inform individualized treatment strategies. Materials and Methods: We analyzed microarray gene expression data from public databases to identify patients with ER-positive, HER2-negative early breast cancer. In this study, Curebest™ 95GC, developed in Japan, was used post-analysis for research purposes only. Based on microarray expression data, we calculated PAM50, 21GC (Oncotype DX® surrogate analyses), EndoPredict (EP), and either 95GC or 155GC. In Study 1(n=555), we assessed the prognostic value of each MGA and evaluated recurrence risk based on the number of high-risk classifications. In study2(n=550), we evaluated the predictive value of each MGA for pCR rate and analyzed the relationship between NAC sensitivity and the combined assessment of the number of high-risk classifications treated with NAC. Results: In Study 1, all four MGAs (PAM50, 21GC, EP, and 95GC) significantly stratified DRFS between high- and low-risk groups (p =8.93e-08, 2.31e-08, 3.64e-07, and 9.25e-10), with comparable prognostic performance. Patients were grouped by the number of high-risk classifications. A 5-year DRFS of 97% was observed in patients with 0 high-risk classifications, compared to 66% in those with 4. Patients were further stratified into two groups: those with 0 or 1 high-risk classification and those with ≥2. The 0-1 group showed a 5-year DRFS of 96.7%, while the ≥2 group had a significantly worse prognosis at 79.0% (p=2.04e-11). The combined assessment provided better prognostic accuracy than any individual MGA alone. Notably, patients with only one high-risk result showed excellent outcomes, suggesting endocrine therapy alone may suffice. Conversely, those deemed low-risk by all MGAs may not require adjuvant chemotherapy.In Study 2, high-risk patients had significantly higher pCR rates across all MGAs. 155GC showed the strongest stratification (p=1.62e-08). Patients classified as high-risk by all four MGAs had significantly higher pCR rates than those with 0-3 high-risk classifications (p=9.37e-11). 95GC provides CEL files containing expression data for all 20,000 genes. This allows concurrent calculation of multiple MGAs, facilitating evaluation and reducing cost. Use of CEL files supports integrated MGA analysis, and may support precise personalized treatment. Conclusion: Combining four MGAs improves prediction over single MGAs. This integrated genomic approach offers a promising strategy to optimize individualized treatment in ER-positive, HER2-negative early breast cancer. Citation Format: M. Nishida, R. Tsunashima, N. Hirotani, S. Kitano, C. Matsui, S. Matsumoto, A. Watanabe, C. Kato, M. Morita, K. Sakaguchi, Y. Naoi. Integrated Prognostic and Chemotherapy Sensitivity Assessment Using Multiple Gene Assays in ER-positive, HER2-negative Early Breast Cancer [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 PS3-08-25.