Hidaka Kaori, Goto-Yamaguchi Lisa, Sueta Aiko, Tomiguchi Mai, Yamamoto Yutaka
Department of Thoracic Surgery and Breast Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Breast and Endocrine Surgery, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan.
Breast Cancer Res Treat. 2025 Jun;211(3):717-725. doi: 10.1007/s10549-025-07693-8. Epub 2025 Apr 9.
Estrogen receptor (ER)-positive breast cancer is the most common subtype, accounting for approximately 80% of cases, with endocrine therapy as the standard postoperative treatment. However, despite risk-reducing therapies, the risk of recurrence remains substantial. Studies, including the POETIC trial, have demonstrated that low Ki67 levels following short-term neoadjuvant endocrine therapy (sNAET) are associated with a favorable prognosis. The objective of this study is to identify genes associated with the suppression of cell cycle progression by sNAET in postmenopausal patients with ER-positive/human epidermal growth factor receptor 2-negative breast cancer.
Ninety-seven tissue samples were collected and classified into groups based on Ki67 expression levels before and after treatment. RNA sequencing and real-time quantitative reverse transcription PCR were performed to analyze gene expression in tumor samples from patients stratified into High-High (H-H) or High-Low (H-L) groups based on Ki67 levels before and after sNAET.
Among the differentially expressed genes identified, CXCL9 and ABCA12 were significantly upregulated in the H-H group and were associated with a poor response to endocrine therapy. Conversely, NPY1R was significantly upregulated in the H-L group, suggesting greater responsiveness. In multivariate logistic regression analysis, CXCL9 (OR: 0.65, p = 0.024) and NPY1R (OR: 1.61, p = 0.048) were significant predictors of Ki67 reduction.
These findings suggest that CXCL9 and NPY1R could serve as predictive biomarkers for endocrine therapy response. Identifying these biomarkers may facilitate personalized treatment strategies, including the addition of therapies such as chemotherapy for resistant cases.
雌激素受体（ER）阳性乳腺癌是最常见的亚型，约占病例的80%，内分泌治疗是标准的术后治疗方法。然而，尽管有降低风险的治疗方法，复发风险仍然很大。包括POETIC试验在内的研究表明，短期新辅助内分泌治疗（sNAET）后Ki67水平低与预后良好相关。本研究的目的是确定在绝经后ER阳性/人表皮生长因子受体2阴性乳腺癌患者中，与sNAET抑制细胞周期进程相关的基因。
收集97份组织样本，并根据治疗前后的Ki67表达水平进行分组。对根据sNAET前后的Ki67水平分层为高-高（H-H）或高-低（H-L）组的患者的肿瘤样本进行RNA测序和实时定量逆转录PCR，以分析基因表达。
在鉴定出的差异表达基因中，CXCL9和ABCA12在H-H组中显著上调，并与内分泌治疗反应不佳相关。相反，NPY1R在H-L组中显著上调，表明反应性更强。在多因素逻辑回归分析中，CXCL9（比值比：0.65，p = 0.024）和NPY1R（比值比：1.61，p = 0.048）是Ki67降低的显著预测因子。
这些发现表明，CXCL9和NPY1R可作为内分泌治疗反应的预测生物标志物。识别这些生物标志物可能有助于制定个性化治疗策略，包括为耐药病例增加化疗等治疗方法。
