Bi Zhao, Zhang Yue, Song Xian-Rang, Zheng Wen-Hao, Chen Peng, Qiu Peng-Fei, Liu Yan-Bing, Lu Yong-Jin, Song Xing-Guo, Wang Yong-Sheng
Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.
Shanghai Pudong New Area Center for Disease Control and Prevention, Shanghai, People's Republic of China.
Int J Surg. 2025 May 1;111(5):3677-3684. doi: 10.1097/JS9.0000000000002349.
A nomogram to predict shrinkage modes after neoadjuvant therapy (NAT) was constructed in HER-2 positive (HER2+) breast cancer. The value and mechanism of targeting long noncoding RNA (lncRNA) as efficacy prediction biomarker was also evaluated.
All enrolled patients received six cycles of chemotherapy (Docetaxel + Carboplatin) and anti-HER-2 dual-targeted therapy (Trastuzumab + Pertuzumab) before surgery. According to pathological three-dimensional (3D) models of residual tumor from 71 HER2+ patients, shrinkage modes were divided into concentric shrinkage mode (CSM) and non-CSM (NCSM). LncRNAs in core biopsy tissues in the CSM and NCSM groups were selected by microarray and validated by RT-PCR. A nomogram was constructed to predict shrinkage modes after NAT in combination with clinical-pathological and transcriptome signatures. Cell proliferation was used CCK-8 and colony formation assay. PAPIS Kit was used to perform nuclear and cytoplasmic separation. The cell drug resistance assays were to explore the value of paclitaxel. The ChIRP-MS assay was to search RNA-binding proteins and verified by WB. Cell cycle analysis was carried out by flow cytometry.
Independent predictors of NCSM were lymph nodes downstaging after NAT, mammographic malignant calcification, hormone receptor expression, and RUVBL1-AS1 expression. A nomogram was constructed in combination with these predictors, which showed an area under the curve of 0.883, supporting the predictive power of the method. Overexpression of RUVBL1-AS1 inhibited HER2+ cells proliferation. Overexpression of RUVBL1-AS1 increased the number of cells in G1/S phase and decreased that of cells in G2 phase. RUVBL1-AS1 increased paclitaxel resistance and downregulated VCP expression. RUVBL1-AS1 affects cell cycle progression by downregulating VCP, resulting in the reduction of cells in G2/M phase, thereby weakening the sensitivity to paclitaxel.
The nomogram could accurately predict shrinkage modes after NAT, and may help guide the individualized selection of breast conserving surgery candidates after NAT. RUVBL1-AS1 might be a promising therapeutic target of paclitaxel-based chemotherapy inHER2+ breast cancer.
构建一种列线图，用于预测HER-2阳性（HER2+）乳腺癌新辅助治疗（NAT）后的退缩模式。同时评估靶向长链非编码RNA（lncRNA）作为疗效预测生物标志物的价值和机制。
所有入组患者在手术前接受六个周期的化疗（多西他赛+卡铂）和抗HER-2双靶向治疗（曲妥珠单抗+帕妥珠单抗）。根据71例HER2+患者残余肿瘤的病理三维（3D）模型，将退缩模式分为同心退缩模式（CSM）和非同心退缩模式（NCSM）。通过微阵列选择CSM组和NCSM组核心活检组织中的lncRNAs，并通过RT-PCR进行验证。结合临床病理和转录组特征构建列线图，以预测NAT后的退缩模式。采用CCK-8和集落形成试验检测细胞增殖。使用PAPIS试剂盒进行细胞核和细胞质分离。通过细胞耐药试验探索紫杉醇的价值。采用ChIRP-MS试验寻找RNA结合蛋白，并通过WB进行验证。通过流式细胞术进行细胞周期分析。
NCSM的独立预测因素为NAT后淋巴结降期、乳腺钼靶恶性钙化、激素受体表达和RUVBL1-AS1表达。结合这些预测因素构建了列线图，其曲线下面积为0.883。支持该方法的预测能力。RUVBL1-AS1的过表达抑制HER2+细胞增殖。RUVBL1-AS1的过表达增加了G1/S期细胞数量，减少了G2期细胞数量。RUVBL1-AS1增加了紫杉醇耐药性并下调了VCP表达。RUVBL1-AS1通过下调VCP影响细胞周期进程，导致G2/M期细胞减少，从而削弱对紫杉醇的敏感性。
该列线图可准确预测NAT后的退缩模式，并可能有助于指导NAT后保乳手术候选者的个体化选择。RUVBL1-AS1可能是HER2+乳腺癌基于紫杉醇化疗的一个有前景的治疗靶点。
