Zhang Xiangmei, Li Jingping, Yang Qing, Wang Yanfang, Li Xinhui, Liu Yunjiang, Shan Baoen
Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Breast Cancer Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Ann Transl Med. 2020 Sep;8(17):1052. doi: 10.21037/atm-20-3773.
In locally advanced triple-negative breast cancer (TNBC), patients who did not achieve pathologic complete response (non-pCR) after neoadjuvant chemotherapy develop rapid tumor metastasis. Tumor mutation burden (TMB) is a potential biomarker of cancer therapy, though whether it is applicable to TNBC is still unclear.
A total of 14 non-pCR TNBC patients were enrolled, and tissue samples from radical operation were collected. Of these, 7 cases developed disease progression within 12 months after operation [short disease-free survival (short DFS)], while others showed longer DFS over 1 year (long DFS). Next generation sequencing (NGS) analysis targeting 422 cancer-related genes and studies were performed.
A total of 72 mutations were detected within 14 patients, which ranged from 1 to 8 per patient with a median mutations number of 5. The median number of mutations in the short-DFS group was higher than that in the long-DFS group (6.0 . 4.3; P0.094). Furthermore, 6 gene mutation types were detected, with missense mutations displayed in the majority (36/72, 50.0%). No correlation between mutation type and DFS was found. Among 422 cancer-related genes, alterations in 30 genes were detected. (12/14, 85.7%) was the most common mutation gene in the entire cohort. mutations significantly occurred in patients with high Ki-67 scores (P=0.013). Additionally, 4 mutations of (57.1%, 4/7) and 3 of (42.9%, 3/7) were only detected in the short-DFS group, while patients with mutation had a significantly shorter DFS period (P=0.026). Experiments confirmed that gene was widely expressed in various breast cancer cell lines. Knockdown of in MD-MBA-231 cells by small interfering RNA (siRNA) decreased the expression of , and increased the levels of vimentin, , and .
In non-pCR TNBC, mutation and TMB elevated in patients with short-DFS, indicating the potential prognostic biomarkers and therapeutic molecular targets for locally advanced TNBC.
在局部晚期三阴性乳腺癌（TNBC）中，新辅助化疗后未达到病理完全缓解（非pCR）的患者会发生快速的肿瘤转移。肿瘤突变负荷（TMB）是癌症治疗的一个潜在生物标志物，但其是否适用于TNBC仍不清楚。
共纳入14例非pCR的TNBC患者，并收集根治性手术的组织样本。其中，7例患者在术后12个月内出现疾病进展[无病生存期短（短DFS）]，而其他患者的DFS超过1年（长DFS）。对422个癌症相关基因进行了二代测序（NGS）分析并开展了研究。
14例患者共检测到72个突变，每位患者的突变数为1至8个，中位数为5个。短DFS组的突变中位数高于长DFS组（6.0对4.3；P=0.094）。此外，检测到6种基因突变类型，其中错义突变占大多数（36/72，50.0%）。未发现突变类型与DFS之间存在相关性。在422个癌症相关基因中，检测到30个基因发生改变。（12/14，85.7%）是整个队列中最常见的突变基因。该突变在高Ki-67评分的患者中显著发生（P=0.013）。此外，仅在短DFS组中检测到4个（57.1%，4/7）的突变和3个（42.9%，3/7）的突变，而有该突变的患者DFS期明显较短（P=0.026）。实验证实该基因在各种乳腺癌细胞系中广泛表达。通过小干扰RNA（siRNA）敲低MD-MBA-231细胞中的该基因可降低其表达，并增加波形蛋白、和的水平。
在非pCR的TNBC中，短DFS患者中该基因突变和TMB升高，表明其可能是局部晚期TNBC的预后生物标志物和治疗分子靶点。
