CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
整合基因组突变与 TIL（肿瘤浸润淋巴细胞）改善 HER2 阳性乳腺癌患者对曲妥珠单抗辅助治疗反应的预测
英文原题：Integrating genomic mutations and tumor-infiltrating lymphocytes improves prediction of response to trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer.
查看英文原题
Integrating genomic mutations and tumor-infiltrating lymphocytes improves prediction of response to trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer.
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中文摘要
曲妥珠单抗耐药仍是早期HER2阳性乳腺癌（HER2+ BC）治愈的主要障碍。本研究考察基因组改变和TIL（肿瘤浸润淋巴细胞）密度对治疗耐药及生存结局的影响。
回顾性分析2009至2019年在瑞金医院接受辅助曲妥珠单抗治疗的315例HER2+ BC患者。对手术标本进行全外显子组测序和TIL评分，并收集临床及病理资料；采用癌症基因组图谱（TCGA）队列进行外部验证。比较曲妥珠单抗敏感与耐药肿瘤的基因组改变和TIL密度，并开展生存分析以识别预后标志物。
中位随访109.3个月后，67例肿瘤（21.3%）对曲妥珠单抗耐药；与敏感肿瘤相比，其TIL密度较低（均值19.8% vs 26.3%，P=.001），FLG、MAP1A、BRCA1、PTPRD、PAPPA2、NCOR2、FBXW7、MYH7和VCAN突变频率较高，TP53/NOTCH通路改变也更常见（均P<.05）。由15个基因构成的曲妥珠单抗应答相关基因（TRAG）特征，可在本队列（HR 3.57，P<.001）和TCGA队列（HR 4.99，P=.037）中独立预测较差DFS。高拷贝数改变负荷与较差OS相关（HR 2.49，P=.043）；TIL密度>10%则与DFS改善相关（HR 2.44，P=.003）。整合肿瘤大小、淋巴结状态、雌激素受体状态、TIL及TRAG特征的预后模型区分能力较强（训练集C指数0.743；验证集0.915）。
基因组改变和TIL密度降低是曲妥珠单抗耐药的基础。新型TRAG特征和整合预后模型可改善风险分层，并有望指导早期HER2+ BC个体化辅助治疗。
展开英文摘要原文
Aim: Resistance to trastuzumab remains a major barrier to cure in early-stage HER2-positive breast cancer (HER2+ BC).
We investigated the impact of genomic alterations and tumor-infiltrating lymphocyte (TIL) density on treatment resistance and survival outcomes. Methods: We retrospectively analyzed 315 patients with HER2+ BC who received adjuvant trastuzumab at Ruijin Hospital (2009-2019). Whole-exome sequencing and TIL scoring were performed on surgical specimens, and clinical and pathological data were collected. The Cancer Genome Atlas (TCGA) cohort was used for external validation. Genomic alterations and TIL density were compared between trastuzumab-sensitive and -resistant tumors. Survival analyses were conducted to identify prognostic biomarkers. Results: After a median follow-up of 109. 3 months, 67 tumors (21. 3%) were trastuzumab-resistant, exhibiting lower TIL density (mean 19. 8% vs. 26. 3%, P = 0. 001), higher mutation frequencies in FLG , MAP1A , BRCA1 , PTPRD , PAPPA2 , NCOR2 , FBXW7 , MYH7 , and VCAN , and more frequent alterations in the TP53/NOTCH pathways compared with sensitive tumors (all P < 0.
05). A 15-gene trastuzumab response-associated gene (TRAG) signature independently predicted poorer disease-free survival (DFS) in both our cohort (HR, 3. 57, P < 0. 001) and the TCGA cohort (HR, 4. 99, P = 0. 037). A high copy number alteration burden was associated with worse overall survival (HR, 2. 49, P = 0. 043), whereas TIL density > 10% was associated with improved DFS (HR, 2. 44, P = 0. 003).
A prognostic model integrating tumor size, nodal status, estrogen receptor status, TILs, and the TRAG signature showed strong discriminatory power (c-index 0. 743 in the training set; 0. 915 in the validation set). Conclusion: Genomic alterations and reduced TIL density underpin trastuzumab resistance. The novel TRAG signature and integrated prognostic model enhance risk stratification and may guide personalized adjuvant therapy in early-stage HER2+ BC.
论文信息
- 作者
- Lu S、Zhang Y、Tong Y、Shu L、Huang R、Gu Y、Wang C、Li J
- 单位
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.China
- 期刊
- Cancer drug resistance (Alhambra, Calif.)2025
- 原文标识
- PubMed 41019979 · DOI 10.20517/cdr.2025.133
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