Olsson Erik, Lindman Henrik, Digkas Evangelos, Thurfjell Viktoria, Ali Haidar Mir, Krüger Ute, Wennstig Anna-Karin, Sundqvist Marie, Valachis Antonios
Department of Oncology, Uppsala University Hospital, Sweden.
Department of Clinical Pathology, Uppsala University Hospital, Sweden.
Breast. 2025 Feb;79:103874. doi: 10.1016/j.breast.2025.103874. Epub 2025 Jan 2.
We aimed to characterize genomic alterations with potential prognostic or predictive significance in patients with metastatic triple-negative breast cancer (mTNBC) treated with chemotherapy in a real-world setting.
Next-generation sequencing with FoundationOne® CDx was conducted primarily on primary tumor tissue from 112 consecutive patients with mTNBC. Genomic alterations were subdivided into canonical oncogenic pathways and noted for their involvement in homologous recombination deficiency (HRD). Altered genes and pathways were correlated with overall survival (OS) and evaluated regarding their association with real-world progression-free survival (rwPFS) in patients treated with different chemotherapy agents. Occurrence of alterations were compared between patients with exceptional response and rapid progression to chemotherapy.
After exclusion due to insufficient tumor tissue or clinical data, material from 97 patients was analyzed. The most frequently altered genes were TP53 (82 %), RAD21 (25 %) and PIK3CA (23 %). Altogether, 26 % of patients had an alteration leading to HRD. None of the analyzed alterations were associated with OS. Variants leading to HRD were associated with a prolonged rwPFS in patients treated with platinum-based chemotherapy in the first line setting (hazard ratio [HR], 0.31 [95 % CI: 0.12-0.84]). Exceptional responders more often exhibited alterations in the MYC and RAS/RTK pathways compared to rapid progressors.
Patients with tumor alterations in HRD-related genes seem to define subgroups that respond favorably to platinum-based chemotherapy. Further research into the genomic landscape of tumors from patients with rapid progression or exceptional response to different treatment strategies can provide insights into mechanisms of resistance and identify predictive biomarkers.
我们旨在对在真实世界中接受化疗的转移性三阴性乳腺癌（mTNBC）患者具有潜在预后或预测意义的基因组改变进行特征分析。
主要对112例连续的mTNBC患者的原发性肿瘤组织进行FoundationOne® CDx二代测序。基因组改变被细分为经典致癌途径，并记录其与同源重组缺陷（HRD）的关系。将改变的基因和途径与总生存期（OS）相关联，并评估其与接受不同化疗药物治疗患者的真实世界无进展生存期（rwPFS）的关联。比较对化疗有特殊反应和快速进展患者之间改变的发生率。
由于肿瘤组织或临床数据不足而排除后，对97例患者的材料进行了分析。最常改变的基因是TP53（82%）、RAD21（25%）和PIK3CA（23%）。共有26%的患者发生导致HRD的改变。分析的改变均与OS无关。导致HRD的变异与一线接受铂类化疗患者的rwPFS延长相关（风险比[HR]，0.31[95%CI：0.12 - 0.84]）。与快速进展者相比，特殊反应者更常表现出MYC和RAS/RTK途径的改变。
HRD相关基因存在肿瘤改变的患者似乎可定义为对铂类化疗反应良好的亚组。对不同治疗策略快速进展或有特殊反应患者的肿瘤基因组格局进行进一步研究，可为耐药机制提供见解并识别预测性生物标志物。
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