Stanford University School of Medicine, Stanford, CA, USA.
Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Breast Cancer Res Treat. 2018 Aug;171(1):21-31. doi: 10.1007/s10549-018-4807-x. Epub 2018 May 7.
Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit.
We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection.
Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise.
HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.
三阴性乳腺癌（TNBC）与其他乳腺癌亚型相比，预后更差。化疗仍然是局部或转移性疾病患者的标准治疗方法，几乎没有生物标志物来指导获益。
我们将讨论对 TNBC 中两个关键生物学过程的理解的最新进展，即同源重组（HR）DNA 修复缺陷和宿主抗肿瘤免疫及其交叉。
我们对同源重组（HR）缺陷的理解的最新进展，包括 FDA 批准 PARP 抑制剂奥拉帕利用于 BRCA1 或 BRCA2 突变携带者，以及 TNBC 中的宿主抗肿瘤免疫，为治疗 TNBC 提供了新的和基于生物标志物的方法的潜力。检测 HR DNA 修复能力的检测方法可能指导用诱导或靶向 DNA 损伤修复的药物进行治疗。肿瘤浸润淋巴细胞（TILs）与 TNBC 的预后改善相关，最近努力表征浸润免疫细胞亚群并激活宿主抗肿瘤免疫具有希望，但仍然存在挑战，特别是在缺乏预先存在的免疫浸润的肿瘤中。这些领域的进展为 TNBC 患者提供了分层和指导治疗的潜在生物标志物：在 HR 缺陷肿瘤中诱导 DNA 损伤和激活或募集现有的宿主抗肿瘤免疫细胞。重要的是，这些进展为指导现有疗法的使用和开发 TNBC 的新疗法提供了机会。利用 HR 缺陷来增强免疫导向疗法的活性的联合疗法的努力具有希望。
HR 缺陷仍然是一个重要的生物标志物靶点，并且可能是增强“免疫冷”TNBC 免疫原性的有效辅助手段。
