Unit of Oncology 1, Department of Medical and Oncological Area, Pisa University Hospital, 56126 Pisa, Italy.
Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy.
Int J Mol Sci. 2022 Jan 31;23(3):1665. doi: 10.3390/ijms23031665.
Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase () gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.
三阴性乳腺癌（TNBC）与高复发率、远处转移发生率高和总体生存率（OS）差有关。紫杉烷和蒽环类药物化疗（CT）是目前 TNBC 的主要全身治疗选择，而铂类化疗在新辅助和转移性环境中显示出有希望的结果。内在或获得性 CT 耐药的早期出现是常见的，是成功治疗 TNBC 的主要障碍。已经发现了许多导致化疗耐药的机制。这些包括新辅助化疗（NACT）后癌症干细胞（CSC）的诱导、ATP 结合盒（ABC）转运蛋白、缺氧和避免细胞凋亡、单一因素如酪氨酸激酶受体（EGFR、IGFR1）、解整合素和金属蛋白酶 10（ADAM10），以及一些病理分子途径。一些能够预测对特定化疗药物耐药的生物标志物已被确定，并有望在未来的研究中得到验证，以便更准确地选择要使用的药物，并在新辅助和晚期环境中采用更具针对性的方法。最近，根据特定的生物标志物，一些疗法针对 TNBC 亚组进行了调整，并在临床实践中得到应用：奥拉帕利和他拉唑帕利用于胚系突变携带者；拉罗替尼和恩曲替尼用于神经营养性原肌球蛋白受体激酶（TRK）基因融合携带者；抗滋养细胞表面抗原 2（Trop2）抗体药物偶联物用于预处理后转移性三阴性乳腺癌（mTNBC）。针对一些病理分子途径、细胞凋亡、miRNAS、表皮生长因子受体（EGFR）、胰岛素生长因子 1 受体（IGF-1R）和雄激素受体（AR）的进一步治疗正在研究中。其中，磷脂酰肌醇 3 激酶（PI3K）/蛋白激酶 B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）和 EGFR 抑制剂以及抗雄激素已显示出有希望的结果，并正在 II/III 期临床试验中进行评估。新兴的治疗方法允许选择特定的抗白血病药物，这些药物单独或通过整合常规治疗方法，可能克服/阻碍化疗耐药性。
