Dysregulated cellular proliferation represents a hallmark feature across all cancers. Aberrant activation of the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway, independent of mitogenic signaling, engenders uncontrolled breast cancer cell proliferation. Consequently, the advent of CDK4/6 inhibition has constituted a pivotal milestone in the realm of targeted breast cancer therapy. The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) has emerged as the foremost therapeutic modality for patients afflicted with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer. At present, the Food and Drug Administration (FDA) has sanctioned various CDK4/6i for employment as the primary treatment regimen in HR + /HER2- breast cancer. This therapeutic approach has demonstrated a substantial extension of progression-free survival (PFS), often amounting to several months, when administered alongside endocrine therapy. Within this comprehensive review, we systematically evaluate the utilization strategies of CDK4/6i across various subpopulations of breast cancer and explore potential therapeutic avenues following disease progression during application of CDK4/6i therapy.

Triple-negative breast cancer (TNBC) is an aggressive, difficult-to-treat subtype of cancer with a poor prognosis; there is an urgent need for effective, targeted molecular therapies. The cyclin D/cyclin-dependent kinase (CDK)4/6–retinoblastoma protein (Rb) pathway plays a critical role in regulating cell cycle checkpoints, a process which is often disrupted in cancer cells. Selective CDK4/6 inhibitors can prevent retinoblastoma protein phosphorylation by invoking cell cycle arrest in the first growth phase (G1), and may therefore represent an effective treatment option. In this article, we review the molecular mechanisms and therapeutic efficacy of CDK4/6 inhibitors in combination with other targeted therapies for the treatment of triple-negative breast cancer. Three selective CDK4/6 inhibitors have so far received the approval of the Food and Drug Administration (FDA) for patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2) breast cancer. Trilaciclib, a small molecule short-acting inhibitor of CDK4/6, has also been approved recently for people with small cell lung cancer, and is also expected to be clinically effective against breast cancer. Although the efficacy of CDK4/6 inhibitors in patients with triple-negative breast cancer remains uncertain, their use in conjunction with other targeted therapies may improve outcomes and is therefore currently being explored. Identifying biomarkers for response or resistance to CDK4/6 inhibitor treatment may optimize the personalization of treatment strategies for this disease. Ongoing and future clinical trials and biomarker studies will shed further light on these topics, and help to realize the full potential of CDK4/6 inhibitor treatment in triple-negative breast cancer.

Breast cancer has become the most prevalent malignant tumor worldwide and remains one of the leading causes of cancer-related mortality among women globally. The prognosis for patients with metastatic breast cancer remains poor, necessitating the exploration of novel therapeutic strategies to improve survival rates. In the era of precision medicine, antibody-drug conjugates (ADCs) have gained significant attention as a targeted therapeutic strategy in breast cancer treatment. ADCs, a relatively new treatment for breast cancer, deliver cytotoxic drugs (payloads), directly into the tumor space, turning chemotherapy into a targeted agent, which enables patients to experience significant improvements with manageable drug toxicity. For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. Recent clinical studies have demonstrated that the benefits of ADC therapies extend beyond HER2-positive breast cancer toinclude hormone receptor (HR)-positive breast cancer, triple-negative breast cancer (TNBC), and HER2-low expressing breast cancer. Notably, the DESTINY-Breast series of studies, particularly focusing on T-Dxd, encompass neoadjuvant, adjuvant, and multiple lines of therapy for advanced breast cancer. This marks the advent of a comprehensive ADC era in breast cancer treatment. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment.

Breast cancer in women is the first leading tumor in terms of incidence worldwide. Some subtypes of BC lack distinct molecular targets and exhibit therapeutic resistance; these patients have a poor prognosis. Thus, the search for new molecular targets is an ongoing challenge for BC therapy. The Notch signaling pathway is found in both vertebrates and invertebrates, and it is a highly conserved in the evolution of the species, controlling cellular fates such as death, proliferation, and differentiation. Numerous studies have shown that improper activation of Notch signaling may lead to excessive cell proliferation and cancer, with tumor-promoting and tumor-suppressive effects in various carcinomas. Thus, inhibitors of Notch signaling are actively being investigated for the treatment of various tumors. The role of Notch signaling in BC has been widely studied in recent years. There is a growing body of evidence suggesting that Notch signaling has a pro-oncogenic role in BC, and the tumor-promoting effect is largely a result of the diverse nature of tumor immunity. Immunological abnormality is also a factor involved in the pathogenesis of BC, suggesting that Notch signaling could be a target for BC immunotherapies. Furthermore, angiogenesis is essential for BC growth and metastasis, and the Notch signaling pathway has been implicated in angiogenesis, so studying the role of Notch signaling in BC angiogenesis will provide new prospects for the treatment of BC. We summarize the potential roles of the current Notch signaling pathway and its inhibitors in BC angiogenesis and the immune response in this review and describe the pharmacological targets of Notch signaling in BC, which may serve as a theoretical foundation for future research into exploring this pathway for novel BC therapies.

Platinum-based chemotherapy (PBC) remains the mainstay of treatments for triple-negative breast cancer (TNBC). TNBC is a heterogeneous group, the issue of whether BRCA1/2 mutation carriers have a particular sensitivity to platinum agents is inconclusive. We conducted a meta-analysis to explore the relationship between BRCA1/2 mutation and PBC susceptibility in individuals with TNBC, aiming to gain more information on the size of the benefit of PBC in BRCA1/2 mutation carriers. All studies applying PBC with a subgroup of BRCA1/2 status were included. All endpoints, including pCR and RCB in the neoadjuvant phase, DFS in the adjuvant phase, ORR, PFS, and OS in the advanced phase, were assessed using HRs and 95% Cl. From the 22 studies included, there were 2158 patients with TNBC, with 392 (18%) bearing the BRCA1/2 gene mutation. Based on 13 studies applying neoadjuvant PBC, we discovered that BRCA1/2 mutation was substantially associated with a 17.6% increased pCR rate (HR 1.32, 95% CI 1.17–1.49, p < 0.00001; I² = 51%). Same result was observed in RCB0/I index (HR 1.38, 95% CI 1.08–1.76, P = 0.009; I² = 0%). The meta-analysis of 6 trials addressing advanced therapy revealed that ORR rates were significantly higher in patients with BRCA1/2 mutation (HR 1.91, 95% CI 1.48–2.47, p < 0.00001; I² = 32%), as well as PFS(HR 1.13, 95% CI 0.81–1.57, P = 0.47; I² = 0%) and OS (HR 1.89, 95% CI 1.22–2.92, P = 0.004; I² = 0%). According to our meta-analysis of 22 trials in TNBC, BRCA1/2 mutation carriers were significantly more sensitive to PBC regimens, especially in neoadjuvant and advanced therapy.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer with high metastatic potential. To date, no directed treatment options have been developed for the treatment of metastatic or advanced TNBC. The oncogene TMEM158, also known as RIS1, is upregulated by Ras-induced cellular senescence. Although TMEM158 has been shown to be involved in tumor progression, little is known about the molecular function and expression of TMEM158 in breast cancer. The present study evaluated the expression and prognostic relevance of TMEM158 in breast cancer patients from several databases. Gene set enrichment analysis (GSEA) showed that TMEM158 was closely associated with epithelial-mesenchymal transition (EMT) and TGF-β pathways. Gain- and loss-of-function assays indicated that overexpressed TMEM158 might participate in EMT by activating the TGF-β pathway, which in turn promotes tumor migration, invasion, and metastasis. These findings suggest that TMEM158 has the potential to become a new therapeutic target for TNBC.