Currently, we only have preliminary data available for this agent in patients with heavily pretreated HER3 expressing metastatic breast cancer, demonstrating an ORR of 30

Currently, we only have preliminary data available for this agent in patients with heavily pretreated HER3 expressing metastatic breast cancer, demonstrating an ORR of 30.1% in HR+/HER2-negative breast cancer, 22.6% in HER3 high TNBC and 42.9% in HER3 high HER2-positive breast cancer.88TOT-HER3 [NCT04610528] is a single-arm window-of-opportunity study investigating the response to patritumab deruxtecan in patients with HR+/HER2-negative breast cancer with tumors greater than or equal to 1 cm in size in the early-stage setting. == LIV-1 Antibody-Drug Conjugates == LIV-1 is a transmembrane protein with metalloproteinase activity, belonging to a subfamily of ZIP (IRT-like proteins) zinc transporters with heterogenous expression across different normal tissues with high expression in both HR+ breast Eugenin cancer and TNBC.89Ladiratuzumab vedotin (LV) is an ADC with a humanized monoclonal antibody targeting LIV-1 by a cleavable linker to a cytotoxic payload, monomethyl auristatin E with antitubulin effects. financial implications of bringing newer therapies to the forefront. In this review, we discuss the evolving landscape of ICIs and ADCs in managing early-stage breast cancer and provide an overview of potential future advancement in the field. Keywords:breast cancer, immunotherapy, neoadjuvant therapy, adjuvant therapy, human epidermal growth factor receptor 2, immune checkpoint inhibitors, TROP2, antibody-drug conjugates, early-stage breast cancer, novel therapies This review reports on the use of immune checkpoint inhibitors and antibody-drug conjugates to manage early-stage breast cancer and provides an overview of potential future advancement in the field. == Implications for Practice. == With strides made in discovering new molecular targets, there is a growing interest in exploring agents with novel mechanisms of action in the realm of breast cancer. These include immunotherapy and antibody-drug conjugates which are thought to be better tolerated than conventional cytotoxic chemotherapy and have also demonstrated improved outcomes. Early identification of optimal candidates for these therapies will help minimize toxicities and personify the true essence of personalized medicine. == Introduction == In the last few years, the development of innovative anti-cancer therapies with novel mechanisms of action has resulted in significant strides in the outcomes of patients with cancer, including breast cancer. Among these, immune checkpoint inhibitors (ICIs) and antibody drug-conjugates (ADCs) stand out. ADCs are designed to deliver potent cytotoxic agents that explicitly target cancer cells and spare normal cells, thus limiting toxicity while improving efficacy. ADCs comprise 3 key components, an antibody specific for a target antigen, a connecting linker, and a payload (Fig. 1). When the antibody binds to its specific antigenic target on the cancer cell surface, the ADC internalizes and processes to release the cytotoxic payload through lysosomal degradation, causing target cell death and, occasionally, neighboring cancer cells not expressing the antigen by a process called the bystander effect. Connecting linkers in ADCs may be cleavable or non-cleavable, triggering payload release based on factors like pH or enzyme-related changes.1Due to the specificity conferred by the antigenic target, the cytotoxic payload of ADCs can be 100 to 1000 times more concentrated than is tolerated with traditional systemic chemotherapy.2 == Figure 1. == Antibody-drug conjugate structure. Created with BioRender.com ICIs function by blocking critical immunosuppressive receptors such as programmed cell death (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).3,4PD-1 is a vital inhibitory protein expressed on immune cells, including T cells, B cells, and antigen-presenting cells.3When it binds to PD-L1, it induces apoptosis of antigen-specific T cells and decreases T-regulatory cell apoptosis, reducing the overall immune response. ICIs enhance immune surveillance and antitumoral response by blocking these regulatory proteins. In this review, we analyze the landscape of ICIs and ADCs in managing patients with early-stage breast cancer, firstly discussing how their use came about and finally providing an overview of future directions in the field. == Immunotherapy == Although once considered immunologically silent, expanding research in breast cancer has shed new light on the immunogenicity of this cancer. Expression of tumor-infiltrating lymphocytes (TILs) and Eugenin PD-L1 differ based on subtypes of breast cancer, with triple-negative breast cancer (TNBC) displaying the highest expressions.5-10These features are associated with an increased response to immunotherapy.11Hence, ICIs were initially approved for treating patients with metastatic, PD-L1-positive TNBC based on improved survival outcomes.12,13Evidence suggested a better efficacy of ICIs when administered early, in TNBC, potentially due to the progression of immune escape mechanisms during the disease advancement.14,15Hence, treating patients with ICIs before surgery became a consideration. == Checkpoint Inhibitors in Triple-Negative Breast Cancer == The KEYNOTE-522 (KN522) brought ICIs to the forefront Eugenin of treatment CCNA2 for patients with early-stage TNBC. This study demonstrated that the addition of pembrolizumab to chemotherapy preoperatively improved pathologic complete response (pCR) (63% vs. 55.6%, P < .001) and event-free survival (EFS) (84.5% vs. 76.8%,P< .001) compared to chemotherapy alone.16Patients in the pembrolizumab arm received 9 cycles of adjuvant pembrolizumab after definitive surgery, regardless of pCR. Several other studies have investigated the addition of ICIs to neoadjuvant chemotherapy in patients with early-stage breast cancer (Table 1). This includes the IMpassion031 trial, which improved pCR with the addition of atezolizumab to anthracycline-based chemotherapy (58%.