Antibody-drug conjugates in breast cancer.

The human epidermal growth factor receptor 2 (HER2)/erythroblastic oncogene B2 (ERBB2) is a tyrosine kinase receptor protein that plays an important role in the pathogenesis and aggressive nature of the tumors. It is well studied in various cancers, including breast, gastric, esophageal, ovarian, lung, and endometrial cancers. It is a well-known negative prognostic indicator in breast cancer associated with decreased disease-free survival and overall survival. Breast cancer treatment has been revolutionized with the invention of targeted monoclonal antibody therapies against the HER2 receptor, particularly trastuzumab and its antibody-drug conjugates (ADCs). HER2-targeted therapies have proven to improve progression-free survival and overall survival when added to chemotherapy in adjuvant, neoadjuvant, and metastatic settings in patients who are HER2-positive. ADCs approved for breast cancer include trastuzumab emtansine (Kadcyla, T-DM1) and trastuzumab deruxtecan (Enhertu, T-DXd). With enthusiasm and reported benefit, particularly in metastatic disease, HER2-targeted therapies are now widely used in breast cancer patients classified as HER2-negative based on binary classification but categorized as “HER2-low” with some degree of HER2 expression. HER2-targeted therapies are not approved for patients who have HER2 (ERBB2) mutation and have no HER2 expression of any degree (immunohistochemistry (IHC) 0+). We could not find any such reported cases, research studies, or clinical trials of HER2-targeted therapies being used in patients with HER2 mutation in our extensive search of the literature. We present a rare practice-changing case of a patient with triple negative metastatic breast cancer (estrogen receptor (ER), progesterone receptor (PR), and HER2 negative, HER2 0+ on IHC) and positive HER2 mutation, who achieved a disease-free survival of more than 2.5 years with trastuzumab deruxtecan monotherapy. This case makes a compelling argument for considering HER2-targeted therapies, mainly ADCs, in HER2-mutant breast cancer patients either as a monotherapy or in combination with other therapies, particularly in metastatic disease. This case report also indicates that further research and clinical trials looking into the efficacy and safety profile of anti-HER2 treatments in HER2-mutant breast cancers are warranted.

The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumab- and lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.

Background: Antibody-drug conjugates (ADCs) are increasingly used in the treatment of breast cancer due to their superior efficacy compared to conventional chemotherapy. The management of male breast cancer is largely extrapolated from clinical data in females and evidence regarding the efficacy of ADCs in men remains limited. This study aimed to compare survival outcomes between male and female breast cancer patients treated with ADCs across the spectrum of human epidermal growth factor receptor 2 (HER2) expression. Methods: We included total of 2,954 (Male: 34, Female: 2,920 breast cancer samples) from patients who underwent treatment with ADCs. We excluded patients with triple-negative breast cancer status due to the rarity of this subtype in males and the worse prognosis of triple-negative breast cancer, so that the cohorts would be more homogeneous without overrepresentation of triple-negative breast cancer in females. We categorized patients by HER2 status as: HER2-null (if there was 0% stain on HER2 IHC), HER2-ultra low (if HER2 IHC was 0 but with stain 1-10%), HER2-low (if HER2 IHC was 1+ or 2+ with a negative chromogenic in situ hybridization [CISH] assay), and HER2-positive (if HER2 IHC was 3+ or 2+ with a positive CISH assay). Real-world median overall survival was derived from insurance claims and calculated from the start of first ADC with either trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) or sacituzumab govitecan (SG) to last contact using Kaplan-Meier. Statistical significance was assessed using chi-square and Mann-Whitney U. Results: The distribution of sex by HER2 expression group was: HER2-null: 8 males vs 612 females; HER2-ultra low 6 males vs 467 females; HER2-low 11 males vs 903 females; HER2-positive 9 males vs 938 females. Median survival from treatment initiation with either T-DXd or SG in the HER2-null cohort was 21.31 months in males vs 15.72 months in females (HR 0.82, 95% CI 0.33 - 2.01, p=0.67); in the HER2-ultra low cohort was 17.73 months in males vs 14.47 months in females (HR 0.84, 95% CI 0.26 - 2.63, p=0.76); in the HER2-low cohort was 11.08 months in males vs 18.62 months in females (HR 1.53, 95% CI 0.63 - 3.7; p=0.34). In the HER2-positive cohort, 5/9 males (55.5%) and 544/938 females (58%) were treated with T-DXd. Median survival from treatment initiation with either T-DXd or T-DM1 in the HER2-positive cohort was 36.55 months in males vs 46.52 months in females (HR 1.77, 95% CI 0.84 - 3.74, p=0.12). Conclusions: In this study, survival appears to be comparable between males and females with breast cancer across the spectrum of HER2 expression when both are treated with ADCs, although the survival in the HER2-positive cohort appears numerically lower in males, consistent with data on HER2-positive MaBC. An important limitation is the small sample size of the male breast cancer cohorts, and the lack of a categorization of HER2 in HR+ vs HR-, for the small MaBC sample size. However, to our knowledge this is the first analysis evaluating outcomes of men treated with ADCs across the spectrum of HER2 expression. Citation Format: D. Trapani, S. Deshmukh, S. Wu, J. Xiu, N. Lin, G. Curigliano, P. Spanheimer, S. Gandhi, S. Chumsri, S. Graff, M. Lustberg, G. Sledge Jr, S. Tolaney, J. Leone. Comparative efficacy of antibody drug conjugates (ADCs) in male versus female breast cancer across the spectrum of HER2 expression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-13.

Antibody-drug conjugates (ADCs) provide specificity for cytotoxic drugs as well as monoclonal antibodies (mAbs) and represent an important step in the treatment of breast cancer. This review summarizes the current status, efficacy, safety, and future prospects of ADCs in the treatment of breast cancer. mAbs enable drug delivery by detecting specific antigens on cancer cells. Cytotoxic payloads cause cell death upon internalization. The linker binds the mAb to the payload and influences drug release. All three components together form an ADC. Transtuzumab Emtansine 1 (T-DM1) (Kadcyla) targets human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has shown activity against both metastatic and early disease. Fam-trastuzumab deruxtecan (T-DXd; Enhertu) has shown improved progression-free survival and overall survival for T-DM1 in HER2-positive metastatic breast cancer. Sacituzumab govitecan (SG) targets the Trophoblast Antigen 2 (TROP2) receptor and has been shown to be effective in triple-negative breast cancer and hormone receptor-positive, HER2-negative advanced breast cancer. Fatigue, nausea, and diarrhea are the most common. Some ADCs have their own side effects. T-DXd, which can cause interstitial lung disease, and SG, which increases the risk of diarrhea. Monitoring and controlling these adverse events is important to achieve good patient outcomes. There are ongoing issues with ADC use including drug-related and other issues. The drug-related issues include side effects and ADCs drug resistance. This resistance can be due to a variety of reasons including downregulation of the target antigen, reduced internalization, increased drug efflux, and reduced burden. Strategies to reduce resistance include the use of combination therapies, early detection of resistance, and the development of more effective products. Second-generation ADCs with improved structure and potency are under development. There is ongoing research focusing on novel targets beyond HER2, such as Trop-2 and Claudin-18.2. Non-drug-related issues include tumor heterogeneity, patient selection, manufacturing issues, and increased costs. In conclusion, ADCs are a huge improvement over conventional chemotherapy for breast cancer treatment. The importance and use of ADCs in cancer treatment is bound to increase. The future of ADCs in breast cancer treatment looks promising with ongoing research into new targets, new therapeutic agents, and advances in drug resistance leading to mediated and effective methods.

The Her2 subtype of breast cancer (BC) accounts for about 20-25% of all the BC patients. This subtype is defined by the overexpression of human epidermal growth factor receptor 2 (Her2) which drives elevated downstream signaling promoting tumorigenesis. Trastuzumab emtansine (T-DM1) is an antibody drug conjugate in which an anti-Her2 antibody targets Her2 overexpressing tumor cells and delivers emtansine, a highly potent microtubule inhibitor. Metastatic BC patients who have progressed on Trastuzumab show improved overall survival with T-DM1 treatment. However, there is an unmet medical need in a group of patients where their initial response is followed by disease recurrence due to the development of acquired resistance. Therefore, it is important to investigate the molecular mechanisms of resistance to T-DM1. In this study, we established minimal residual disease (MRD) following T-DM1 treatment of HMLE-Her2 xenografts. Upon removal of the drug, tumors relapsed and were no longer responsive to T-DM1. In addition, immunohistochemistry staining revealed that these T-DM1 drug-resistant tumors lost their Her2 expression. In contrast to these in vivo results, continuous treatment of HMLE-Her2 cells with T-DM1 failed to show any acquired resistance in vitro. However, induction of epithelial-mesenchymal transition (EMT) via pretreatment with TGF-β facilitated acquisition of drug resistance to T-DM1. Similar to our in vivo resistant model, these in vitro resistant cells showed diminution in Her2 expression. Flow cytometry analysis suggested that TGF-β treatment may promote a heterogeneous expression of Her2, which helps the selection of a low Her2 expressing, T-DM1 resistant population. Next, we performed cell viability assays in the presence various kinase inhibitors. While the T-DM1 resistant cells were not sensitive to Lapatinib and Afatinib; they showed a dramatic response to FIIN-4, a covalent inhibitor of FGFR. Indeed, we observed elevated expression of FGFR1 at both the mRNA and protein levels in the T-DM1 resistant models. Moreover, we have found that ectopic overexpression of a truncated FGFR1 splice variant, FGFR1β, was sufficient to increase cell survival in response to T-DM1 treatment. Along these lines, orthotopic HMLE-Her2 tumors were less responsive to T-DM1 upon FGFR1β overexpression. Furthermore, overexpression of FGFR1β also leads to enhanced tumor recurrence following T-DM1 treatment. In line with these observations, we found that a patient-derived xenograft (PDX) from a Her2+ BC patient who had progressed on trastuzumab, were responsive to FIIN-4 while showing limited response to T-DM1. Currently, we are investigating potential mechanisms of FGFR mediated survival of T-DM1 resistant cells. Finally, we are exploring combination therapeutics using T-DM1 and FGFR inhibitors in various models of Her2 BC. Citation Format: Saeed Salehin Akhand, Connor Purdy, Michael Wendt. FGFR signaling facilitates recurrence of minimal residual disease post trastuzumab emtansine treatment in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2850.

Background: 15-20% of metastatic breast cancers are characterized by overexpression or amplification of human epidermal growth factor receptor 2 (HER2). First-line treatment for HER2-positive metastatic breast cancer includes the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab in combination with chemotherapy. Second-line therapy includes T-DM1, an antibody-drug conjugate (ADC) consisting of trastuzumab conjugated to maytansinoid (DM1). Until recently, patients who progress on T-DM1 were left with few treatment options. Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody linked to a novel topoisomerase I inhibitor payload using a cleavable tetrapeptide-based linker and was recently approved for unresectable or T-DM1-refractory HER2+ breast cancer. In addition, DS-8201a is currently being evaluated as a treatment in breast cancers with low and medium expression of HER2. To better understand the potential for DS-8201a as a treatment in these cancer types, we evaluated this therapy in a panel of ER+/- XPDX models with differential HER2 expression. In addition, we compared DS-8201a activity to T-DM1 and benchmarked efficacy of the topoisomerase I inhibitor irinotecan in all tested models. Methods: One hundred (50ER+/50ER-) breast XPDX models were evaluated in this study. Models were established and characterized for estrogen receptor and HER2 expression by IHC and profiled using WES and RNAseq. For in vivo studies, DS-8201a and T-DM1 were administered IV at 3 mg/kg and irinotecan IP at 100 mg/kg on a weeklyx3 schedule. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Results: Models were grouped by ER positivity (+/-) and model HER2 score and designated as null (0), low (1+), medium (2+) or high (3+); models established from clinically HER2+ patients were also noted. In the ER+ group, HER2 low and medium expressing models accounted for over 80% of the total, while 15% were categorized as high and less than 5% as null. All models with high and 30% with medium HER2 staining were from clinically HER2+ patients, no low or null models were established from breast cancer assigned HER2+ clinically. In the ER- group, HER2 low and medium expressing models accounted for 75% of the total, while 12% were categorized as high and 13% as null. All models with high and 13% with medium HER2 staining were from clinically HER2+ patients; 5% of low or null models were established from breast cancer assigned HER2+ clinically. In vivo, 65% of the ER+ group reported sensitivity to DS-8201a versus 25% to T-DM1; 10% of DS-8201a, and 40% of T-DM1 sensitive models were high expression models and the remaining low and medium with no null models reporting sensitivity to either agent. 35% of tested ER+ models were sensitive to both HER2 therapies and 50% of models sensitive to DS-8201a were also sensitive to irinotecan. In the ER- group, 70% reported sensitivity to DS-8201a versus 25% to T-DM1; 20% of DS-8201a and 25% of T-DM1 sensitive models were high expression models and the remaining low and medium with one null model (ST069) sensitive to both agents. 25% of tested ER- models were sensitive to both HER2 therapies and 40% of models sensitive to DS-8201a were also sensitive to irinotecan. Conclusion: We have compared activity of DS-8201a, T-DM1 and irinotecan in a panel of ER+/- XPDX models and correlated activity based on HER2 expression. This data and panel can be utilized as a valuable tool in better understanding the potential for DS-8201a and other HER2-targeting therapies as a treatment in cancers driven by HER2 expression. Citation Format: Alyssa Simonson, Peter Forofontov, Johnnie R Flores, Kimberly Hernandez, April Cabang, Amy Lang, Gladys Rodriguez, Kyriakos Papadopoulos, Murali Beeram, Arthur Rosenthal, Brittany DeBerry, Lon Smith, Ronald Drengler, Amita Patnaik, Drew Rasco, Luis Rodriguez, Steven Abbate, Scott Ulmer, Michael Wick. Correlation of HER2 receptor expression and in vivo activity of the HER2-targeting therapies trastuzumab deruxtecan (DS-8201a) and T-DM1 activity in a panel of breast XPDX models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-04.

Trastuzumab Beyond Progression in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: UK Practice now and in the Future

Despite the availability of multiple treatment options for breast cancer, challenges such as adverse events, drug resistance, and disease progression persist for patients. The identification of human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers, alongside the development of HER2-targeted therapies, has significantly improved the prognosis of HER2-amplified breast cancers. However, therapeutic options remain limited for HER2-overexpressing or HER2-negative breast cancers. In response to this gap, antibody-drug conjugates (ADCs) have emerged as a promising approach. ADCs combine the specificity of monoclonal antibodies with the cytotoxic effects of chemotherapy, which allows for the targeted delivery of a cytotoxic payload to cancer cells. ADCs have been used as adjuvant chemotherapeutic treatments and salvage therapies across various breast cancer subtypes, which have greatly improved the prognosis of breast cancer patients. Numerous ongoing clinical trials seek to optimize dosing strategies and identify patient populations that would benefit most from ADCs. This review presents an updated and comprehensive overview of emerging investigational ADCs for treating breast cancer patients with various HER2 subtypes. These ADCs are spearheading a new era in targeted cancer therapy, promising to innovate treatment paradigms for both HER2-positive and HER2-low breast cancers.

Background: The definition of human epidermal growth factor receptor-2(HER2) low was proposed with the development of T-DXd, a novel antibody-drug conjugate (ADCs) targeting HER2 in the field of breast cancer (BC) treatments. However, whether HER2 low is a distinct subgroup is still an ongoing debate with mixed results. Current retrospective studies focused on HER2 low concentrated more on metastatic BC, less was known in early BC. The retrospective study was conducted based on HER2 low early BC to comprehensively analyze its clinicopathological features and prognostic roles compared with HER2 IHC0. Methods: This single institution retrospective study enrolled 999 early stage (stage I through III) HER2 negative invasive BC patients diagnosed at Chinese PLA General Hospital from January 2010 to December 2015. Tumors with HER2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay were defined as HER2 low. Clinicopathological characteristics s and survival outcomes including disease-free survival (DFS) and overall survival (OS) were compared between HER2 IHC0 and HER2 low groups. The correlations between HER2 expression and estrogen receptor (ER) status were determined by Mantel-Haenszel χ2 test. Cohen’s kappa coefficient (k) was adopted to evaluate the concordance between HER2 expression on primary tumors and matched biopsies. Results: 999 patients were eligible for inclusion criteria, among which the percentages of HER2 low in the whole cohort, HR positive group and HR negative group were 83.6%, 86.54%, 72.14% respectively. It was observed the presence of a significant higher proportion of ER level > 10% (p < 0.001), PgR positive (p < 0.001) and more patients who received endocrine therapy (p = 0.002). In HR positive group, clinicopathological features were balanced between HER2 IHC0 and HER2 low. In HR negative group, HER2 low manifested a higher proportion of invasive ductal type (p = 0.016) compared with HER2 IHC0. Survival analysis showed a significantly longer OS in HER2 low BC than HER2 IHC0. (HR: 0.458, 95%CI: 0.262-0.800, p = 0.0005). Nevertheless, the independent role was not reached in DFS. When stratified by HR status, patients with HER2 low in HR positive group demonstrated a longer OS than HER2 IHC0 (HR: 0.55, 95%CI: 0.273-1.105, p = 0.0385). The same trend was observed in HR negative group (HR: 0.385, 95%CI: 0.158-0.939, p = 0.0132). Neither the HR positive group nor the HR negative group achieved significant DFS. Besides, a positive correlation was observed between ER status and the rate of HER2 low (Mantel-Haenszel c2 test, p < 0.001, Pearson’s R = 0.159, P < 0.001). No regularity of survival differences between HER2 IHC0 and HER2 low was found in each ER level in the exploratory study. Finally, 119 patients who developed relapsed or metastatic disease were identified, with the most prevalent metastatic site being bone (31.1%), following by lung (16.80%) and lymph node (13.44%). Among 52 patients with matched biopsy samples, dynamic changes of HER2 IHC status were confirmed in both primary and relapsed statuses, with an discordance rate of 28.84% (K = 0.194, 95%CI: 0.168-0.219). conclusion: HER2 low expression breast cancer may not be regarded as a unique BC group in this real-world population due to similar clinicopathological features and prognostic roles especially in hormone-receptor positive cases. ER level was positively correlated with the rate of HER2 low population. Overall, whether HER2 low is a distinct subgroup remains to be supported and validated by more data both in clinical and molecular levels. Key words: HER2 low; Breast cancer; Clinicopathological Features; Prognosis; Molecular type Clinicopathological Features and Prognostic Role of HER2 Low in Early Breast Cancer: A real world study Citation Format: Ziqing Kong, Weihong Zhao. Clinicopathological Features and Prognostic Role of HER2 Low in Early Breast Cancer: A real world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-07.

HER-2 is a member of the EGF receptor family and is overexpressed in 20-30% of breast cancers. HER-2 overexpression causes increased expression of VEGF at both the RNA and protein levels. HER-2 and VEGF are therefore considered good targets for cancer treatment, which has led to the development of two humanized monoclonal antibodies (mAb) pertuzumab and bevacizumab. Although passive immunotherapy with these Abs are approved for treatment of advanced breast cancer, a number of concerns exist. Treatment is expensive, has a limited duration of action, and is usually accompanied by serious side effects. We hypothesized that therapy with conformational peptide mimics aimed at blocking receptor-ligand interaction is potentially safer with little toxicity, cheaper with a longer half-life, and has greater penetrating abilities than mAbs. We designed and synthesized peptides based on the binding of HER-2 with pertuzumab and VEGF with VEGFR2. We show that treatment with the peptide mimics induces potent anti-tumor responses in vitro as determined by cell viability, proliferation, and HER2 phosphorylation assays. We also demonstrate in a transplantable BALB/c mouse tumor model that treatment with the peptide mimics resulted in a greater delay in tumor growth and development. Similarly, treatment with the peptide mimics inhibited angiogenesis in vivo as assessed by a Matrigel plug assay. To address the problem of degradability of L-amino acid peptides in vivo, we synthesized the retro-inverso D-peptide mimics that resulted in higher efficacy in treatment. Our study shows that combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments.

The advent of next-generation antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), has transformed our understanding of human epidermal growth factor receptor 2 (HER2) targetability for breast cancer (BC) treatment. Historically categorized as HER2-positive or HER2-negative on the basis of trastuzumab eligibility, this classification has evolved significantly over the past 5 years. The DESTINY-Breast04 trial marked the entry of anti-HER2 therapies for patients with HER2-low BC, while DESTINY-Breast06 demonstrated the potential for earlier and broader use of T-DXd. The latter trial revealed that even minimal HER2 expression in tumors previously classified as HER2-0 might be clinically relevant and targetable with T-DXd. This has led to further refinement of HER2 classification, introducing the concepts of HER2-ultralow (HER2-0 with staining) and HER2-null BC (HER2-0 without staining). With these findings, most patients with metastatic BC are currently considered eligible for T-DXd. Accurately identifying candidates for these therapies has highlighted the limitations of current HER2 diagnostic practices, on the basis of immunohistochemistry (IHC)/in situ hybridization assessment. IHC assay, optimized to detect high levels of HER2 protein, faces limitations in discriminating finer variations at the lower end of the HER2 expression spectrum. This is further complicated by the heterogeneity of HER2 expression. To overcome these barriers, new approaches may be required. Quantitative methods for HER2 membrane assessment, genomic and transcriptomic evaluations of HER2, and the integration of artificial intelligence into tissue analysis hold promise and are currently under investigation. Additionally, noninvasive strategies, such as analysis of circulating tumor DNA or circulating tumor cells, may enable real-time HER2 status assessment and better patient selection for ADC. However, these techniques require rigorous validation to ensure their clinical utility. This evolving landscape underscores the need for improvement of diagnostic approaches to support the expanding role of ADCs in BC treatment.

Antibody-drug conjugates (ADCs)-a groundbreaking class of agents for targeted oncological therapies-consist of monoclonal antibodies with strong antigenic specificity coupled with highly active cytotoxic agents (also referred to as "payloads"). Over the past 2 decades, breast cancer research has evolved into a focal point for the research and development of ADCs, leading to several recent landmark publications. These advancements are ushering in a transformative era in breast cancer treatment and redefining conventional classifications by introducing a prospective subtype termed "HER2-low." The latest iterations of ADCs have demonstrated enhanced efficacy in disease management through the optimization of various factors, notably the incorporation of the bystander effect. These conjugates are no longer limited to the oncogenic driver human epidermal growth factor receptor 2 (HER2). Other antigens, including human epidermal growth factor receptor 3 (HER3), trophoblast cell surface antigen 2 (Trop-2), zinc transporter ZIP6 (LIV-1), and folate receptor α (FRα), have recently emerged as intriguing tumor cell surface nondriver gene targets for ADCs, each with one or more specific ADCs that showed encouraging results in the breast cancer field. This article reviews recent advances in the application of ADCs in the treatment of HER2-low breast cancer. Additionally, this review explores the underlying factors contributing to the impact of target selection on ADC efficacy to provide new insights for optimizing the clinical application of ADCs in individuals with low HER2 expression in advanced breast cancer.

Unveiling the future of breast cancer therapy: Cutting-edge antibody-drug conjugate strategies and clinical outcomes

Breast cancer is the most common cancer and the most important cause of cancer-related death in females worldwide. Antibody-drug conjugates (ADCs) represent a novel class of targeted therapies that combine the precision of monoclonal antibodies with the potent cell-killing activity of cytotoxic drugs. This review highlights recent mechanistic, technological, and clinical developments of ADCs in breast cancer, including next-generation ADCs beyond those that target HER2 (human epidermal growth factor receptor 2). Authors performed a systematic literature study for ADCs and their structural features, including their components (antibody, linker, and payload) and their therapeutic efficacy. A frame of preclinical research findings and clinical evidence integration of HER2-targeted therapy outcomes in HER2-positive, HER2-low, and triple-negative breast cancer (TNBC) subtypes were presented. Clinical studies of antibody-drug conjugates such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have demonstrated significant improvements in progression-free survival and overall survival across diverse breast cancer patient populations. ADCs offer unique advantages in breast cancer therapy by combining the precision of targeted antibodies with the potency of chemotherapy drugs. This allows them to selectively kill cancer cells, overcome resistance, reduce toxicity to healthy tissues, and expand treatment options for difficult subtypes like HER2-low and triple-negative breast cancer. Unlike previous reviews focusing on HER2-targeted ADCs, herein we review exciting ADCs targeting HER3 HER3 (human epidermal growth factor receptor 3) and Nectin-4, as well as the implications of bispecific and immune-stimulatory ADCs in the clinic. Additionally, it features mechanism-based innovations and novel trial data that revolutionize ADC applications in the HER2-low as well as the triple-negative breast cancer subtypes. The advent of ADC is changing precision oncology in breast cancer. With a new design and indications evolving, they are an attractive avenue for bypassing resistance and reducing toxicity and ultimately improving patient outcomes in the molecular subtypes. The present review summarizes recent advancements in antibody-drug conjugates (ADCs) and emerging targeted therapeutic strategies for breast cancer. It covers mechanistic insights, linker-payload innovations, receptor-based targeting approaches, clinical trial progress, and next-generation modalities that extend beyond HER2-directed ADCs. Current challenges, safety profiles, and future opportunities in engineering more selective and effective ADC platforms are also discussed.

The treatment of breast cancer with low expression of human epidermal growth factor receptor 2 (HER-2) has become a focused area in recent years. With the proved therapeutic effect of antibody-drug conjugates on breast cancer patients with HER-2-low expression, who has become a new targeting population in breast cancer. Recent studies have shown that patients with HER-2-ultralow breast cancer can also benefit from novel antibody-drug conjugates. To better standardize the rational clinical diagnosis and treatment of HER-2-low and HER-2-ultralow breast cancer, the Breast Cancer Working Group of the International Medical and Exchange Branch of the Chinese Anti-Cancer Association and the Chinese Medical Doctor Association Oncology Branch reviewed the latest domestic and international clinical studies and important publications in recent years. Integrating the clinical experience of Chinese pathologists and oncologists, and following expert panel discussions, a consensus on the clinical diagnosis and treatment of HER-2-low and HER-2-ultralow breast cancer was developed. This consensus aims to deepen clinicians' understanding of HER-2-low and HER-2-ultralow breast cancer, promote more precise clinical decision-making, and ultimately improve patient survival and quality of life.