Recently, the use of antibody-drug conjugates (ADCs) in the research and management of solid tumors has increased, making them a key focus in the field of oncology. In this study, we performed a comprehensive literature review of ADCs use in solid tumor treatment. We retrieved data from the Web of Science Core Collection (WoSCC). Following literature retrieval, we conducted a thorough bibliometric and knowledge-mapping analysis of the collected articles. There was a rapid growth in the number of annual publications in this field. The United States had the highest publication volumes and led ADC research for solid tumors. Additionally, The Dana-Farber Cancer Institute had the highest output, and G. Curigliano was identified as the most productive author. The journal "Cancers" led in the publishing of ADC research on solid tumors. Furthermore, key clustering terms such as "breast cancer," "targeted therapy," "bladder cancer," "ovarian cancer," "expression," and "drug delivery" emerged in this field as the research progressed. We identified six key themes by literature co-citation analysis, involving the research on the application of four ADCs in breast cancer, as well as the analysis of ADCs design, mechanisms, and strategies for reducing cytotoxicity. At the same time, based on the analysis of papers that have experienced a citation burst recently, we explored the future development trends of this field. Overall, our inaugural bibliometric analysis of ADCs for solid tumor research provides a systematic framework to guide future studies in this field. Therefore, facilitating and promoting further development in this area.

Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.

Rare cancers of the genitourinary (GU) tract are often clinically aggressive yet have few or no standard-of-care treatments. Multiple antibody-drug conjugates (ADCs) have been approved in solid malignancies. This review explores the use of ADCs in rare GU tumors in the context of biological pathways and ongoing research in solid tumors.

Few clinical trials of ADCs focus on recruiting participants with rare tumors of the GU tract, including trials testing enfortumab vedotin as monotherapy or combined with pembrolizumab, and sacituzumab govitecan as monotherapy or combined with atezolizumab. We highlight many ongoing trials of novel ADCs for advanced/metastatic solid tumors and emphasize the potential eligibility of patients with rare GU tumors for tumor-agnostic trials.

ADCs are being tested in multiple solid tumors, including rare GU tumors. Ongoing preclinical research supports the use of some ADCs in several rare GU tumors and improves our understanding of their pathophysiology.

In HER2+ breast cancer (BC), neoadjuvant therapy represents an ideal scenario for translational research, considering pathological complete response (pCR) as an endpoint. In these patients, achieving pCR after neoadjuvant therapy is associated with a better prognosis. However, biomarkers are needed to tailor optimal treatment for each patient. Evaluating tumour-infiltrating lymphocytes (TILs) has gained attention in predicting pCR. In the context of metastatic disease, TILs also appear to play a role in predicting outcomes. The interaction between the presence of TILs and reactive oxygen species (ROS) remains an area to be explored. ROS are critical for tumour cell homeostasis, and different levels can trigger differential biological responses in cancer cells and their microenvironment. Nevertheless, the influence of ROS on treatment efficacy and prognosis in patients with HER2+ BC remains to be elucidated. In this article, we reviewed the interplay between treatment response, immune system activation, and ROS production in HER2+ BC and suggested novel areas of intervention and research. We also present a bioinformatic analysis demonstrating that the altered expression of several redox-related genes could be associated with the prevalence of immune cell populations in the tumour microenvironment and with patient survival. New biomarkers are thus suggested and should be further explored to tailor the best treatment to each patient.

The design and construction of synthetic therapeutic protocells capable of engaging in high-order assembly with living cells represent a significant challenge in synthetic biology and bioengineering. Inspired by cell membrane receptor-ligand systems, a protocell bioreactor is developed for targeted cancer cell elimination. This is achieved by constructing orthogonal, polysaccharide-based protocells (polysaccharidosomes, P-somes) through a bottom-up approach that leverages host-guest chemistry. The protocells are assembled via electrostatically-driven self-assembly of β-cyclodextrin (β-CD)-modified amino-dextran on a sacrificial template encapsulating glucose oxidase (GOx). To enable specific cancer cell targeting and catalytic activity, cell-targeting ligands (arginylglycylaspartic acid, cRGD) and catalase-like platinum-gold nanoparticles (Pt-AuNPs) are introduced through host-guest interactions, forming a fully functional, cell-targeting, bio-catalytic killer protocell. These protocells are programmed to spatially couple the GOx/Pt-AuNP catalytic reaction cascade. In the presence of glucose and hydroxyurea, this cascade generates a localized flux of nitric oxide (NO), which is exploited for in vitro cancer cell inhibition. Overall, the results highlight the potential of integrating orthogonal and synergistic tumor inhibition mechanisms within synthetic microcompartments. This platform demonstrates promise for future therapeutic applications, especially in cancer treatment, and represents a step forward in the development of programmable protocell-based therapeutic systems.

Assessing cardiac risk prior to initiating breast cancer treatment, monitoring cardiac function during treatment, and implementing appropriate follow-up strategies are essential components of managing cardiotoxicity in breast cancer patients. A comprehensive cardiovascular evaluation should be conducted before treatment, including a detailed medical history, physical examination, and baseline cardiac imaging. Risk stratification tools can aid in determining the individual patient's risk profile. Close monitoring of cardiac function, including regular assessment of left ventricular ejection fraction (LVEF) and monitoring for signs and symptoms of cardiac dysfunction, is crucial during treatment. Prompt action should be taken if an adverse cardiovascular event is detected, including considering discontinuing or modifying the treatment regimen. Appropriate follow-up care is essential to monitor for long-term cardiac effects and optimize cardiovascular health in breast cancer survivors. Regular cardiovascular assessments, lifestyle modifications, and collaboration between healthcare professionals are important in managing cardiotoxicity effectively.

Cardiovascular toxicity is a significant side effect of breast cancer treatment and has emerged as a leading cause of non-tumor-related deaths among breast cancer survivors, emphasizing the critical need for effective monitoring and management of these complications. As breast cancer remains the most prevalent cancer among women, advancements in survival rates have been achieved through treatments such as chemotherapy, targeted therapy, endocrine therapy, immunotherapy, and radiotherapy. This review provides a comprehensive understanding of the cardiovascular toxicity mechanisms associated with both established and emerging breast cancer therapies, identifies potential therapeutic targets and monitoring strategies, and highlights key deficiencies and challenges in the field. By offering insights into the early detection, prevention, and management of cardiovascular complications, this review aims to guide future research directions and clinical practices, ultimately improving outcomes for breast cancer patients.

Tumor heterogeneity is a major obstacle to effective targeted therapies, including those utilizing antibody-drug conjugates (ADCs). Although some ADCs employ the bystander effect to eliminate neighboring antigen-negative cells, their efficacy often diminishes as antigen-positive cell populations decrease within heterogeneous tumors. To address this limitation in ADC therapies, we developed a novel ADC using a caspase substrate, Asp-Glu-Val-Asp (DEVD), as a linker to generate a more potent and sustained bystander effect. The DEVD ADC effectively targeted antigen-positive cells and released its payload via cathepsin B cleavage. Notably, it exhibited a significant bystander effect mediated by the caspase-3-triggered extracellular cleavage of the linker, enhancing payload release into the tumor microenvironment. In breast cancer xenograft models, the DEVD ADC maintained its efficacy and continued to exert a bystander effect even after the depletion of antigen-positive cells, thereby overcoming challenges posed by tumor heterogeneity. These findings emphasize the potential of DEVD linkers in enhancing ADC efficacy against heterogeneous solid tumors, offering a promising strategy to improve therapeutic outcomes.

Breast cancer is one of the most prevalent malignant tumors among women and ranks as the second leading cause of cancer-related deaths in females, primarily due to delays in diagnosis and shortcomings in treatment strategies. Consequently, there is a pressing need to identify reliable therapeutic targets and strategies. In recent years, the identification of effective biomarkers-particularly novel molecular therapeutic targets-has become a focal point in breast cancer research, aimed at predicting disease aggressiveness and monitoring treatment responses. Simultaneously, advancements in understanding the molecular mechanisms underlying cellular programmed death have opened new avenues for targeting kinase-regulated programmed cell death as a viable therapeutic strategy. This review summarizes the latest research progress regarding kinase-regulated programmed death (including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis) in breast cancer treatment. It covers the key kinases involved in this mechanism, their roles in the onset and progression of breast cancer, and strategies for modulating these kinases through pharmacological interventions.

Salivary Gland Carcinomas (SGC) are a heterogeneous group of diseases with varied histologies, biology, clinical behaviors, and therapeutic approaches. The World Health Organization classifies SGCs into Low Aggression and High Aggression categories. Due to their rarity and unique biology, managing SGCs is challenging, often requiring expert histological diagnosis and treatment based on low-level evidence. Despite recent international guidelines, several critical aspects of SGC management remain unresolved, in particular regarding systemic treatment. Recent discoveries of molecular alterations, such as HER2 amplification, and AR overexpression, have provided diagnostic, prognostic, and predictive biomarkers for alternative treatments. While some targeted treatment have corresponding EMA-approved therapies, others do not. Treatment strategies are further complicated by synchronous alterations, such as AR-positive SGCs with concomitant HER2 amplification. Open questions remain on the optimal use of these drugs, whether in early-stage disease, post-surgery, or in palliative settings. Given the rarity of the disease and the consequent lack of high quality data in literature, it is of importance a cross-fertilization process from other, more common disease such as breast and prostate cancers. In the current narrative review we analyze current evidence on the targeted treatment on salivary gland carcinomas and shared features with breast and prostate cancer.

Therapeutic affinity proteins offer a targeted mode of action due to their typically high affinity and specificity for disease-associated molecules. In cancer therapy, such target molecules are often overexpressed receptors on tumor cells. However, their presence in healthy tissues can lead to on-target, off-tumor toxicity, necessitating strategies to enhance tumor selectivity. Here, we present an affibody-based prodrug concept that exploits tumor-associated proteases for selective activation. As proof of concept, we designed, produced, and characterized HER2-specific prodrug candidates, each incorporating a distinct protease substrate for selective activation by tumor-associated proteases. Their activation by corresponding proteases and subsequent HER2 binding were assessed. The most promising prodrug candidate was conjugated to the cytotoxic agent DM1 and evaluated for cytotoxicity in HER2-positive cancer cells. The results demonstrated potent, HER2-dependent cell killing, with markedly reduced cytotoxicity in the absence of prodrug activation. These findings support the feasibility of affibody-based prodrugs as a strategy to enhance tumor selectivity and minimize off-tumor toxicity in targeted cancer therapy.

Antibody-drug conjugates (ADCs) have demonstrated remarkable therapeutic efficacy in refractory cancers, however, ophthalmotoxicity remains a serious concern. This study aimed to investigate the association between ADCs and ophthalmotoxicity.

A retrospective pharmacovigilance study was conducted utilizing data extracted from the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) from 2004 to 2023. Disproportionality analyses were performed using the reporting odds ratio (ROR) and information component (IC), with sensitivity analyses and subgroup evaluations by age and sex.

A total of 1992 cases of ophthalmotoxicity linked to ADCs were identified, with a median latency of 40 days. The correlation between ophthalmotoxicity and ADCs was higher than with other medications (IC = 0.67, 95% CI:0.64-0.70). Signal detection revealed 36 adverse events unreported in product labeling. Sensitivity analyses confirmed the robustness of our results on the association between ADCs and ocular toxicity, with higher reporting in females compared to males (OR = 1.25, 95% CI: 1.11-1.40).

ADCs had different profiles of ophthalmotoxicity. Our pharmacovigilance study suggested increased reporting of ophthalmotoxicity associated with ADCs.

Over the past several decades, there has been a significant increase in the number of breast cancer patients. Among the four subtypes of breast cancer, Her2-positive breast cancer is one of the most aggressive breast cancers. In this study, we screened the differentially expressed genes from The Cancer Genome Atlas-Breast cancer database and analyzed the relationship between immune cell infiltration and differentially expressed genes using weighted gene co-expression network analysis. By constructing a module-trait relationships heatmap, the red module, which had the highest correlation value with M1 macrophages, was selected. Twenty hub genes were selected based on a protein-protein interaction network. Then, four overlapping M1 macrophage infiltration-related genes (M1 MIRGs), namely CCDC69, PPP1R16B, IL21R, and FOXP3, were obtained using five machine-learning algorithms. Subsequently, nomogram models were constructed to predict the incidence of Her2-positive breast cancer patients. The outer datasets and receiver operating characteristic curve analysis were used to validate the accuracy of the four M1 MIRGs and nomogram models. The average value of the area under the curve for the nomogram models was higher than 0.75 in both the training and testing sets. After that, survival analysis showed that higher expression of CCDC69, PPP1R16B, and IL21R were associated with overall survival of Her2-positive breast cancer patients. The expression of CCDC69 and PPP1R16B could lead to more benefits than the expression of IL21R and FOXP3 for immunotherapy. Lastly, we conducted immunohistochemistry staining to validate the aforementioned results. In conclusion, we found four M1 MIRGs that may be helpful for the diagnosis, prognosis, and immunotherapy of Her2-positive breast cancer.

Real-time imaging of antibody-drug conjugates (ADCs) offers valuable insights for assessing tumor targeting specificity, monitoring therapeutic efficacy, and detecting off-target accumulation that may cause adverse effects. To enable precise tracking, we developed a versatile fluorescent platform based on an NIR-II emitting aza-BODIPY dye, which can be site-specifically grafted onto an IgG1 antibody to generate well-defined fluorescent ADCs. As a proof of concept, we synthesized an HER2-targeting trastuzumab immunoconjugate bearing a NIR-II aza-BODIPY fluorophore. The cytotoxic monomethyl auristatin E (MMAE) payload was introduced in the final step, resulting in a trackable and homogeneous ADC suitable for both in vitro and in vivo investigations. The resulting Trastu-azaNIRII-MMAE selectively accumulated in HER2-positive subcutaneous tumors, significantly reducing the tumor growth. Using NIR-II optical imaging, a single injection of the NIR-II-ADC allowed for the detection of the conjugate over a period of more than one month, highlighting its potential for long-term tracking and therapeutic applications.

As novel human epidermal growth factor receptor-2 (HER2) and drug conjugates have proven to be effective treatments for both HER2-positive breast cancer (BC) and HER2-low BC, the need to develop more accurate methods to quantify HER2 status has increased. We compared the correlation between the HER2 mRNA score (HS), obtained using the Oncotype DX (ODX) test, and HER2 immunohistochemistry (IHC) to verify the accuracy of HER2 quantification and its correlation with clinicopathologic characteristics. We retrospectively collected ODX test data from 1524 estrogen-receptor positive, HER2-negative patients with BC. No significant differences in clinicopathologic characteristics, including ODX Recurrence Score (RS), were observed between HER2-0 and HER2-low BC. The median HS value of the HER2-low subgroup was significantly higher than that of the HER2-0 subgroup ( P <0.001) and increased significantly between the 4 subgroups classified by HER2 IHC ( P <0.001). The receiver operating characteristic curve showed acceptable utility in distinguishing HER2-0 from HER2-low (area under the curve=0.76) and HER2-null and HER2-ultralow subgroups (area under the curve=0.81), but the overlap between subgroups was also prominent. After defining 8.9 as a suboptimal cutoff mRNA score, multivariate analysis revealed that low Ki-67 (<20%) and RS (≤25) were statistically associated with higher HS (>8.9), whereas progesterone receptor negativity, high Ki-67, high nuclear grade, lower HS, and older age (>50 y) were statistically associated with high RS. Our study revealed that HS is significantly associated with HER2 IHC results and clinicopathologic parameters other than HER2 IHC.

Breast cancer remains a major global health challenge. While advances in precision oncology have contributed to improvements in patient outcomes and provided a deeper understanding of the biological mechanisms that drive the disease, historically, research and patients' allocation to treatment have heavily relied on single-omic approaches, analyzing individual molecular dimensions such as genomics, transcriptomics, or proteomics. While these have provided deep insights into breast cancer biology, they often fail to offer a complete understanding of the disease's complex molecular landscape.

In this review, the authors explore the recent advancements in multi-omic research in the realm of breast cancer and use clinical data to show how multi-omic integration can offer a more holistic understanding of the molecular alterations and their functional consequences underlying breast cancer.

The overall developments in multi-omic research and AI are expected to complement precision diagnostics through potentially refining prognostic models, and treatment selection. Overcoming challenges such as cost, data complexity, and lack of standardization is crucial for unlocking the full potential of multi-omics and AI in breast cancer patient care to enable the advancement of personalized treatments and improve patient outcomes.

With treatment options for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) expanding, updated assessments of contemporary treatment patterns and clinical outcomes are needed. This study aimed to conduct such an assessment using data from real-world oncology practices.

Adult HER2+ mBC patients initiating first-line (1L) treatment from January 2013 to January 2021 (index date) were selected from the US Flatiron Health database and followed through January 2022. Patient characteristics and treatment patterns were summarized. Clinical outcomes were examined using Kaplan-Meier analyses.

Among 2074 HER2+ mBC patients with at least 1 line of therapy (LoT), median age was 61 years and 62.8% had known hormone receptor-positive disease. During a median follow-up of 26.0 months, 1159 (55.8%) had at least 2 LoTs, and 584 (28.2%) had 3 or more. The most common 1L regimens included docetaxel, trastuzumab, and pertuzumab (THP; 38.9%) followed by THP+ platinum agent (7.5%) and ado-trastuzumab emtansine (T-DM1) monotherapy (6.1%). By the end of follow up, 18.1% of patients remained on treatment, 20.2% died, and 5.8% discontinued without starting a new treatment. Median overall survival from 1L start was 40.3 months.

Approximately one-quarter of the patients died or discontinued 1L therapy without receiving further treatment. Overall survival from the start of 1L was just over 3 years. This highlights a need for more effective therapies in earlier LoTs that prolong the time to progression and provide longer clinical benefits.

Concurrent chemo-radiotherapy is standard of care for locally advanced cancer patients. While radiotherapy and immuno-oncology have advanced precision oncology, chemotherapies in the chemo-radiotherapy paradigm remain non-targeted cytotoxins. Antibody drug conjugates offer an opportunity for targeted radiosensitization that stimulates immune responses while protecting normal tissues. Here, we discuss the rationale for combining antibody drug conjugates, radiotherapy and immunotherapies and opportunities for clinical translation to advance towards targeted chemo-radio-immunotherapy precision cancer care.

Antibodies are therapeutic proteins with many applications in medicine, such as treating viral infections, different types of cancer, and common diseases such as psoriasis and multiple sclerosis. Chinese Hamster Ovary (CHO) cells are the most widely used cells for antibody production due to their well-established use and favorable features. However, the current design of antibody production systems often relies on a "trial and error" approach to manipulate CHO cells. This approach is time-consuming and costly, and can lead to suboptimal process performance. The use of mathematical models has the potential to greatly accelerate and improve the design and optimization of antibody production. Starting from a systematic and formal approach, the aim is to achieve an automatic design of the whole process that allows optimal productivity to be reached. To this end, we develop mathematical models and methods for the design and optimization of antibody manufacturing systems. The mathematical models are based on Flexible Nets (FNs), a modeling formalism that accommodates uncertain parameters and nonlinear dynamics. FNs enable the development of comprehensive models that encompass both the metabolic network of CHO cells and the dynamics of the bioreactor in which the cells are cultured. Thus, by integrating macroscopic variables (e.g. dilution rate, substrate concentration, cell density, etc.) with microscopic variables (such as intracellular metabolic fluxes), our model represents a multi-scale system and facilitates global optimization.

Colorectal cancer is the second leading cause of cancer-related deaths following lung cancer in recent years. Therefore, lung or colorectal cancer therapy is very important for reducing mortality. In this study, we developed and characterized CD47-specific antibody-drug conjugates, namely 7DC-DM1 ADCs, to evaluate their therapeutic effects on lung and colorectal cancer. Both 7DC2-DM1 and 7DC4-DM1 demonstrated good binding affinities of 0.56 nM and 0.49 nM, respectively, and exhibited significant cytotoxicity, though they displayed different penetration effects. These findings suggest that the binding complexes of 7DC2-DM1 and 7DC4-DM1 with CD47 receptors adopt different conformations, leading to variations in their cellular internalized efficiencies. Molecular docking simulations revealed that 7DC2 and 7DC4 bind to CD47 molecules in distinct orientations and epitopes, differing between conserved and non-conserved regions. Furthermore, treatments with 7DC2-DM1 and 7DC4-DM1 displayed notable differences in antitumor effects in murine syngeneic tumor models derived from the MC38 cell line in C57BL/6 mice. In the tumor model treated with 7DC4-DM1, immunofluorescence staining analysis revealed a large area of necrosis in the tumor stroma, accompanied by a significant infiltration of CD11b-expressing immune cells. In summary, these results indicate that 7DC4-DM1 holds promise as a therapeutic agent for colorectal cancer treatment.

This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2-amplified biliary tract cancer (BTC).

This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort.

Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2-amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2-amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001).

HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2-amplified BTC derive significant benefit from HER2-targeted therapy.

Approximately 50%-74% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients.

In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400 mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cutoff date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% confidence interval [CI], 8.3 to 18.5). With all patients evaluated, an ORR of 38.9% (95% CI, 23.1 to 56.5) and a DCR of 83.3% (95% CI, 67.2 to 93.6) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs.

Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Breast cancer remains a leading cause of cancer-related mortality worldwide, with elderly patients (aged >65 years) comprising a substantial portion of those affected. The treatment of breast cancer in this population is often complicated by frailty, comorbidities and polypharmacy. This review explores the application of antibody-drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), in treating breast cancer among elderly populations. The underrepresentation of older patients in clinical trials complicates efficacy and safety assessments in this group. Current evidence indicates that ADCs are both effective and tolerable in elderly patients, demonstrating improved progression-free survival (PFS) and overall survival (OS) alongside a manageable safety profile. Data from several trials like the EMILIA, TH3RESA and DestinyBreast studies demonstrate that T-DM1 and T-DXd maintained benefit in PFS and OS for HER2-positive breast cancer in older patients, despite a slight increase in adverse events. The ASCENT and TROPiCS-02 trials further confirm that SG provides significant improvements in PFS and OS in elderly patients at the cost of an increase in some toxicity. Emerging ADCs, including datopotamab deruxtecan and ARX-788, show promise but lack extensive geriatric-specific data. While the ADCs offer encouraging results in terms of efficacy and safety, with appropriate dose adjustments, further research is needed to optimize their use in elderly patients with breast cancer.

Breast cancer (BC) remains a significant threat to women's health worldwide. The oncology field had an exponential growth in the abundance of medical images, clinical information, and genomic data. With its continuous advancement and refinement, artificial intelligence (AI) has demonstrated exceptional capabilities in processing intricate multidimensional BC-related data. AI has proven advantageous in various facets of BC management, encompassing efficient screening and diagnosis, precise prognosis assessment, and personalized treatment planning. However, the implementation of AI into precision medicine and clinical practice presents ongoing challenges that necessitate enhanced regulation, transparency, fairness, and integration of multiple clinical pathways. In this review, we provide a comprehensive overview of the current research related to AI in BC, highlighting its extensive applications throughout the whole BC cycle management and its potential for innovative impact. Furthermore, this article emphasizes the significance of constructing patient-oriented AI algorithms. Additionally, we explore the opportunities and potential research directions within this burgeoning field.

Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These "magic bullets" have a complex structure, including a monoclonal antibody, a linker, attachment sites, and a payload usually disrupting microtubules, targeting DNA, or inhibiting topoisomerase 1. By targeting specific tumor antigens, they are expected to be exquisitely effective in releasing "supertoxic" payloads inside tumor cells after intracellular trafficking. Additionally, they may exert a bystander effect, wherein the released payloads act on neighboring cells, amplifying their therapeutic impact regardless of target expression. ADCs have been game-changing drugs to treat tumors with once dismal prognoses or with previously considered unactionable targets, such as HER2-low or triple-negative breast cancer. To what extent there is room for personalized medicine to improve the toxicity/efficacy ratio remains unknown. However, there are inherent issues related to the complexity of the pharmacokinetics of ADCs and their assessments: efficacy or toxicity may be influenced by the clearance of the intact ADC, the circulating payload, or the payload-linker complex. Deciphering these multifaceted exposure-outcomes relationships for both efficacy and safety endpoints, is critical for advancing precision medicine and enabling personalized dosing strategies. To improve future developments and broaden their therapeutic scope, several strategies can be developed, including developing adequate combinations with other treatment classes (cytotoxic agents, immune-checkpoint inhibitors, oral molecular-targeted therapies). In this review, we will discuss the PK/PD aspects of ADCs and their dosing to improve their use in current and future indications.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is an effective therapy for HER2-positive breast cancer; however, its efficacy is limited by drug resistance. While multiple mechanisms of resistance have been proposed, these are not yet well understood. Greater understanding of T-DM1 sensitivity and resistance could provide new combination strategies to overcome resistance or predictive biomarkers to guide therapy.

We have conducted CRISPR/Cas9 functional genomics modifier screens in HER2-positive breast cancer cell lines to allow for unbiased discovery of T-DM1 sensitivity and resistance genes. Whole-genome knockout screens were carried out in MDA-MB-361 and MDA-MB-453 cells treated with T-DM1 and its payload cytotoxin DM1. Hits were validated in secondary T-DM1 screens using a focused single-guide RNA (sgRNA) library and subsequently by individual gene knockout.

The whole-genome CRISPR screens with T-DM1 and DM1 identified 599 genes as potential modifiers of T-DM1 sensitivity and resistance. Of these, 17 genes were significantly enriched and 3 genes depleted at P < 0.001 in either or both MDA-MB-361 and MDA-MB-453 libraries in the secondary screens. Among the top hits, were known T-DM1 sensitivity genes ERBB2 and SLC46A3, in addition to negative regulators of mTOR complex 1: TSC1 and TSC2. MDA-MB-453 clones with knockout of TSC1 or partial knockout of TSC2 were more resistant to T-DM1 than wild type cells in competition growth assays and to T-DM1 and other HER2 targeting therapies (T-DXd, lapatinib and neratinib) in growth inhibition assays, and had increased internalisation of T-DM1 at 6 h. T-DM1 and the mTOR inhibitor everolimus demonstrated synergistic activity at inhibiting cell proliferation at multiple T-DM1 concentrations across four HER2-positive breast cancer cell lines.

Our CRISPR screening approach with T-DM1 in HER2-positive breast cancer cell lines identified genes not previously implicated in T-DM1 sensitivity or resistance, including TSC1 and TSC2. These genes may inform new strategies to enhance T-DM1 therapy in the clinic.

Antibody-drug conjugates (ADCs) offer a promising therapeutic approach for various cancers, enhancing the therapeutic window while mitigating systemic adverse effects on healthy tissues. ADCs have achieved remarkable clinical success, particularly in treating breast cancer, becoming a standard therapy across all subtypes, including hormone receptor-positive, human epidermal growth factor receptor 2-positive, and triple-negative breast cancer. Although designed to selectively target antigens via monoclonal antibodies, ADCs can exhibit toxicity in normal tissues, often due to off-target effects of their cytotoxic payloads. Understanding and managing these toxicities according to established guidelines are crucial for enhancing ADC clinical efficacy, minimizing adverse events, and ultimately improving patient outcomes. This review comprehensively examines the toxicities of ADCs employed in breast cancer treatment and explores their management strategies. Furthermore, we investigate novel ADCs beyond trastuzumab deruxtecan and sacituzumab govitecan, evaluating their potential efficacy and corresponding safety profiles.

Antibody-drug conjugates (ADCs) are a rapidly evolving class of antitumor drugs and have already revolutionized the treatment strategy of many hematologic and solid cancers. So far, trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) are the four ADCs that have been approved by US food and drug administration (FDA) in treatment of breast cancer, and SKB264 has been approved by Chinese national medical products administration (NMPA). Many ADCs for treatment of breast cancer are currently being tested in late-phase clinical trials, with several encouraging results achieved recently. However, major issues arise during the use of ADCs, including emergence of acquired resistance, occurrence of treated-related toxicities, and identification of biomarkers of response and resistance. ADCs are being increasingly tested in combination with other agents, and novel next-generation ADC development is progressing rapidly. A better understanding of the design and development of ADCs will promote ADC development for cancer treatment. In this review, we aim to provide a broad overview of the design and the recent advances of ADCs in breast cancer. We also propose several notable future directions of ADCs in treatment of breast cancer.

BackgroundCompassionate drug use (CDU) is a topic of debate in the scientific community characterized by a lack of information, especially in the onco-hematology area.AimThe Compass-O study aimed to provide updated data on CDU of onco-hematological drugs for the period 2016-2021.MethodCompass-O is a retrospective observational study with data obtained from 7 Italian Units for cytotoxic drug preparations (Unità Farmaci Antiblastici, UFA). Drugs and Therapeutic Indications (TI) were described separately and as drug-TI combinations, providing the mean Patients Per Year (mPPY) and the Years of Use (YoU).ResultsA total of 783 requests of CDU were retrieved, referring to 156.3 mPPY (max: 272 in 2021; min: 84 in 2018). The 52.2% of subjects was female, and the 63.2% aged >60 years. A total of 709 (90.5%) CDUs referred to solid tumors and 74 (9.5%) to liquid tumors. CDU referred to 93 drug-TI combinations. The most recurrent drug-TIs were nivolumab-lung carcinoma (mPPY: 36.5; YoU: 2) for solid tumors, and azacytidine-acute myeloid leukemia (6.0; 1) for liquid tumors. The most frequent TIs were lung carcinoma (45.7; 6) and breast cancer (37.0; 4) for solid tumors, and chronic lymphocytic leukemia (5.0; 2) and multiple myeloma (4.7; 6) for liquid tumors.ConclusionCompass-O provided an updated framework of the CDU in onco-hematology, showing its large-scale phenomenon and the relevance of UFA as a data source, underlining the need for a national observatory to monitor CDU.

This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.

Triple-positive breast cancer (TPBC), a unique subtype of luminal breast cancer, is characterized by concurrent positivity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Owing to the crosstalk between the ER and HER2 signaling pathways, the standard of care and drug resistance of this particular subtype are difficult challenges. Recent research and clinical trials have indicated a shift in the treatment paradigm for TPBC from single-target therapies to multi-pathway, multitarget strategies aiming to comprehensively modulate intricate signaling networks, thereby overcoming resistance and enhancing therapeutic outcomes. Among multiple strategies, triple-drug therapy has emerged as a promising treatment modality, demonstrating potential efficacy in patients with TPBC. Moving forward, there is a critical need to perform in-depth analyses of specific mechanisms of cancer pathogenesis and metastasis, decipher the complex interactions between different genes or proteins, and identify concrete molecular targets, thus paving the way for the development of tailored therapeutic strategies to combat TPBC effectively.

HER2-positive gastric cancer (GC), a unique molecular subtype, has garnered significant interest in recent years. Here, we review clinical trial data on advanced HER2-positive GC from the past 15 years. Trastuzumab plus standard chemotherapy remain the first-line treatment. The initial survival benefits conferred by immune checkpoint inhibitors plus trastuzumab and standard chemotherapy are encouraging. The combination of ramucirumab and mono-chemotherapy, as well as the antibody conjugated drug trastuzumab deruxtecan, is the recommended second-line regimen. Treatment with immune checkpoint inhibitors plus ramucirumab and mono-chemotherapy shows promise. Despite the limited treatment options for third line and beyond, development of novel therapeutic strategies is expected. Although clinical cure of advanced HER2-positive GC is unlikely, current clinical studies offer valuable insight into regimens that prolong survival.

Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H2O2, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H2O2-rich microenvironments (H2O2 hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H2O2 underwent partial epithelial-mesenchymal transition through p38-MYC axis activation and migrated away from H2O2 hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H2O2 hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation.

Most HER2-positive breast or gastric cancers eventually become resistant to the approved anti-HER2 antibody-drug conjugates (ADC) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Disitamab vedotin (DV) is a novel anti-HER2 ADC that binds to a different epitope on HER2 compared to trastuzumab. We assessed the efficacy of DV in breast and gastric cancer cell lines and xenografts, including tumor models resistant to T-DM1 and T-DXd. Additionally, we investigated whether combining two anti-HER2 ADCs could enhance the efficacy of the individual ADCs.

The efficacy of DV, T-DM1, and T-DXd, both as single agents and in combinations, was assessed using an AlamarBlue cell proliferation assay in HER2-positive breast and gastric cancer cell lines, including those resistant to T-DM1 and T-DXd. The efficacy of DV was evaluated also in breast and gastric cancer SCID mouse xenografts that had progressed on T-DM1 and/or T-DXd. ADC combinations were tested in breast and gastric cancer xenografts.

DV was effective in cell lines resistant to T-DM1 and/or T-DXd, and it inhibited the growth of breast and gastric cancer xenografts that had progressed on T-DM1 and/or T-DXd. The combinations of DV plus T-DM1 and DV plus T-DXd showed greater efficacy than the corresponding single agents in both breast and gastric cancer cell lines and xenografts.

DV was effective in treating breast and gastric cancer xenograft tumors resistant to T-DM1 and/or T-DXd. The combination of DV with T-DM1 or T-DXd demonstrated promising activity.

Antibody-drug conjugates are novel antineoplastic agents whose use is expanding, both in terms of the number of drugs and the number of patients being treated. This article reviews the known toxicities and complications of antibody-drug conjugates that are currently approved for the treatment of cancer in the United States, with a focus on their emergency presentation and management. Similar to many other cancer therapies, most antibody-drug conjugates can cause diarrhea, nausea/vomiting, rash, peripheral neuropathy, and cytopenia, which are generally treated following standard-of-care. Interstitial lung disease, which may mimic pneumonia and cause respiratory failure and death, has been seen with trastuzumab deruxtecan and mirvetuximab soravtansine; emergency treatment of this condition includes oxygenation, ventilatory support, and corticosteroids. Inotuzumab ozogamicin and gemtuzumab ozogamicin are both associated with sinusoidal obstruction syndrome, a potentially fatal liver dysfunction that presents with weight gain, fluid overload, and jaundice. Abnormal liver function tests in patients who have been recently treated with these agents should be cautiously evaluated. Cardiac adverse events with antibody-drug conjugates are rare, but trastuzumab emtansine and trastuzumab deruxtecan may cause a decrease in cardiac contractility, and heart rate corrected QT interval prolongation is a rare effect of trastuzumab deruxtecan. Ocular adverse events, especially blurred vision, and keratopathy, are common with mirvetuximab soravtansine and tisotumab vedotin. Progressive multifocal leukoencephalopathy has been reported with brentuximab vedotin and polatuzumab vedotin. Tumor lysis syndrome may occur after treatment with gemtuzumab ozogamicin, polatuzumab vedotin, and brentuximab vedotin. Patients receiving enfortumab vedotin or brentuximab vedotin may develop hyperglycemia, sometimes presenting as diabetic ketoacidosis. Tisotumab vedotin and trastuzumab emtansine are associated with bleeding; although it is minor in most cases, severe bleeding and intracranial hemorrhage have occurred. Several antibody-drug conjugates can cause an anaphylactoid infusion-related reaction, which occurs most commonly during or soon after infusion but may be delayed up to 24 hours. Further research is needed to establish the real-world incidence of rare complications and how often patients with these complications present to the emergency department.

The advent of Antibody-Drug Conjugates (ADC) represents a significant advancement in targeted therapy for gynaecological malignancies. However, the ocular toxicities associated with ADCs, particularly Tisotumab Vedotin (TV) and Mirvetuximab Soravtansine (MIRV) necessitate effective mitigation in order to optimise patient care.

This review synthesises findings from clinical trials to delineate the spectrum of ocular adverse events induced by ADCs. The analysis focuses on the incidence, onset, severity and reversibility of adverse events. It examines the underlying mechanisms of toxicity and provides management strategies based on study protocols.

Adverse events mainly impact the anterior ocular segment, resulting in conjunctivitis and keratopathy. They affect up to 56 % of patients treated with MIRV and 50 to 60 % of those receiving TV. Symptoms like blurred vision, dryness and pain hinder the patient's quality of life. Events are CTCAE grade 3 or higher in less than 10 % of cases. The median time to onset is 1.3 months. However, ocular toxicity may appear up to 10 months after treatment initiation, indicating a need for prolonged vigilance. Primary prophylaxis calls for local corticotherapy, lubricants and in some cases, vasoconstrictors. Despite the potential for severity, most cases are reversible with local treatment and transient dose reduction and/or delay. Close monitoring is crucial for early detection and subsequent management.

Clinicians ought to be cognizant of the potential ocular toxicity of ADCs. Proactive prophylaxis, patient education and a multidisciplinary approach involving ophthalmologists are paramount to minimising the impact of these AEs. Further research is essential to measure the real outcome of preventive strategies and balance their benefits with potential short and long-term risks.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .

Breast cancer remains the most prevalent malignancy among women globally and ranks as the leading cause of cancer-related mortality in this demographic. Approximately 13 %-15 % of all breast cancer cases are classified as HER2-positive, a subtype associated with a particularly unfavorable prognosis. A large number of patients with HER2-positive breast cancer continue to face disease progression after receiving standardized treatment. Given these challenges, a thorough exploration into the mechanisms underlying drug resistance in HER2-targeted therapy is imperative. This review focuses on the factors related to drug resistance in HER2-targeted therapy, including tumor heterogeneity, antibody-binding efficacy, variations in the tumor microenvironment, and abnormalities in signal activation and transmission. Additionally, corresponding strategies to counteract these resistance mechanisms are discussed, to advance therapeutic efficacy and clinical benefits in the management of HER2-positive breast cancer.