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The main objective of this study is to determine whether the employment of fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC; and Phesgo as brand name) to treat metastatic HER2-positive breast cancer patients would minimize costs compared to the traditional treatment of separate intravenous doses of pertuzumab and trastuzumab in Peru. To achieve this, we used EsSalud (the social security health insurance) data and assessed it through a mixed strategy, which consisted of a quantitative and a qualitative approach. The first one aimed to calculate the direct (non-drug consumables, drugs, and healthcare professionals) and indirect costs of both treatments to develop a comparison, whilst the second aimed to validate information and internalize the procedure in an EsSalud context. Overall, we found that the usage of PH FDC SC would be cost saving in EsSalud's context. Specifically, we found three main advantages. Firstly, PH FDC SC generates a savings of 62% in non-drug consumables, which helps alleviate the healthcare system budget constraint. Secondly, its adoption frees up 61 hours of treatment and observation time for a single patient per year, which in turn increases the attention capacity of the healthcare system in terms of nursing hours and chemotherapy couches. Thirdly, the reduction of clinic time supposes an advantage for the patient in the form of increased productivity and well-being. Hence, the adoption of this drug would improve the quality of life of patients while reducing costs and pressure on the healthcare system. This is aligned with the strategy of prioritizing the appropriate breast cancer treatment within the National Cancer Care Plan. In this regard, we also found that the savings produced from switching from the traditional intravenous treatment to the subcutaneous one would allow EsSalud to afford full annual costs of 2 additional treatments, but without increasing their budget. This would cover 7% of the gap of 29 patients who do not have access to full treatment. [ABSTRACT FROM AUTHOR]

HER2 antagonists remain the cornerstone of therapy for patients with HER2-positive breast cancer. This study introduces a novel small-molecule inhibitor of DNA methyltransferase 1 (DNMT-1), referred to as DI-1, designed to synergize with HER2 antagonists in treating HER2-positive breast cancer cells. Clinical data reveal a negative correlation between DNMT-1 expression and PTEN levels, and a positive correlation with the methylation rates of PTEN's promoter. In experiments with SKBR3 and BT474 cells, DI-1 effectively reduced the methylation of PTEN's promoter region, thereby upregulating PTEN expression. This upregulation, in turn, enhanced the cells' sensitivity to HER2 antagonists, indicating that DI-1's mechanism involves inhibiting DNMT-1's recruitment to PTEN's promoter region. Consequently, by increasing PTEN expression, DI-1 amplifies the sensitivity of HER2-positive breast cancer cells to treatment, suggesting its potential as a promising therapeutic strategy in this context. [ABSTRACT FROM AUTHOR]

Gold nanorods (AuNRs) are powerful photothermal agents (PTAs) in cancer treatment due to their near-infrared laser light absorption ability. However, the cytotoxicity of AuNRs caused by the presence of cationic surfactants often used and their lack of specificity affect their application in photothermal therapy. Thus, we herein developed a bioconjugate obtained from the functionalisation of AuNRs to gelatin (Gel@AuNRs), followed by the conjugation of the as-synthesised material to a breast cancer antibody, trastuzumab (Trast-Gel@AuNRs) to address these issues. The optical and structural characterization of the as-synthesized indicated no significant changes in the optical properties of AuNRs after their functionalisation with gelatin and conjugation with the antibody. The photothermal profiling of the as-synthesised materials showed that AuNRs still have an excellent photothermal conversion efficiency (PCE) after their functionalisation (20%) and their conjugation to an antibody (19%). In addition, the In vitro photothermal depth response showed that Trast-Gel@AuNRs is a promising photothermal agent for HER2-positive breast cancer treatment. [ABSTRACT FROM AUTHOR]

Relapse and metastasis occur in 30–40% of breast cancer patients, even after targeted treatments like trastuzumab for HER2-positive breast cancer. Accurate individual prognosis is essential for determining appropriate adjuvant treatment and early intervention. This study aims to enhance relapse and metastasis prediction using an innovative framework with machine learning (ML) and ensemble learning (EL) techniques. The developed framework is analyzed using The Cancer Genome Atlas (TCGA) data, which has 123 HER2-positive breast cancer patients. Our two-stage experimental approach first applied six basic ML models (support vector machine, logistic regression, decision tree, random forest, adaptive boosting, and extreme gradient boosting) and then ensembled these models using weighted averaging, soft voting, and hard voting techniques. The weighted averaging ensemble approach achieved enhanced performances of 88.46% accuracy, 89.74% precision, 94.59% sensitivity, 73.33% specificity, 92.11% F-Value, 71.07% Mathew's correlation coefficient, and an AUC of 0.903. This framework enables the accurate prediction of relapse and metastasis in HER2-positive breast cancer patients using H&E images and clinical data, thereby assisting in better treatment decision-making. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of breast cancer associated with a poor prognosis when sub-optimally treated. Recent advances include new and effective targeted therapies that have significantly improved outcomes for patients. Despite these advances, there are significant gaps across Canada, underscoring the need for evidence-based consensus guidance to inform treatment decisions. Addressing these gaps is crucial to ensuring that effective therapies are integrated into clinical practice, so as to improve the lives of patients affected by this aggressive form of breast cancer. The Research Excellence, Active Leadership (REAL) Canadian Breast Cancer Alliance is a standing nucleus committee of clinical-academic oncologists across Canada and Breast Cancer Canada, a patient organization. The mandate of this group is to provide evidence-based guidance on best practices in the management of patients with breast cancer. These consensus recommendations were developed using a modified Delphi process with up to three rounds of anonymous voting. Consensus was defined a priori as ≥75% of voters agreeing with the recommendation as written. There are 9 recommendations in the early setting; 7 recommendations in the metastatic setting; and 10 recommendations for patients with brain metastases. [ABSTRACT FROM AUTHOR]

[Display omitted] Breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) have poor prognosis. Moreover, available chemotherapies cause numerous side effects due to poor selectivity. To advance more effective and safer therapies for HER2-positive breast cancer, we explored the fusion of drug delivery technology and immunotherapy. Our research led to the design of immunocubosomes loaded with panobinostat and functionalized with trastuzumab antibodies, enabling precise targeting of breast cancer cells that overexpress HER2. We characterised the nanostructure of cubosomes using small-angle X-ray scattering (SAXS), cryo-transmission electron microscopy (cryo-TEM), and dynamic light scattering (DLS). Moreover, we confirmed the integrity of the trastuzumab antibodies on the immunocubosomes by Fourier-transform infrared spectroscopy (FTIR) and sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Additionally, we found that panobinostat-loaded immunocubosomes were more cytotoxic, and in an uptake-dependant manner, towards a HER2-positive breast cancer cell line (SKBR3) compared to a cell line representing healthy cells (L929). These results support that the functionalization of cubosomes with antibodies enhances both the effectiveness of the loaded drug and its selectivity for targeting HER2-positive breast cancer cells. [ABSTRACT FROM AUTHOR]

TRPM7 is a divalent cation-permeable channel that is highly active in cancer cells. The pharmacological inhibitors of TRPM7 have been shown to suppress the proliferation of tumor cells, highlighting TRPM7 as a new anticancer drug target. However, the potential benefit of combining TRPM7 inhibitors with conventional anticancer therapies remains unexplored. Here, we used genome-wide transcriptome profiling of human leukemia HAP1 cells to examine cellular responses caused by the application of NS8593, the potent inhibitor of the TRPM7 channel, in comparison with two independent knockout mutations in the TRPM7 gene introduced by the CRISPR/Cas9 approach. This analysis revealed that TRPM7 regulates the expression levels of several transcripts, including HER2 (ERBB2). Consequently, we examined the TRPM7/HER2 axis in several non-hematopoietic cells to show that TRPM7 affects the expression of HER2 protein in a Zn2+-dependent fashion. Moreover, we found that co-administration of pharmacological inhibitors of HER2 and TRPM7 elicited a synergistic antiproliferative effect on HER2-overexpressing SKBR3 cells but not on HER2-deficient MDA-MB-231 breast cancer cells. Hence, our study proposes a new combinatorial strategy for treating HER2-positive breast cancer cells. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignant tumor among women worldwide, with incidence rates rising annually. The treatment of breast cancer has undergone significant transformations, evolving from an initial reliance on a single surgical approach to the incorporation of systemic therapy, and more recently, to subtype-specific therapy. Clinically, breast cancer is classified into luminal, HER2-positive, and triple-negative breast cancer (TNBC) based on the expression of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2), with corresponding treatments including endocrine therapy, anti-HER2 targeted therapy, and chemotherapy. However, the current subtype-based treatment strategies lack personalization, with approximately 30% of patients still facing resistance and relapse. While the overall survival rate of patients with HER2-positive breast cancer has been steadily increasing, significant survival improvements have not been observed in patients with triple-negative and luminal breast cancer. To overcome the clinical bottleneck of "incomplete classification and imprecise treatment", the concept of "subtype-precise" therapy has emerged. This innovative approach involves further subclassification of existing subtypes to identify specific targets for precision treatment, characterized by broad population coverage and high specificity. Over the past decade, the multidisciplinary team at Fudan University Shanghai Cancer Center has established a comprehensive molecular portrait of Chinese Breast Cancer Genome Atlas (CBCGA). They deeply analyzed the molecular characteristics of TNBC, leading to the development of a "Fudan subtype" closely related to clinical outcomes: luminal androgen receptor subtype (LAR), which can be targeted with anti-HER2 and CDK4/6 inhibitors; the immunomodulatory subtype (IM), suitable for immunotherapy; basal-like immune-suppressed subtype (BLIS), which can be treated with platinum-based drugs or poly (ADP-ribose) polymerase (PARP) inhibitors; and mesenchymal-like subtype (MES), which can be treated with anti-cancer stem cell and anti-angiogenic therapies. The team then extended the concept of "subtype-precise" to luminal breast cancer, the subtype with the largest number, the highest proportion and the risk of recurrence for decades. They divided it into four molecular subtypes and proposing corresponding precision treatment strategies: canonical luminal subtype (SNF1), sensitive to endocrine therapy; immunogenic subtype (SNF2), amenable to immunotherapy; proliferative subtype (SNF3), treatable by CDK4/6 inhibitors; and receptor tyrosine kinase-driven subtype (SNF4), targetable with tyrosine kinase inhibitors. The team is currently conducting phase IH randomized controlled trials to further validate the "subtype-precise" therapy and promote the "subtype-precise" Fudan experience to enhance overall breast cancer treatment efficacy. Looking forward, the integration of emerging diagnostic tools, such as artificial intelligence, coupled with the continuous update of subtype-specific targets and targeted therapies, is expected to further refine and expand "subtype-precise" therapy. This approach holds great promises for enhancing patient prognosis and leading a new revolution in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Single-vesicle molecular profiling of cancer-associated extracellular vesicles (EVs) is increasingly being recognized as a powerful tool for cancer detection and monitoring. Mask and target dual imaging is a facile method to quantify the fraction of the molecularly targeted population of EVs in biofluids at the single-vesicle level. However, accurate and efficient dual imaging vesicle analysis has been challenging due to the interference of false signals on the mask images and the need to analyze a large number of images in clinical samples. In this work, we report a fully automatic dual imaging analysis method based on machine learning and use it with dual imaging single-vesicle technology (DISVT) to detect breast cancer at different stages. The convolutional neural network Resnet34 was used along with transfer learning to produce a suitable machine learning model that could accurately identify areas of interest in experimental data. A combination of experimental and synthetic data were used to train the model. Using DISVT and our machine learning-assisted image analysis platform, we determined the fractions of EpCAM-positive EVs and CD24-positive EVs over captured plasma EVs with CD81 marker in the blood plasma of pilot HER2-positive breast cancer patients and compared to those from healthy donors. The amount of both EpCAM-positive and CD24-positive EVs was found negligible for both healthy donors and Stage I patients. The amount of EpCAM-positive EVs (also CD81-positive) increased from 18% to 29% as the cancer progressed from Stage II to III. No significant increase was found with further progression to Stage IV. A similar trend was found for the CD24-positive EVs. Statistical analysis showed that both EpCAM and CD24 markers can detect HER2-positive breast cancer at Stages II, III, or IV. They can also differentiate individual cancer stages except those between Stage III and Stage IV. Due to the simplicity, high sensitivity, and high efficiency, the DISVT with the AI-assisted dual imaging analysis can be widely used for both basic research and clinical applications to quantitatively characterize molecularly targeted EV subtypes in biofluids. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common malignancy in women globally. Genome-wide association studies on breast cancer have found a strong association with fibroblast growth factor receptor 2 (FGFR2). Using publicly available data, we found a higher gene expression of FGFR2 in the less aggressive luminal cancers, and a lower gene expression in HER2-positive breast cancers. The FGFR2 IIIb splice isoform was more common in oestrogen-receptor-positive cancer, while the FGFR2 IIIc splice isoform was more common in HER2-positive carcinomas. Fibroblast growth factor receptor 2 (FGFR2) has been associated with breast cancer. We performed in silico analyses to investigate the FGFR2 mRNA expression and splice variants associated with breast cancer subtypes. Online databases, including cBioPortal and TCGA SpliceSeq, were used to examine the association between the FGFR2 expression and splice variants with breast cancer subtypes. A higher FGFR2 mRNA was significantly associated with luminal, oestrogen receptor (ER)-positive breast cancers, and invasive lobular carcinomas, whereas a lower FGFR2 was associated with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and invasive ductal carcinomas. The epithelial alternatively spliced FGFR2 IIIb isoform was significantly enriched in ER+ breast cancer, while the mesenchymal FGFR2 IIIc isoform was significantly prevalent in HER2+ cancer. Increased levels of FGFR2 and IIIb splice isoforms are associated with less aggressive breast cancer phenotypes, while decreased levels of FGFR2 and increased IIIc splice isoform are associated with more aggressive phenotypes. [ABSTRACT FROM AUTHOR]

Objective: Pyrotinb has been approved for the treatment of HER2-positive advanced or metastatic breast cancer in China. However, the plasma concentration of pyrotinb in different patients varies greatly, and in the course of treatment, if patients have intolerable adverse reactions, the drug dosage will be reduced or even stopped. This study set out to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the determination of pyrotinb in human plasma, analyze the population pharmacokinetics (PPK) of pyrotinib and assess the influence of patient variables on PK of pyrotinib in patients with HER2 positive breast cancer. Method: An UPLC-MS/MS method was developed to measure pyrotinib in human plasma. Utilizing a gradient elution procedure and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 μm), sample separation was accomplished in 5.5 min. Pyrotinb extraction via protein precipitation was used as a sample pre-treatment technique. In total, 50 patients provided 158 plasma samples, which were identified and used in the PPK investigation. The non-linear mixed-effects modeling (NONMEM) approach was used to assess the plasma concentrations and covariates information. For the final PPK model evaluation, external evaluation, non-parametric bootstrap, visual predictive check (VPC), and goodness-of-fit (GOF) were used. Results: The UPLC-MS/MS method for determining plasma concentration of pyrotinib in patients had good selectivity and linearity in the range of 1–1,000 ng/mL. Pyrotinib concentration profile in HER2-positive breast cancer patients was well described by a single-compartment PPK model with first-order absorption and elimination. The formulas for the final estimated values of overall parameters of CL/F and Vd/F and Ka are respectively: C L / F L / h = 88.8 × e TP / 67.2 × 0.376 , V / F L = 3940 , K A h − 1 = 0.357 F I X E D. No dosage adjustment was advised, despite the possibility that the total protein levels could have a substantial impact on the apparent distribution volume of pyrotinib with limited magnitude. Conclusion: In this study, an UPLC-MS/MS method was established to determine the concentration of pyrotinib in human plasma. A population pharmacokinetic model of pyrotinib in HER2 positive breast cancer patients suggested that low serum total protein reduced the clearance rate of pyrotinib in patients. Clinical medical staff should pay attention to the liver function of patients with abnormal serum total protein and be alert to the occurrence of adverse drug reactions. [ABSTRACT FROM AUTHOR]

Background: The advent of antibody-drug conjugates (ADCs) represents a landmark advance in cancer therapy, permitting targeted delivery of a potent cytotoxic agent to tumor cells with minimal damage to surrounding cells. Although ADCs can induce sustained therapeutic responses in heavily pretreated patients, they can also cause significant toxicity and thus require careful monitoring. The prototype ADC, ado-trastuzumab emtansine (T-DM1) is comprised of a humanized, monoclonal human epidermal growth factor receptor 2 (HER2)-directed antibody, trastuzumab, linked to the cytotoxic agent, DM1, and is used for the treatment of early-stage and advanced HER2-positive breast cancer. Liver toxicities, including transaminitis and nodular regenerative hyperplasia resulting in portal hypertension have been described. We report a case series of four patients who developed hepatopulmonary syndrome (HPS) during treatment with T-DM1. HPS is characterized by hypoxemia, portal hypertension, and intrapulmonary shunting, and it can be associated with severe hypoxic respiratory failure. HPS secondary to noncirrhotic portal hypertension occurring with long-term exposure to T-DM1 has not previously been reported. Case series presentation: Four patients who received T-DM1 in our institutional cohort (n=230) developed HPS, which can be associated with severe hypoxic respiratory failure. Each patient diagnosed with HPS received >50 doses of T-DM1. Only one patient at diagnosis had resting hypoxia, while the other three patients became hypoxic with exertion only. Discontinuation of T-DM1 led to clinical improvement in hypoxia in three of the four patients. The spectrum of liver injury that occurs with long-term use of T-DM1 remains incompletely defined. Conclusions: As T-DM1 is approved for use in the management of early-stage operable and advanced breast cancer, awareness of HPS as a potential complication of long-term administration of T-DM1 is necessary. The emergence of dyspnea alone or combined with low oxygen saturation and signs of hypoxemia (clubbing or elevated hemoglobin) should raise clinical suspicion and prompt evaluation for HPS. Cancer care team members should be vigilant regarding the potential for new and serious side effects associated with novel targeted therapies, which may emerge years beyond initial regulatory approval. [ABSTRACT FROM AUTHOR]

The editorial in Frontiers in Immunology discusses the emerging field of immune metabolism in auto- and allo-immunity. The editorial highlights the critical link between metabolic pathways and immune responses, focusing on research articles related to autoimmune diseases like Systemic Lupus Erythematosus and Type 1 Diabetes Mellitus, as well as transplant immunology. The articles explore how metabolic changes in immune cells impact disease pathogenesis and potential therapeutic strategies. Additionally, the editorial discusses the role of proline metabolism in asthma and the potential of immune cell metabolism in transplant tolerance. [Extracted from the article]

Background: Non-coding RNAs have received increasing attention in human tumors, with RNA interaction networks playing important roles in breast cancer. This study aims to explore novel circular RNAs and their mechanisms of biological function in breast cancer. Methods: Six HER2-positive breast cancer tissues and paired normal tissues were obtained for the whole transcriptome RNA sequencing. Differentially expressed (DE) circRNAs, miRNAs and mRNAs were identified and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DERNAs were performed. DECircRNAs- DEmiRNAs- DEmRNAs networks were constructed and further verified by bioinformatics database analyses, luciferase assays and RIP assays. The expression level of circDOCK1 in breast cancer specimens was measured using qRT-PCR. Functional rescue experiments were conducted to explore the role of circDOCK1/miR-138-5p/GRB7 axis in breast cancer cells. The correlation of circDOCK1 expression and clinicopathologic features of 102 HER2 positive breast cancer patients was analyzed. Results: A total of 6960 DEmRNAs, 133 DE miRNAs and 1691 DE circRNAs were identified from HER2-positive breast cancer tissues and paracancerous tissues. Enrichment Analysis showed that the differential mRNAs were associated with cell division in biological processes and cell cycle and signaling pathways. GO and KEGG analysis demonstrated that DE circRNAs were mainly enriched in double-strand break repair, positive regulation of transcription by RNA polymerase II, nucleoplasma, nucleus, chromatin binding and protein binding. Forty networks of competing endogenous RNAs (ceRNAs) were constructed and circDOCK1/miR-138-5p/GRB7 axis was verified. Functional experiments revealed that the axis promotes migration and invasion of breast cancer cells. CircDOCK1 expression was elevated in breast cancer patients and correlated with adverse clinicopathologic parameters. Patients with high circDOCK1 level had poor outcomes. Conclusion: A novel circDOCK1/miR-138-5p/GRB7 axis promotes HER2 positive breast cancer metastasis and progression, providing a potential therapeutic target in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Background: HER2-positive breast cancer is one of the high-risk subtypes of breast cancer for which dual-targeted therapy has become an important treatment option. However, for some patients, complete control of the disease is still not possible and additional treatment is required. Pyrrolitinib, an inhibitor of ALK and MET, has shown promising efficacy in breast cancer treatment. The aim of this study was to investigate the feasibility of adjuvant intensive therapy with pyrrolitinib in the treatment of HER2-positive breast cancer tumors. Materials and Methods: Twenty-eight patients with HER2-positive breast cancer who were treated at the Breast Surgery Department of the Provincial Hospital of Weihai City, Shandong Province, China, between January 1, 2019, and January 1, 2023, were selected for this study. All of these patients received dual-targeted therapy with the addition of pyrrolitinib therapy adjuvant intensive therapy. We recorded data on the patients' basic information, pathological characteristics, treatment regimens, effects of treatment regimens, and adverse reactions, and statistically analyzed them. Results: Of the 28 patients with HER2-positive breast cancer, all of them were added to adjuvant intensive therapy with pyrrolitinib. After examination of the samples during treatment, the breast cancer mass had been significantly reduced with the assistance of pyrrolitinib. In addition, no serious adverse reactions were found. Conclusion: Adjuvant intensification of pyrrolitinib in the treatment of HER2-positive breast cancer tumors is feasible. The results of this study suggest that pyrrolitinib is a safe and effective therapeutic option that can significantly improve the outcome of HER2-positive breast cancer. More studies are needed to further validate this finding. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology Background: Trastuzumab (Herceptin) is a recombinant DNA-derived humanized monoclonal antibody that the US Food and Drug Administration (FDA) approved in 1998 for metastatic human epidermal growth factor receptor 2 (HER2)- positive breast cancer therapy. It selectively binds to the extracellular domain of HER2 and mediates an antibody-dependent cellular toxicity in various tissues. Trastuzumab use alone does not typically cause aggressive ocular complications. However, herein is a case report of a patient presenting with corneal ulceration in both eyes and perforation in the left eye after 2 months of trastuzumab therapy. Case Report: A 59-year-old woman with a history of metastatic breast cancer receiving chemotherapy was consulted for ophthalmic evaluation. She denied any history of ocular conditions and complained of eyelid crusting and sandy sensation in both eyes for 2 weeks. She had been using antibiotic eyedrops for presumed eye infection before her vision deteriorated 3-4 days prior to presentation. A thorough workup for autoimmune and infectious diseases was unyielding. Ophthalmologic examination revealed multiple epithelial defects with ulceration in the right eye and a corneal ulcer with perforation in the left eye. Corneal cultures were negative. Orbital imaging revealed metastases with optic nerve compression. In conjunction with the oncology team, further trastuzumab treatment was deferred. Therapeutic keratoplasty along with ocular surface therapy eventually stabilized both eyes. Conclusions: Ocular adverse effects such as corneal epithelial changes and melts have been reported with trastuzumab. We recommend ophthalmology consultation for any ocular symptoms in patients on trastuzumab treatment. [ABSTRACT FROM AUTHOR]

Globally, breast cancer is the most prevalent cancer and one of the leading causes of cancer-related death among women. HER2-low breast cancer represents a recently identified molecular category within breast cancer characterized by tumors displaying only slight overexpression of HER2 or lacking gene amplification. To illustrate, HER2-low tumors typically have an IHC (immune histochemistry) score of 1+ or 2+ with negative amplification. Nonetheless, recent findings indicate that even a slight amplification of HER2 could notably influence both therapeutic responses and prognostic outcomes. Our study aims to unveil the impact of HER2-low expression on the response to anthracycline and taxane-based neoadjuvant chemotherapy (NACT) in comparison to the HER2-negative group in non-metastatic breast cancer. This is a retrospective cohort study. All patients’ profiles with non-metastatic, HER2- low, and HER2-negative breast cancers who were administered neo-adjuvant chemotherapy and had surgery performed within the period spanning from 1 January 2018 to 30 August 2022 were enrolled. HER2-positive breast cancer patients were excluded. The evaluation of patients’ responses was conducted through the examination of surgical pathology reports to compare the two study groups (HER2-low and HER2-negative). The primary objective was evaluating the response to NACT comparing the objective response rate (ORR) in each of the two groups of HER2-low and HER2-negative patients. The total number of patients included was 262 patients; the majority were HER2-low 89% (233/ 262) vs. 11% (29/262) HER2-negative. An ORR (complete and partial response) to NACT was shown in 71% (185/262) of all patients. The ORR was similar in both groups, 70% (164/233) in the HER2-low group vs. 73% (21/29) in the HER2- negative group, with a statistical difference, OR: 1 (95% CI: 0.8–1), p-value 0.8. Similarly, the pathological complete response (pCR) rate was the same in both study groups at 14%, OR: 0.7 (95% CI: 0.2–3), p-value: 0.6. Interestingly, patients with hormone-positive tumors across both study groups had a higher response rate compared to hormone-negative patients. In the HER2-low cohort, the ORR was higher in patients with hormone-positive tumors in comparison with those with hormone-negative tumors [73% vs. 27%, OR: 0.8 (95% CI:0.8–1), p-value: 0.001]. Comparatively, in the HER2-negative cohort, ORR was also higher in patients with hormone-positive tumors compared to hormone-negative tumors [52% vs. 48%, OR: 2 (95% CI: 1–5), p-value: 0.05]. Subsequently, the ORR of all hormone-positive tumors with a positive outcome (CR or PR) was assessed categorizing the patients based on their HER2 expression. Concerning patients who expressed partial response (N = 115), a statistically significant difference was observed in HER2- low hormone-positive tumors as opposed to HER2-negative hormone-positive tumors [90% vs. 10%, OR: 0.7 (95% CI: 0.5–0.9), p-value: 0.001]. Remarkably, all patients with complete responses were from the HER2- low cohort. Our findings demonstrated a significant influence of HER2-low expression on the response to neoadjuvant chemotherapy among patients with hormone-positive HER2-low breast cancer within the studied cohort. Further studies are needed to evaluate the influence of hormonal expression on the response rate to NACT in the HER2-low patients in our population. [ABSTRACT FROM AUTHOR]

Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers. [ABSTRACT FROM AUTHOR]

Purpose: Resistance to Trastuzumab is a significant challenge in the management of HER2-positive Metastatic Breast cancer (HER2-MBC), and a better understanding of the molecular causes of resistance is required to develop more effective treatment plans. While elevated plasma levels of miR-200 and FOXP3 have been linked to breast cancer progression and treatment response, no clinical studies have confirmed these results. Methods: The study involved 40 patients with HER2-positive metastatic breast cancer (HER2-MBC). The expression levels of miR-200c-3p and the FOXP3 gene were assessed in plasma samples at two time points: baseline (BL) and after the consent completion of one cycle of Trastuzumab, utilizing quantitative polymerase chain reaction (qPCR). Clinical response to Trastuzumab was evaluated 12 months post-therapy and correlated with the time to progression (TTP) through Kaplan-Meier analysis. Results: Low plasma expression level of miR-200c-3p was detected before therapy in HER2-MBC, compared to healthy controls, and decreased dramatically in the follow-up sample at disease progression, while increased after one cycle of Trastuzumab therapy in patients who were sensitive to Trastuzumab. At baseline, a low expression level of miR-200c was significantly associated with overexpression of FOXP3, poor prognosis, and shorter time to progression. Conclusions: The findings suggest that miR-200c-3p may be a promising biomarker for predicting the response to Trastuzumab in HER2-MBC patients. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant targeted therapy has shown that improve pathologic complete response and facilitate breast-conserving surgery, but the difference between single-agent treatment or dual-HER2 blockade to the conversion of breast-conserving surgery has not been well described. Methods: Via the systematic literature search of PubMed, Web of Science and Cochrane Library databases, 5 eligible studies used to perform this meta-analysis, which was carried out using RevMan version 5.4. Results: A total of 1306 patients from five randomized controlled trials were included in the analysis, revealing a significant increase in the conversion rate to breast-conserving surgery with neoadjuvant targeted therapy (OR 0.30, 95% CI 0.15–0.57; p = 0.0003). The odds ratio (OR) for single-agent treatment compared to dual-HER2 blockade was 1.04 (95% CI 0.73–1.48; p = 0.82). For pathological complete response (pCR), the OR for single-HER2 blockade versus dual-HER2 blockade was 0.43 (95% CI 0.34–0.55; p = 0.01), and for clinical response, it was 0.81 (95% CI 0.59–1.10; p = 0.17). The OR for serious adverse events between single-HER2 and dual-HER2 blockade was 0.72 (95% CI 0.55–0.95; p = 0.02). The risk ratio (RR) for pCR and the shift from mastectomy to BCS was 1.16 (95% CI 0.78–1.72; p = 0.47), while for clinical response and the shift from mastectomy to BCS, it was 2.40 (95% CI 1.44–4.01; p = 0.0008). Conclusion: Neoadjuvant targeted treatment obviously promote the actual implementation rate of breast-conserving surgery, nevertheless, there was no statistically significant increase in single-agent treatment versus dual-HER2 blockade. [ABSTRACT FROM AUTHOR]

Background: Exploration of novel combination mode of pyrotinib and chemotherapy for heavily pretreated HER2-positive metastatic breast cancer (MBC) and how to balance survival benefits and compliance are still urgent problems in clinical practice. The current single-arm prospective phase II study aimed to evaluate the efficacy and safety of pyrotinib in combination with metronomic oral etoposide in heavily pretreated HER2-positive MBC. Methods: HER2-positive MBC patients previously treated with trastuzumab were enrolled to receive oral pyrotinib 400 mg per day and metronomic oral etoposide 50 mg per day d1-21 every 28 days, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 22 patients were enrolled with a median of 4 prior treatment regimens for MBC. During the follow-up of 20 evaluable patients, the median PFS was 9.0 months (95% CI, 7.6–10.4 months), and the median OS was 27.0 months (95%CI, 20.9–33.1 months). The ORR was 30% (6/20), the DCR was 80% (16/20), and the CBR was 65% (13/20). The most common grade 3 adverse events (AEs) included nausea (15%), vomiting (15%), diarrhea (5%), anemia (5%), and peripheral neuropathy (5%). No grade 4 or lethal AEs were observed. Conclusion: The combination of pyrotinib with metronomic oral etoposide has achieved promising clinical benefits in heavily pretreated HER2-positive MBC, with acceptable and manageable toxicity. Trial registration: Registry number: NCT03923179. Registered April 18, 2019. [ABSTRACT FROM AUTHOR]

This case series presents four instances of late neurotoxicity observed in HER2- positive breast cancer patients with brain metastases following treatment with stereotactic radiosurgery (SRS) and subsequent trastuzumab emtansine (T-DM1) therapy. Despite initial control of intracranial disease, patients experienced neurological deterioration months to years post-treatment. Radiological assessments revealed distinct patterns consistent with radiation necrosis, particularly in areas previously treated with SRS and subsequent T-DM1 administration. These changes, characterized by enlarging cystic masses with hemorrhagic components, emphasize the importance of vigilant monitoring in patients undergoing combined SRS and T-DM1 therapy for brain metastatic breast cancer. This report underscores the need for further investigation into the long-term effects of combining SRS with novel systemic therapies, particularly in HER2-positive breast cancer patients with brain metastases. Understanding and mitigating late neurotoxicity are critical for optimizing treatment strategies and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Distinguishing between pathologic complete response and residual cancer after neoadjuvant chemotherapy (NAC) is crucial for treatment decisions, but the current imaging methods face challenges. To address this, we developed deep-learning models using post-NAC dynamic contrast-enhanced MRI and clinical data. A total of 852 women with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer were randomly divided into a training set (n = 724) and a validation set (n = 128). A 3D convolutional neural network model was trained on the training set and validated independently. The main models were developed using cropped MRI images, but models using uncropped whole images were also explored. The delayed-phase model demonstrated superior performance compared to the early-phase model (area under the receiver operating characteristic curve [AUC] = 0.74 vs. 0.69, P = 0.013) and the combined model integrating multiple dynamic phases and clinical data (AUC = 0.74 vs. 0.70, P = 0.022). Deep-learning models using uncropped whole images exhibited inferior performance, with AUCs ranging from 0.45 to 0.54. Further refinement and external validation are necessary for enhanced accuracy. [ABSTRACT FROM AUTHOR]

Objective: Pyrotinb has been approved for the treatment of HER2-positive advanced or metastatic breast cancer in China. However, the plasma concentration of pyrotinb in different patients varies greatly, and in the course of treatment, if patients have intolerable adverse reactions, the drug dosage will be reduced or even stopped. This study set out to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the determination of pyrotinb in human plasma, analyze the population pharmacokinetics (PPK) of pyrotinib and assess the influence of patient variables on PK of pyrotinib in patients with HER2 positive breast cancer. Method: An UPLC-MS/MS method was developed to measure pyrotinib in human plasma. Utilizing a gradient elution procedure and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 µm), sample separation was accomplished in 5.5 min. Pyrotinb extraction via protein precipitation was used as a sample pre-treatment technique. In total, 50 patients provided 158 plasma samples, which were identified and used in the PPK investigation. The non-linear mixed-effects modeling (NONMEM) approach was used to assess the plasma concentrations and covariates information. For the final PPK model evaluation, external evaluation, non-parametric bootstrap, visual predictive check (VPC), and goodness-of-fit (GOF) were used. Results: The UPLC-MS/MS method for determining plasma concentration of pyrotinib in patients had good selectivity and linearity in the range of 1-1,000 ng/mL. Pyrotinib concentration profile in HER2-positive breast cancer patients was well described by a single-compartment PPK model with first-order absorption and elimination. The formulas for the final estimated values of overall parameters of CL/F and Vd/F and Ka are respectively: CL/F(L/h) x 88.8 × e(TP/67.2)×0.376, V/F(L) x 3940, KA(h-1) x 0.357FIXED. No dosage adjustment was advised, despite the possibility that the total protein levels could have a substantial impact on the apparent distribution volume of pyrotinib with limited magnitude. Conclusion: In this study, an UPLC-MS/MS method was established to determine the concentration of pyrotinib in human plasma. A population pharmacokinetic model of pyrotinib in HER2 positive breast cancer patients suggested that low serum total protein reduced the clearance rate of pyrotinib in patients. Clinical medical staff should pay attention to the liver function of patients with abnormal serum total protein and be alert to the occurrence of adverse drug reactions. [ABSTRACT FROM AUTHOR]

This article presents a study on the development and validation of an ultrasound-based radiomics nomogram for predicting HER2-low expression breast cancer. The study included 222 patients with breast cancer, and machine learning methods were used to extract radiomics features from ultrasound images. The features were then used to construct a prediction model, which was validated using a training cohort and a test cohort. The nomogram, incorporating radiomics features and clinical risk factors, showed high prediction value for HER2-low expression breast cancer. This non-invasive approach could be useful for early detection and clinical therapy planning. [Extracted from the article]

Objective: To investigate the clinical efficacy and the safety of pegylated liposomal doxorubicin (PLD) in patients with advanced breast cancer who had previously used anthracyclines. Methods: The clinical data of 79 patients with advanced breast cancer treated with PLD-contained regimen in our hospital from May 2019 to January 2021 were retrospectively analyzed. The clinical efficacy, influencing factors and adverse reactions were evaluated between the group of PDL re-use and initial use. Results: Among 79 patients, 65 patients could be evaluated for efficacy, of which the objective response rate (ORR) was 13.85%, and the disease control rate (DCR) was 63.08%. In HER-2 positive advanced breast cancer, the ORR was 20.00%, the DCR was 75.00%, and the median progression free survival (PFS) was 3.23 months. The most common adverse reactions are bone marrow suppression, hand foot syndrome, and oral mucositis. Conclusion: The adjuvant chemotherapy with doxorubicin liposomes can achieve good efficacy in the treatment of advanced breast cancer, and the anti HER-2 treatment combined with doxorubicin liposomes has better efficacy and safety in the treatment of HER-2 positive advanced breast cancer. [ABSTRACT FROM AUTHOR]

The 2024 Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) guidelines have been influential in China and internationally, with multiple versions published in various languages. The guidelines emphasize evidence-based recommendations and contributions from Chinese scholars, particularly in the field of HER2-positive breast cancer treatment. The guidelines also address triple-negative breast cancer and hormone receptor-positive breast cancer, highlighting the importance of CDK4/6 inhibitors and immunotherapy. Additionally, the guidelines provide recommendations for HER2 low-expression breast cancer, offering treatment options based on HR status and HER2 expression levels. [Extracted from the article]

The article discusses the role of inflammatory signaling in resistance to targeted therapy, focusing on EGFR-targeted treatment. It highlights how tumor cells develop resistance to targeted therapies by activating alternative pathways and acquiring genetic mutations. The interplay between immune and inflammatory pathways in the tumor microenvironment influences treatment response and resistance. The study suggests that targeting inflammatory and immune signals may offer promising strategies to overcome resistance to targeted therapy in cancer. [Extracted from the article]

Background: Multilocus inherited neoplasia allelic syndrome (MINAS) is a recently coined term that describes the coexistence of two or more pathogenic variants (PVs) in cancer susceptibility genes (CSGs) in a single individual. Case presentation: This article presents two cases of MINAS due to rare CSG combinations. The first was a 37-year-old woman carrying PVs in the mutated ataxia telangiectasia (ATM) and CHEK2 genes, with HER-2 positive unilateral breast cancer at 29. The second was a 53-year-old woman carrying PVs in the BRCA1 and CDKN2A genes, who presented with triple-negative breast cancer at 51. We describe their family history and treatment, where the lack of evidence for personalised management becomes evident. Conclusion: Predicting the phenotypic effect of harbouring two variants in CSG is challenging. It is essential to encourage the notification of other cases and carry out functional studies to establish specific risks for affected individuals to develop personalised follow-up guidelines to reduce the associated morbimortality. [ABSTRACT FROM AUTHOR]

Background and Objective: Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers. Methods: A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks. Results: A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration–time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics. Conclusions: The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model. Clinical Trial Registration: NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192. [ABSTRACT FROM AUTHOR]

Leptomeningeal metastases (LM) occurs in approximately 5% of individuals diagnosed with metastatic breast cancer (BC). Both systemic and intrathecal (IT) agents can be used for treatment. However, data to support the effectiveness of IT therapy are insufficient. The primary aim of this study was to assess the efficacy and safety of IT therapy in BC patients with LM. This was a retrospective observational study. SPSS version 27 was used for statistical analysis. Kaplan--Meier and Cox regression analyses were used for survival analysis. The study included 14 patients (median age, 52 years). The predominant histopathological t ypes were invasive ductal carcinoma (57%) and invasive lobular carcinoma (36%). In IT treatment, methotrexate was used in 64% of the patients and trastuzumab was used in 36%. Notably, 36% of patients had a partial response, 14% had a stable response, and 5 0% had disease progression. It was found that approximately 50% of patients with positive cerebrospinal fluid (CSF) cytology became negative after treatment. Furthermore, toxicity of grade 2 or higher was observed in 49% of patients. The median progression-free survival duration among patients who received methotrexate was 1.46 months (95% CI, 0.29-2.0) and among those who received trastuzumab was 5.1 months (95% CI, 0-13.1). The median overall survival duration among all patients was 3.8 months. LM is an indicator of poor prognosis among patients with breast cancer. However, IT therapy is one of the few treatment options. IT trastuzumab should be considered as a treatment if leptomeningeal metastases develop in HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background and purpose: Human epidermal growth factor receptor 2 (HER2) serves as one of the paramount drivers of breast cancer metastasis, with roughly 20%-30% of breast cancer patients exhibiting high expression of HER2. The expression level of HER2 is regulatable at multiple molecular levels and determines the metastatic potential of breast cancer cells; however, the manner in which HER2 expression is modulated at the mRNA level remains ambiguous. Circ-0007766 is a circRNA originated from the coding gene ERBB2 for HER2, and whether circ-0007766 can regulate HER2 expression via the ceRNA mechanism has not been reported. This study aimed to analyze whether circ-0007766 acts as a miR-1972 sponge to promote breast cancer cell migration and invasion via upregulation of HER2 expression. Methods: In this study, a high-throughput circRNA chip was employed to screen for circRNAs that exhibited highly specific expression in HER2-positive breast cancer cells. RNA fluorescence in situ hybridization (FISH) was utilized to detect the subcellular localization of circ-0007766. The BaseScope experiment was conducted to analyze the expression level of circ-0007766 in breast cancer tissues and its clinical diagnostic significance. Breast cancer cell models with overexpression and knockdown of circ-0007766 were constructed by transfecting cloning plasmids and siRNA in vitro. The effect of circ-0007766 on the migration and invasion of breast cancer cells was assessed using transwell migration and invasion experiments, and the migration and invasion abilities of MDA-MB-231 and SK-BR-3 cells were measured. Additionally, it was evaluated whether circ-0007766 could promote the migration and invasion of breast cancer cells through miR-1972. A dual luciferase reporter gene assay was used to verify whether circ-0007766 could regulate HER2 expression by binding to miR-1972. The direct interaction between circ-0007766 and miR-1972 was further verified through the RAP experiment. RIP detection was performed in MDA-MB-231 cells, and the relative 3'UTR of HER2 mRNA was measured by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR). Western blot was used to detect the protein expressions. Results: Circ-0007766 was conspicuously highly expressed in HER2-positive breast cancer cells and distributed in both the cytoplasm and nucleus of cells, with the preponderance being in the cytoplasm. The expression level of circ-0007766 was strikingly higher in breast cancer tissues than in para-cancerous tissues. The expression of circ-0007766 was significantly elevated in HER2-positive breast cancer samples compared with HER2-negative samples. The overexpression (knockdown) of circ-0007766 in HER2-negative breast cancer cells (in HER2-positive breast cancer cells) was capable of promoting (inhibiting) the migration and invasion of breast cancer cells. Circ-0007766 directly bound to miR-1972, which inhibited breast cancer cell migration and invasion, thereby forming an endogenous competitive RNA (ceRNA) regulatory network and impeding the downregulation of HER2 mRNA and protein expression mediated by miR-1972. Circ-0007766 could potentiate the inhibitory effect of miR-1972 on HER2-mediated breast cancer cell migration and invasion that was negatively regulated by miR-1972. CircRNAs sequestered miRNAs to function as ceRNAs, thereby regulating gene expression at both the transcriptional and translational levels. Finally, we discovered that the expressions of circ-0007766 and HER2 were positively correlated in breast cancer cell and tissue samples, while the expression levels of miR-1972 and HER2 were negatively correlated. Circ-0007766 could specifically target miR-1972 to hinder its regulatory effect on HER2 expression. Conclusion: This study discovers that circ-0007766 facilitates the migration and invasion of breast cancer cells via the miR-1972/HER2 signal axis, offering a novel biomarker and potential therapeutic target for patients with metastatic HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Fibroblasts, an abundant cell type in the breast tumor microenvironment, interact with cancer cells and orchestrate tumor progression and drug resistance. However, the mechanisms by which fibroblast-derived factors impact drug sensitivity remain poorly understood. Here, we develop rational combination therapies that are informed by proteomic profiling to overcome fibroblast-mediated therapeutic resistance in HER2+ breast cancer cells. Methods: Drug sensitivity to the HER2 kinase inhibitor lapatinib was characterized under conditions of monoculture and exposure to breast fibroblast-conditioned medium. Protein expression was measured using reverse phase protein arrays. Candidate targets for combination therapy were identified using differential expression and multivariate regression modeling. Follow-up experiments were performed to evaluate the effects of HER2 kinase combination therapies in fibroblast-protected cancer cell lines and fibroblasts. Results: Compared to monoculture, fibroblast-conditioned medium increased the expression of plasminogen activator inhibitor-1 (PAI1) and cell cycle regulator polo like kinase 1 (PLK1) in lapatinib-treated breast cancer cells. Combination therapy of lapatinib with inhibitors targeting either PAI1 or PLK1, eliminated fibroblast-protected cancer cells, under both conditions of direct coculture with fibroblasts and protection by fibroblast-conditioned medium. Analysis of publicly available, clinical transcriptomic datasets revealed that HER2-targeted therapy fails to suppress PLK1 expression in stroma-rich HER2+ breast tumors and that high PAI1 gene expression associates with high stroma density. Furthermore, we showed that an epigenetics-directed approach using a bromodomain and extraterminal inhibitor to globally target fibroblast-induced proteomic adaptions in cancer cells, also restored lapatinib sensitivity. Conclusions: Our data-driven framework of proteomic profiling in breast cancer cells identified the proteolytic degradation regulator PAI1 and the cell cycle regulator PLK1 as predictors of fibroblast-mediated treatment resistance. Combination therapies targeting HER2 kinase and these fibroblast-induced signaling adaptations eliminates fibroblast-protected HER2+ breast cancer cells. [ABSTRACT FROM AUTHOR]

Breast Cancer (BC) is the leading cause of cancer-related deaths in women and the most common cancer worldwide. It is classified based on its anatomical origin, the presence of Human Epidermal Growth Factor Receptor 2 (HER-2), and the presence of Estrogen Receptor (ER) and/or Progesterone Receptor (PR). Around 20% of breast cancers are HER-2 positive. While biopsy-based diagnoses are valuable in clinical settings, they have limitations in terms of sampling and interpretation. However, laboratory tests such as Immunohistochemistry (IHC) or Fluorescence In Situ Hybridization (FISH) are also limited, including being time-consuming, expensive, and requiring specialized equipment. Ongoing research and technological advancements aim to address the challenges associated with biopsybased diagnoses and laboratory tests to develop more accurate and efficient methods for assessing HER-2 status. To this end, various radioactively labeled proteins and small compounds, such as single-chain variable Fragments (scFv), F(ab')2, affibody, and nanobody, have been developed to target HER-2 using molecular array techniques. These smaller targeted compounds offer improved image quality, shorter circulating half-life, and reduced immunogenicity compared to their larger counterparts. This is due to their better biodistribution, clearance, and stability. This study investigates the current understanding and ongoing efforts in utilizing antibody fragments for molecular imaging. The specific objectives were to evaluate the advantages of antibody fragments over full-length antibodies regarding biodistribution, clearance, and stability. Additionally, this study aims to assess the current knowledge and ongoing research in utilizing antibody fragments for molecular imaging. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) has the second highest incidence among cancers and is the leading cause of death among women worldwide. The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20%--30% of BC patients. The development of HER2-targeted drugs, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs) and antibody--drug conjugates (ADCs), has improved the operation rate and pathological remission rate and reduced the risk of postoperative recurrence for HER2- positive early-stage BC (HER2+ EBC) patients. This review systematically summarizes the mechanisms, resistance, therapeutic modalities and safety of HER2-targeted drugs and helps us further understand these drugs and their use in clinical practice for patients with HER2+ EBC. [ABSTRACT FROM AUTHOR]

Background: Patients with HER2-positive breast cancer can significantly benefit from HER2-directed therapy – such as the monoclonal antibody trastuzumab. However, some patients can develop therapy resistance or change HER2 status. Thus, we urgently need new, noninvasive strategies to monitor patients frequently. Extracellular vesicles (EVs) secreted from tumor cells are emerging as potential biomarker candidates. These membrane-delimited nanoparticles harbor molecular signatures of their origin cells; report rapidly on changes to cellular status; and can be frequently sampled from accessible biofluids. Results: Using Single Extracellular VEsicle Nanoscopy (SEVEN) platform that combines affinity isolation of EVs with super-resolution microscopy, here we provide multiparametric characterization of EVs with ~ 8 nm precision and molecular sensitivity. We first interrogated cell culture EVs affinity-enriched in tetraspanins CD9, CD63, and CD81; these transmembrane proteins are commonly found on EV membranes. SEVEN robustly provided critical parameters of individual, tetraspanin-enriched EVs: concentration, size, shape, molecular cargo content, and heterogeneity. Trastuzumab-resistant cells (vs. trastuzumab-sensitive) secreted more EVs. Additionally, EVs from trastuzumab-resistant cells had lower tetraspanin density and higher HER2 density. We also evaluated EVs affinity-enriched in HER2; we found that these EVs (vs. tetraspanin-enriched) were larger and more elongated. We further optimized analytical sample processing to assess a rare population of HER2-enriched EVs from patient plasma. In breast cancer patients with elevated HER2 protein expression (vs. controls), HER2-enriched EVs had distinct characteristics including typically increased number of tetraspanin molecules and larger size. Importantly, these EVs were on average 25-fold more abundant compared to no cancer controls. Conclusions: SEVEN revealed unique characteristics of HER2-enriched EVs in cultured cells and complex biological fluid. In combination with current clinical approaches, this method is well poised to support precise therapeutic decisions. [ABSTRACT FROM AUTHOR]

Objective: Challenging differential diagnosis Background: Occult breast cancer (OBC) is diagnosed when regional or distant metastases are found without evidence of a primary tumor. The low overall incidence is a great challenge for the management strategy of OBC. Aggressive diagnosis and personalized treatment are feasible treatment strategies for OBC. We report the case of an OBC patient who achieved pathological complete response (pCR) after neoadjuvant chemotherapy. Case Report: A 43-year-old woman was admitted to the hospital 6 months after detecting a lump in her left axilla, about the size of a quail egg, but not red or swollen, and the lump gradually grew. Mammography, ultrasound, and magnetic resonance imaging showed a visible left axilla lesion but no nodules in bilateral breasts. A core-needle biopsy of the axilla lesion revealed an invasive carcinoma of breast origin. The tumor cells were estrogen receptors (ER)-negative, progesterone receptor (PR)-negative, and HER2-positive (3+) by immunohistochemistry. The patient was finally diagnosed with HER2-positive, hormone receptor-negative occult breast cancer of the left breast, cT0N2M0, stage IIIA. The TCbHP regimen (docetaxel, carboplatin, trastuzumab, and pertuzumab) as neoadjuvant chemotherapy was given. She underwent a modified radical mastectomy, showing a pCR. Subsequent radiotherapy and HER2-targeted therapy were administrated. Conclusions: This case highlights that even aggressive HER2-positive breast cancer can present as an occult primary tumor. Our clinical experience suggests that neoadjuvant chemotherapy followed by modified radical mastectomy can be effective for treating such rare cases. The patient achieved pCR, which can provide a therapeutic strategy for effective treatment of similar OBCs [ABSTRACT FROM AUTHOR]

Background: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib. Methods: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/μL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. Results: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0–9) and 1 (range, 0–7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019). Conclusion: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer. [ABSTRACT FROM AUTHOR]

The first example of sonodynamic therapy (SDT) with a cyanine dye–antibody conjugate is reported. The aim of this study was to evaluate the sonodynamic efficacy of a trastuzumab-guided diiodinated heptamethine cyanine-based sensitizer, 2ICy7–Ab, versus its non-iodinated counterpart, Cy7–Ab, in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model. In addition, the combined sonodynamic and photodynamic (PDT) effects were investigated. A single intravenous injection of 2ICy7–Ab followed by sonication or combined sonication and photoirradiation in mice resulted in complete tumor growth suppression compared with the nontreated control and showed no detectable toxicity to off-target tissues. In contrast, Cy7–Ab provided only a moderate therapeutic effect (~1.4–1.6-fold suppression). SDT with 2ICy7–Ab resulted in a 3.5-fold reduction in tumor volume within 45 days and exhibited 13-fold greater tumor suppression than PDT alone. In addition, 2ICy7–Ab showed more durable sonostability than photostability. The sonotoxicity of the iodinated versus noniodinated counterparts is attributed to the increased generation of hydroxyl radicals, superoxide, and singlet oxygen. We observed no significant contribution of PDT to the efficacy of the combined SDT and PDT, indicating that SDT with 2ICy7–Ab is superior to PDT alone. These new findings set the stage for the application of cyanine–antibody conjugates for fluorescently monitored targeted sonodynamic treatment of cancer. [ABSTRACT FROM AUTHOR]

\nIntroduction: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have shown effectiveness against HER2-positive breast cancer. This makes neoadjuvant chemotherapy (NAC) a valuable option for treating both early and advanced stages of the disease. The tumor’s response to HER2-targeted NAC provides crucial prognostic information. Additionally, it allows for tailoring adjuvant treatment strategies for HER2+ breast cancer based on pathological responses. This study aimed to investigate the clinicopathological factors that influence tumor response. Methods: We retrospectively analyzed 122 patients diagnosed with HER2+ breast cancer. These patients received NAC and HER2-directed therapy between January 2018 and December 2022 at the Pusan National University Yangsan Hospital. Following surgery, tumor response was evaluated, categorizing patients into two groups: pathological complete response (pCR) and non-pCR groups. We analyzed data on various factors, including age, NAC regimen, type of breast and axillary surgery, clinical stage (cTNM), historical grade, and preoperative levels of carcinoembryonic antigen, cancer antigen 15-3 (CA 15-3), estrogen receptor (ER), progesterone receptor (PR), HER2, p53, and KI-67. Results: Out of the 122 patients, 75 achieved pCR, while 47 did not. Most clinicopathological factors showed no significant difference between the pCR and non-pCR groups. However, several factors were associated with a higher pCR rate: normal preoperative CA 15-3 levels (odds ratio [OR]: 3.74, confidence interval [CI]: 1.19–11.72, p = 0.02), preoperative ER positivity (OR: 2.65, CI: 1.25–5.59, p = 0.01), PR negativity (OR: 3.92, CI: 1.82–8.45, p < 0.05), and strong preoperative HER2 immunohistochemistry (IHC) 3+ staining. Multivariate analysis confirmed that PR negativity (OR: 2.8, CI: 1.23–6.42, p = 0.01) and strong preoperative HER2 IHC 3+ staining (OR: 0.18, CI: 0.03–0.84, p = 0.04) were independent predictors of a higher pCR rate. Conclusions: A pCR after NAC impacts patient prognosis and influences the choice of adjuvant treatment for HER2+ breast cancer. Clinicopathological factors can help predict responses to HER2-targeted NAC. In our study, pre-ER/PR negativity, high pre-HER2 levels, and normal CA 15-3 levels were found to be potential predictors of pCR. These findings may contribute to developing more effective treatment strategies for HER2+ breast cancer. Neoadjuvant treatment is the standard approach for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Especially, pathologic response is an important prognostic factor and the adjuvant treatment is dependent on the response. Therefore, predicting the response is important for modulating the treatment sequence, especially in the initial stage of treatment decision. Therefore, we aimed to identify factors that can predict the effectiveness of neoadjuvant chemotherapy, and our results suggest that factors such as tumor size, grade, hormone receptor, and HER2 status should be considered in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Modern cancer treatment strategies aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eradicate the cancer cells. To overcome a relatively short-lived response due to resistance to the administered drugs, combination therapies have been pursued. Objective: The objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the broader implications, and to expand the outlook, of such therapeutic approaches. Specifically, we investigated the systems-level response of a breast cancer cell line model to a mixture of kinase inhibitors that has not been adopted yet as a standard therapeutic regime. Methods: Two critical pathways that sustain the growth and survival of cancer cells, EGFR and PI3K/AKT, were inhibited in SKBR3/HER2+ breast cancer cells with Lapatinib (Tyr kinase inhibitor) and Ipatasertib (Ser/Thr kinase inhibitor), and the landscape of the affected biological processes was investigated with proteomic technologies. Results: Over 800 proteins matched by three unique peptide sequences were affected by exposing the cells to the drugs. The work corroborated the antiproliferative activity of Lapatinib and Ipatasertib and uncovered a range of impacted cancer-supportive hallmark processes, among which immune response, adhesion, and migration emerged as particularly relevant to the ability of drugs to effectively suppress the proliferation and dissemination of cancer cells. Changes in the expression of key cancer drivers such as oncogenes, tumor suppressors, EMT and angiogenesis regulators underscored the inhibitory effectiveness of drugs on cancer proliferation. The supplementation of Lapatinib with Ipatasertib further affected additional transcription factors and proteins involved in gene expression, trafficking, DNA repair, and development of multidrug resistance. Furthermore, over fifty of the impacted proteins represent approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Conclusion: Altogether, the exposure of SKBR3/HER2+ cells to Lapatinib and Ipatasertib kinase inhibitors uncovered a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ ERBB2 and PI3K/AKT pathways. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to identify ultrasound and clinicopathological characteristics related to recurrence in HER2‐positive (HER2+) breast cancer, and to develop nomograms for predicting recurrence. Methods: In this dual‐center study, we retrospectively enrolled 570 patients with HER2+ breast cancer. The ultrasound and clinicopathological characteristics of hormone receptor (HR)−/HER2+ patients and HR+/HER2+ patients were analyzed separately according to HR status. Eighty percent of the original samples from HR−/HER2+ and HR+/HER2+ patients were extracted by bootstrap sampling as the training cohorts, while the remaining 20% were used as the external validation cohorts. Informative characteristics were screened through univariate and multivariable Cox regression in the training cohorts and used to develop nomograms for predicting recurrence. The predictive accuracy was calculated using Harrell's C‐index and calibration curves. Results: Three informative characteristics (axillary nodal status, calcification, and Adler degree) were identified in HR−/HER2+ patients, and another three (histological grade, axillary nodal status, and echogenic halo) in HR+/HER2+ patients. Based on these, two separate nomograms were constructed to assess recurrence risk. In the training cohorts, the C‐index was 0.740 (95% CI: 0.667–0.811) for HR−/HER2+ nomogram, and 0.749 (95% CI: 0.679–0.820) for HR+/HER2+ nomogram. In the validation cohorts, the C‐index was 0.708 (95% CI: 0.540–0.877) for HR−/HER2+ group, and 0.705 (95% CI: 0.557–0.853) for HR+/HER2+ group. The calibration curves also indicated the excellent accuracy of the nomograms. Conclusions: Ultrasound performance of HER2+ breast cancers with different HR status was significantly different. Nomograms integrating ultrasound and clinicopathological characteristics exhibited favorable performance and have the potential to serve as a reliable method for predicting recurrence in heterogeneous breast cancer. [ABSTRACT FROM AUTHOR]

This article explores the significance of molecular subtyping in breast cancer treatment. It discusses the different subtypes of breast cancer, including triple-negative breast cancer (TNBC), HR+/HER2- breast cancer, and HER2+ breast cancer. The authors emphasize the importance of clinical trials in validating precision treatment strategies based on molecular subtyping. They also discuss the potential of noninvasive methods, such as liquid biopsies, in improving patient compliance. The article concludes by highlighting the need for further research and clinical studies to enhance treatment efficacy. [Extracted from the article]

This article explores the use of breast cancer organoids (BCOs) in personalized medicine. The study reveals that BCOs effectively preserve molecular characteristics in hormone receptor-positive and HER2-positive breast cancers, but there are notable differences in triple-negative breast cancer (TNBC) due to culture conditions. BCOs exhibit a decrease in immune and stromal cells compared to primary breast cancer tissues, but an increase in epithelial cells. The study also investigates genomic concordance, gene expression profiling, and drug sensitivity in BCOs. The findings suggest that BCOs are valuable for studying epithelial components of tumors, but may have limitations in accurately predicting drug sensitivity in TNBC. The article provides supporting information for a research project and is authored by a group of individuals whose names are listed at the end of the article. [Extracted from the article]

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 μg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 μg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association with treatment response. Sixty-two HER2+ BC patients were recruited. Pre-treatment samples were obtained before the start of treatment, while post-treatment samples were obtained after completing therapy and before surgery and were analyzed by flow cytometry. The pathologic complete response (pCR) rate achieved was 82.3%. The expression of the NKp30, PD-1, and TIM-3 receptors was reduced in the Natural Killer (NK)-CD56dim subset of patients who did not achieve pCR. Following therapy, many changes were found in leukocytes, including alterations in T cell lymphocyte proportions. Also, the percentage of NK cells decreased, and several phenotypic changes were observed in this population. After treatment, IFN-γ production by NK cells against HER2+-cells with or without trastuzumab was significantly reduced. HER2-targeted therapy plus chemotherapy demonstrated high efficacy in most patients, reducing the statistical power for finding immunological markers. However, NK subset phenotypes correlated better with response groups, and numerous changes in the percentage of leukocytes and T and NK cells, as well as changes in the functionality of NK cells, were observed in most patients after treatment, encouraging further research into these immune populations. [ABSTRACT FROM AUTHOR]

In Mexico, breast cancer (BC) is the principal cause of death in women over 30 years old, with an annual mortality rate of 14.61 deaths per a 100,000 population. Chemotherapy, in combination with trastuzumab (TTZ), improves the survival of cancer patients; however, cardiotoxicity (CT) is the principal consequence. CT prevalence occurs between 10% and 30% of patients; however, there are no data about the prevalence of CT in the Mexican population. This study aims to establish the prevalence of CT in patients treated with anti-HER-2 therapy among BC women in southeast Mexico. A retrospective cross-sectional study was carried out from January 2015 to July 2019. The records of 46 patients diagnosed with HER-2-positive BC who attended the Mexican Social Security Institute in the Ambulatory Care Medicine Unit were analyzed. The diagnostic criterion for CT was a decrease in LVEF > 10% from baseline or a final LVEF < 53%. CT prevalence was observed in 19 (41.3%) of women with cancer, with an average decrease in LVEF of 13%. In the population, we found an association between weight, surface area, and the loading dose of TTZ with CT. Nutritional follow-up and the administration of cardioprotective drugs are necessary to recover LVEF and avoid cardiovascular failure in women with BC and survivors. [ABSTRACT FROM AUTHOR]

Overexpression of HER2 occurs in 25% of breast cancer. Targeting HER2 has proven to be an effective therapeutic strategy for HER2-positive breast cancer. While trastuzumab is the most commonly used HER2 targeting agent, which has significantly improved outcomes, the overall response rate is low. To develop novel therapies to boost trastuzumab efficacy, it is critical to identify the mechanisms underlying trastuzumab action and resistance. We recently showed that the inhibition of breast cancer cell growth by trastuzumab is not through the inhibition of HER2 canonical signaling. Here we report the identification of a novel non-canonical HER2 signaling pathway and its interference by trastuzumab. We showed that HER2 signaled through a non-canonical pathway, regulated intramembrane proteolysis (RIP). In this pathway, HER2 is first cleaved by metalloprotease ADAM10 to produce an extracellular domain (ECD) that is released and the p95HER2 that contains the transmembrane domain (TM) and intracellular domain (ICD). p95HER2, if further cleaved by an intramembrane protease, γ-secretase, produced a soluble ICD p75HER2 with nuclear localization signal (NLS). p75HER2 is phosphorylated and translocated to the nucleus. Nuclear p75HER2 promotes cell proliferation. Trastuzumab targets this non-canonical HER2 pathway via inhibition of the proteolytic cleavage of HER2 by both ADAM10 and γ-secretase. However, p75HER2 pathway also confers resistance to trastuzumab once aberrantly activated. Combination of trastuzumab with ADAM10 and γ-secretase inhibitors completely blocks p75HER2 production in both BT474 and SKBR3 cells. We concluded that HER2 signals through the RIP signaling pathway that promotes cell proliferation and is targeted by trastuzumab. The aberrant HER2 RIP signaling confers resistance to trastuzumab that could be overcome by the application of inhibitors to ADAM10 and γ-secretase. [ABSTRACT FROM AUTHOR]

Background: This study aimed to retrospectively analyse the pathological response and safety of combining albumin-bound paclitaxel (nab-paclitaxel) or docetaxel with anti-HER2 therapy as a neoadjuvant treatment for HER2-positive breast cancer. Methods: From June 2020 to August 2023, 225 HER2-positive breast cancer patients who underwent radical surgery following neoadjuvant treatment were enrolled in this study. The patients were divided into two groups based on the drugs they received: the nab-paclitaxel group (n=166, receiving nab-paclitaxel + platinum along with trastuzumab and pertuzumab) and the docetaxel group (n=59, receiving docetaxel + platinum along with trastuzumab and pertuzumab). The pathological response and adverse events related to the drugs were collected and evaluated in both groups. Results: In the nab-paclitaxel group, the rates of breast and total pathological complete response (bpCR and tpCR) were significantly greater than those in the docetaxel group (69.27% vs. 47.45%, P=0.003; 68.67% vs. 45.76%, P=0.002). For patients who did not achieve pCR after chemotherapy, the pathological response of chemotherapy was analysed using MP grading and RCB grading. The results showed that there was a statistically significant difference between the two groups (P<0.05). Multivariate analysis revealed that therapeutic drugs, clinical stage, ER status, and Ki-67 level were independent predictors of pCR. The nabpaclitaxel group had a significantly greater proportion of patients with peripheral sensory neuropathy than did the docetaxel group (58.43% vs. 38.98%, P=0.035), while the docetaxel group had a greater proportion of patients with allergies and elevated ALT (31.93% vs. 69.49%, P=0.000; 23.49% vs. 40.68%, P=0.021). Conclusions: Our real-world study revealed that nab-paclitaxel combined with anti-HER2 therapy was an effective neoadjuvant therapy for HER2-positive breast cancer. The multivariate analysis revealed that chemotherapy drugs, clinical stage, ER status, and Ki-67 level was the significant factor influencing treatment outcome. These findings offer a valuable reference for the neoadjuvant treatment of patients with HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]