Search

Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2-positive breast cancer develop brain metastases, representing a major clinical challenge. We previously described that cancer-associated fibroblasts are an important source of resistance in primary tumors. Here, we report that breast cancer brain metastasis stromal cell interactions in 3D cocultures induce therapeutic resistance to HER2-targeting agents, particularly to the small molecule inhibitor of HER2/EGFR neratinib. We investigated the underlying mechanisms using a synthetic Notch reporter system enabling the sorting of cancer cells that directly interact with stromal cells. We identified mucins and bulky glycoprotein synthesis as top-up-regulated genes and pathways by comparing the gene expression and chromatin profiles of stroma-contact and no-contact cancer cells before and after neratinib treatment. Glycoprotein gene signatures were also enriched in human brain metastases compared to primary tumors. We confirmed increased glycocalyx surrounding cocultures by immunofluorescence and showed that mucinase treatment increased sensitivity to neratinib by enabling a more efficient inhibition of EGFR/HER2 signaling in cancer cells. Overexpression of truncated MUC1 lacking the intracellular domain as a model of increased glycocalyx-induced resistance to neratinib both in cell culture and in experimental brain metastases in immunodeficient mice. Our results highlight the importance of glycoproteins as a resistance mechanism to HER2-targeting therapies in breast cancer brain metastases.

Breast cancer that overexpresses Human Epidermal Growth Factor Receptor 2 (HER2+) due to gene amplification or overexpression constitutes 15-20% of all breast cancer cases. Trastuzumab, the first FDA-approved monoclonal antibody targeting HER2, serves as the standard first-line treatment for HER2-positive advanced breast cancer, as recommended by multiple clinical guidelines.Currently, accumulated clinical evidence reveals a considerable degree of variability in the response of HER2+ breast cancer to trastuzumab treatment. Specifically, over 50% of patients either do not respond to or develop resistance against trastuzumab.The specific mechanisms of resistance to trastuzumab are currently unclear. This paper aims to review the existing research on the resistance mechanisms of trastuzumab, based on its target, from aspects such as genetic loci, molecular structure, signaling pathways, and the tumor microenvironment and to outline current research progress and new strategies. [ABSTRACT FROM AUTHOR]

Aims: Recently, human epidermal growth factor 2 (HER2)‐low (i.e. HER2 score 1+ or 2+ without amplification) breast cancer patients became eligible for trastuzumab–deruxtecan treatment. To improve assay standardisation and detection of HER2‐low in a quantitative manner, we conducted an external quality assessment‐like study in the Netherlands. Dynamic range cell lines and immunohistochemistry (IHC) calibrators were used to quantify HER2 expression and to assess interlaboratory variability. Methods and results: Three blank slides with a dynamic range cell line and an IHC calibrator were stained with routine HER2 assays by 35 laboratories. Four different antibody clones were used: 19 (54.3%) 4B5, six (17.1%) A0485, five (14.3%) DG44 (HercepTest) and five (14.3%) SP3. Laboratories used two different detection kits for 4B5 assays: 14 (73.7%) ultraView and five (26.3%) OptiView. Variability of HER2 expression in cell lines, measured with artificial intelligence software, was median (min–max) = negative core 0.5% (0.0–57.0), 1+ core 4.3% (1.6–71.3), 2+ core 42.8% (30.4–92.6) and 3+ core 96.2% (91.8–98.8). The calibrators DG44 and 4B5 OptiView had the highest analytical sensitivity, closely followed by 4B5 ultraView. SP3 was the least sensitive. Calibrators of A0485 assays were not analysable due to background staining. Conclusions: As assays were validated for detecting HER2‐amplified tumours, not all assays and antibodies proved suitable for HER2‐low detection. Some tests showed distinct expression in the negative cell line. Dynamic range cell line controls and quantitative analysis using calibrators demonstrated more interlaboratory variability than commonly appreciated. Revalidation of HER2 tests by laboratories is needed to ensure clinical applicable HER2‐low assays. [ABSTRACT FROM AUTHOR]

As the first anti-HER2 targeted agent approved by FDA in 1998, Trastuzumab has significantly improved the outcome of patients with HER2 positive metastatic breast cancer. Unfortunately, resistance to trastuzumab is a severe obstacle to its therapeutic efficacy in clinical application, and its mechanism has not yet been fully elucidated. In our study, we found that stabilization of cyclin D3 could be one reason for trastuzumab resistance. Trastuzumab could induce G1/G0 phase arrest by downregulating cyclin D3 protein expression. However, the protein expression of cyclin D3 was not affected in trastuzumab-resistant cells, which might be related to aberrant activation of ERK signaling pathway. Furthermore, degradation of cyclin D3 protein by trastuzumab was mainly resulted from ubiquitin-dependent proteasome mechanism instead of transcriptional regulation. In trastuzumab-resistant breast cancer cells, trastuzumab-induced degradation of cyclin D3 protein was abrogated. When the ubiquitin pathway was inhibited, cells would show a predisposition to resistance to trastuzumab. Further, CDK4/6 inhibitor can inhibit the proliferation of trastuzumab-resistant HER-2 positive breast cancer cells. Therefore, combination of CDK4/6 inhibitors and anti-HER2 targeted therapy may be an alternative and promising strategy to overcome trastuzumab resistance in the future. [ABSTRACT FROM AUTHOR]

Background: Breast cancer remains the most common invasive cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Trastuzumab (Tz) is typically used to treat HER2-positive breast cancers, but its potential in TNBC is unclear. Objectives: To investigate the effects of trastuzumab on cell viability, apoptosis, cell cycle progression, and gene expression in TNBC cell lines compared with HER2-positive and normal cell lines. Design: This is an in vitro experimental pre-clinical study using cultured cancer cell lines. Methods: MDA-MB-231 and 4T1 (TNBC), MCF-7 (HER2 -positive), and HSF (normal) cell lines were treated with 20 μg/mL trastuzumab for 24 hours. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis by flow cytometry, cell cycle progression by DNA content analysis, and gene expression by qPCR. Results: Trastuzumab significantly reduced cell viability and induced apoptosis in TNBC cell lines, comparable to effects in HER2-positive MCF-7 cells. Cell cycle analysis revealed G2/M phase arrest in TNBC cells. Gene expression analysis showed upregulation of ERBB2, NOTCH1, EGFR, PIK3CA, and PTEN in MDA-MB-231 cells, while 4T1 cells exhibited downregulation of most genes except NOTCH1. Conclusion: This study provides initial evidence for trastuzumab's potential therapeutic effects in TNBC, despite low HER2 expression. The observed cytotoxicity, apoptosis induction, and cell cycle modulation in TNBC cells warrant further investigation into trastuzumab's mechanisms of action in HER2 -negative contexts and its potential repurposing for TNBC treatment. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor receptor 2-targeted (HER2) therapy with antibody-drug conjugates has proven effective for patients with HER2-low breast cancer. However, intratumoral heterogeneity (ITH) poses a great challenge in identifying HER2-low tumors. ITH signatures were developed by quantifying ITH to differentiate HER2-positive, -low and -zero breast cancers. Methods: This retrospective study included 614 patients from two institutions. The study was structured into two primary tasks: task 1 was to differentiate between HER2-positive and -negative tumors, followed by task 2 to differentiate HER2-low and -zero tumors. Whole-tumor radiomics features and habitat radiomics features were extracted from MRI to construct the radiomics and ITH signatures. Multivariable logistic regression analysis was used to determine significant independent predictors. A combined model integrating significant clinicopathologic variables, radiomics signature, and ITH signature was developed for task (1) Subsequently, the better-performing model was established using the same approach for task (2) The area under the receiver operating characteristic curve (AUC) was used to assess the performance of each model. Results: Task 1 comprised 614 patients (training, n = 348; validation, n = 149; and test cohorts, n = 117). Task 2 encompassed 501 patients (training, n = 283; validation, n = 122; and test cohorts, n = 96). For task1, the ITH signature showed outstanding performance, achieving AUCs of 0.81, 0.81, and 0.81 in the training, validation and test cohorts, respectively. The combined model achieved improved performance, with AUCs of 0.83, 0.84 and 0.83 across the three cohorts, respectively. For task2, the ITH signature maintained superior performance, with AUCs of 0.94, 0.93 and 0.84 across the training, validation and test cohorts, respectively. Multivariable logistic regression analysis indicated that none of the clinicopathologic characteristics were retained as predictors associated with odds of HER2-low tumors. Conclusions: Our study developed ITH signatures that quantified ITH using habitat-based MRI radiomics, achieving outstanding performance in differentiating HER2-postive and -negative tumors, and further differentiating HER2-low and -zero breast cancers. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common malignancies affecting women worldwide, with a significant need for novel therapeutic agents to target specific molecular pathways involved in tumor progression. In this study, a series of rhodanine–piperazine hybrids were designed, synthesized, and evaluated for their anticancer activity, targeting key tyrosine kinases such as VEGFR, EGFR, and HER2. Biological screening against breast cancer cell lines (MCF-7, MDA-MB-231, T47D, and MDA-MB-468) revealed 3 of the 13 tested compounds as the most potent, with 5-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}methylidene)-2-thioxo-1,3-thiazolidin-4-one (12) showing the strongest activity, particularly against the MCF-7 and MDA-MB-468 cell lines. Molecular docking studies indicated favorable binding interactions of compound 12 and its 3-phenyl-2-thioxo-1,3-thiazolidin-4-one analogue (15) with HER2, VEGFR, and EGFR, and molecular dynamics simulations further confirmed their stable binding to HER2. These findings highlight the potential of rhodanine–piperazine hybrids as promising leads for developing new anticancer agents targeting breast cancer, particularly HER2-positive subtypes. Further structural optimization could enhance their efficacy and therapeutic profile. [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]

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]

Explore whether the axillary outcomes differ among HER2 positive subgroups receiving standard dual-targeted therapy, aiming to identify subgroups exhibiting enhanced sensitivity to NAT among HER2-positive/node-positive breast cancer patients. HER2 positive female patients with biopsy-proven node-positive disease from April 2020 to May 2023 were included. All patients underwent standard Neoadjuvant HER2-targeted dual therapy and axillary lymph node dissection (ALND) at Breast Surgery Center of Sichuan Cancer Hospital. Univariate and multivariate analyses were used to identify factors associate with axillary pathological complete response (ApCR). Statistical analysis and graphing were performed using SPSS 24.0 and GraphPad Prism 9.0 software. This study enrolled 215 HER2 positive patients with a total ApCR rate of 76.7%, which included 49 HER2 2+/FISH + and 166 HER2 3 + cases with approximate ApCR rates of 63.3% and 80.7% (P = 0.011). Univariate and multivariate analysis indicated that HER2 3 + disease (OR = 2.43, 95% CI 1.21–4.88, P = 0.012), Ki-67 ≥ 20% disease (OR = 3.00, 95% CI 1.26–7.13, P = 0.013) and NAC regimen of TCb (OR = 2.71, 95% CI 1.39–5.38, P = 0.004) were more likely to achieve ApCR. Further subgroup analysis revealed that HER2 3 + patients receiving TCb regimen showed the highest ApCR rate of 88% compared to other subgroups. HER2 3 + breast cancer had a higher ApCR rate than HER2 2+/FISH + breast cancer during Neoadjuvant HER2-targeted dual therapy. HER2 positive patients could benefit from NAC regimen of TCb in axillary response. [ABSTRACT FROM AUTHOR]

Background/Aim: Exosomes are extracellular vesicles produced by both normal and cancer cells. Previous research has demonstrated that circulating exosomes derived from cancer cells may create a niche for future metastasis, distant from the primary tumor. In the present report, circulating exosomes were captured and quantified based on exosomesurface proteins in pre- and post-operative serum of breast cancer patients, focusing on the exosome markers CD9 and CD63, as well as HER2, a therapeutic target for breast cancer. Materials and Methods: Eight breast cancer patients were recruited, and their pre- and post-operative serum samples were analyzed for CD63 and CD9; or CD9 and human epidermal growth factor receptor-2 (HER2), double-positive exosomes. An ExoCounter with antibody-conjugated beads was used to capture serum-derived exosomes. Sera from patients with tumors larger than 10 mm were used for analysis. The resected breast cancer was also histopathologically analyzed for the presence of HER2. Results: CD63 and CD9 double-positive serum exosomes and CD9 and HER2 double-positive serum exosomes decreased after surgery in breast-cancer patients whose tumors expressed HER2, as determined by histopathological analysis. Conclusion: Serum exosomes expressing CD9, CD63 and HER2 are candidate biomarkers of tumor burden in HER2-positive breast-cancer patients. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a leading global concern for women, with 30% being HER2-positive cases linked to poorer outcomes. Targeted therapies like trastuzumab deruxtecan (T-DXd), trastuzumab, pertuzumab, and T-DM1 have revolutionized HER2-positive metastatic breast cancer (MBC) treatment. Although these therapies have improved MBC management and patient outcomes, resistance can develop, reducing effectiveness. Personalized strategies based on tumor characteristics offer hope for better responses and longer outcomes. This review outlines insights into MBC patients responding well to anti-HER2 treatments, even across multiple treatment regimen. Recent immunotherapy, locoregional therapy, and liquid biopsy breakthroughs are covered, suggesting ways to increase long-term responders. Personalized approaches have boosted HER2-positive MBC outcomes, and ongoing research is crucial to uncover new treatments and biomarkers, potentially elevating long-term response rates and prognoses. This may aid in providing new direction to breast cancer clinics. [ABSTRACT FROM AUTHOR]

Objective: This study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval. Methods: We identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response's relative risk (RR) alongside objective response rate (ORR) were meta-analyzed. Results: The median development time for breast cancer drugs was 7.8 years (95% CI 6.2–10.8). 26% of treatments were considered innovative ("first-in-indication") with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA's special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417–752) at 181 centers (IQR 142–223) across 19 countries (IQR 17–20). New drugs' HR were 0.78 for OS (95% CI 0.74–0.82) and 0.59 for PFS (95% CI 0.54–0.64) with a RR for tumor response of 1.61 (95% CI 1.46–1.76). Median improvements of OS were 2.8 months (IQR 1.8–5.8) and PFS were 4.4 months (IQR 2.2–7.1). In single-arm trials, the average ORR was 31% (95% CI 10–53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a 'high-value' ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097–17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840–86,062). Conclusions: Over the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life. [ABSTRACT FROM AUTHOR]

Background: Targeted treatment of different types of cancers through highly expressed cancer cell surface receptors by fusion proteins is an efficient method for cancer therapy. The HER2 receptor is a member of the tyrosine kinase receptors family, which plays a notable role in breast cancer tumor development. About 25–30% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2). Methods: In this study, we evaluated the particulars of a designed recombinant protein formed by HER2-specific Mab Herceptin linked with Arazyme on a HER2-overexpressing breast cancer cell line (SKBR3). Arazyme, a metalloprotease produced by Serratia proteamaculans was fused to the variable area of light and heavy chains of the Herceptin. The cytotoxic assay of the Arazyme-linker-Herceptin in the SKBR3 and MDA-MB-468 cells was evaluated by the MTT and flow cytometry techniques. The Caspase‑3 activity determination and adhesion assay were performed to evaluate the antitumor activity of the Arazyme-linker-Herceptin against SKBR3 cells. Furthermore, RT-PCR was used to measure the expression levels of the Bcl-2, Bax, MMP2, MMP9, and RIP3 genes. Results: The Arazyme-linker-Herceptin showed higher cytotoxicity in SKBR3 cells compared to MDA-MB-468 cells. In addition, flow cytometry results revealed that the Arazyme-linker-Herceptin can significantly induce apoptosis in the HER2-overexpressing breast cancer cell line (SKBR3), which was confirmed by Bax upregulation and the decrease in adhesion of tumor cells and MMP2/MMP9. Conclusion: The findings of this study demonstrated that the Arazyme-linker-Herceptin induced apoptosis and decreased metastatic genes in SKBR3 cells; however, further research is required to confirm the effectiveness of the fusion protein. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether gray-scale ultrasound (US) based radiomic features can help distinguish HER2 expressions (ie, HER2-overexpressing, HER2-low-expressing, and HER2-zero-expressing) in breast cancer. Materials and Methods: This retrospective study encompassed female breast cancer patients who underwent US examinations at two distinct centers from February 2021 to July 2023. Tumor segmentation and radiomic feature extraction were performed on grayscale US images. Decision Tree analysis was employed to simultaneously evaluate feature importance, and the Least Absolute Shrinkage and Selection Operator technique was utilized for feature selection to construct the radiomic signature. The Area Under the Curve (AUC) of the Receiver Operating Characteristic curve was employed to assess the performance of the radiomic features. Multivariate logistic regression was used to identify independent predictors for distinguishing HER2 expression in the dataset. Results: The training set comprised 292 patients from Center 1 (median, 51 years; interquartile range [IQR]: 45-61), while the external validation set included 131 patients from Center 2 (median, 51 years; IQR: 45-62). In the external validation dataset, the radiomic features achieved AUC of 0.76 for distinguishing between HER2-low and positive tumors versus HER2-zero tumors. The AUC for differentiating HER2-low (1+) from HER2-zero tumors was 0.74, and for distinguishing HER2-low (2+) from HER2-zero tumors, the AUC was 0.77. In the multivariate analysis assessing HER2-low and HER2-positive versus HER2-zero tumors, internal echoes (P =.029) and margins (P <.001) emerged as independent predictive factors. Conclusion: The radiomic signature and tumor descriptors from gray-scale US may predict distinct HER2 expressions of breast cancers with therapeutic implications. [ABSTRACT FROM AUTHOR]

Simple Summary: Almost one in five patients with breast cancer have an aggressive subtype that expresses Human Epidermal Growth Factor-2 (HER2) receptor. The introduction of anti-HER2 therapy, like trastuzumab and pertuzumab, has dramatically improved treatment outcomes. However, such therapy is lengthy, costly, and can result in substantial cardiac toxicities. In this review, we discuss ways to de-escalate anti-HER2 therapy by shortening the treatment course to less than the 12-month standard, or minimizing companion chemotherapy. New molecular tools are emerging that should help physicians select which patients with HER2-positive breast cancer benefit most from aggressive and lengthy treatment regimens utilizing single or dual anti-HER2 therapy alone or in combination with chemotherapy. Almost one-fifth of breast cancer cases express Human Epidermal Growth Factor-2 (HER2), and such expression is associated with highly proliferative tumors and poor prognosis. The introduction of anti-HER2 therapies has dramatically changed the natural course of this aggressive subtype of breast cancer. However, anti-HER2 therapy can be associated with substantial toxicities, mostly cardiac, and high cost. Over the past few years, there has been growing interest in de-escalation of anti-HER2 therapies to minimize adverse events and healthcare costs, while maintaining the efficacy of treatment. Data from clinical observations and single-arm studies have eluted to the minimal impact of anti-HER2 therapy in low-risk patients, like those with node-negative and small tumors. Though single-arm, the APT trial, in which patients with node-negative, small tumors received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year, was a practice-changing study. Several other recently published studies, like the PERSEPHONE trial, have shown more convincing data that 6 months of trastuzumab is not inferior to 12 months, in terms of disease-free survival (DFS), suggesting that de-escalating strategies with shorter treatment may be appropriate for some low-risk patients. Other de-escalating strategies involved an adaptive, response-directed approach, and personalized therapy that depends on tumor genomic profiling. [ABSTRACT FROM AUTHOR]

Background: Today, breast cancer is the most diagnosed cancer worldwide. There are many different clinical presentations, radiological characteristics, and histological types of breast cancer. HER2 is overexpressed in a significant number of breast cancer cases reaching 20% of all breast cancers, and its overexpression is seen directly proportionate with a poor outcome and prognosis. Methods: We started this cross-sectional research from January 2022–December 2023 on 202 breast cancer patients who had 220 lesions. The molecular subtypes of the different lesions were determined in all the included cases. Magnetic resonance imaging (MRI) studies were conducted in all included cases. The MRI parameters included conventional MRI, diffusion-weighted analysis, and dynamic post-contrast T1-weighted imaging. Results: The prevalence of irregular margins (P < 0.001), linear and segmental distribution (P = 0.044), heterogeneous pattern (P < 0.001), and type 2 curve was statistically significantly higher in the HER2-positive lesions. Nipple infiltration incidence showed statistically significant elevation in the HER2-positive lesions (P = 0.017). The lesions' ADC and perilesional ADC in the HER2-positive lesions were also statistically significantly elevated. The best cutoff point of ADC to detect lesions with positive HER2 expression was > 0.885 × 10–3 mm2/s, with 65.7% sensitivity and 60% specificity, with a statistically significant value (p = 0.005). Conclusions: Magnetic resonance imaging of breast imaging is a promising noninvasive method for identifying breast tumors with the HER2 molecular subtype. Combining various radiological features by MRI may provide a conclusion for recognizing positive HER2 lesions. [ABSTRACT FROM AUTHOR]

Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN—the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses. [ABSTRACT FROM AUTHOR]

Abstract Background Human epidermal growth factor receptor 2-targeted (HER2) therapy with antibody-drug conjugates has proven effective for patients with HER2-low breast cancer. However, intratumoral heterogeneity (ITH) poses a great challenge in identifying HER2-low tumors. ITH signatures were developed by quantifying ITH to differentiate HER2-positive, -low and -zero breast cancers. Methods This retrospective study included 614 patients from two institutions. The study was structured into two primary tasks: task 1 was to differentiate between HER2-positive and -negative tumors, followed by task 2 to differentiate HER2-low and -zero tumors. Whole-tumor radiomics features and habitat radiomics features were extracted from MRI to construct the radiomics and ITH signatures. Multivariable logistic regression analysis was used to determine significant independent predictors. A combined model integrating significant clinicopathologic variables, radiomics signature, and ITH signature was developed for task (1) Subsequently, the better-performing model was established using the same approach for task (2) The area under the receiver operating characteristic curve (AUC) was used to assess the performance of each model. Results Task 1 comprised 614 patients (training, n = 348; validation, n = 149; and test cohorts, n = 117). Task 2 encompassed 501 patients (training, n = 283; validation, n = 122; and test cohorts, n = 96). For task1, the ITH signature showed outstanding performance, achieving AUCs of 0.81, 0.81, and 0.81 in the training, validation and test cohorts, respectively. The combined model achieved improved performance, with AUCs of 0.83, 0.84 and 0.83 across the three cohorts, respectively. For task2, the ITH signature maintained superior performance, with AUCs of 0.94, 0.93 and 0.84 across the training, validation and test cohorts, respectively. Multivariable logistic regression analysis indicated that none of the clinicopathologic characteristics were retained as predictors associated with odds of HER2-low tumors. Conclusions Our study developed ITH signatures that quantified ITH using habitat-based MRI radiomics, achieving outstanding performance in differentiating HER2-postive and -negative tumors, and further differentiating HER2-low and -zero breast cancers.

Abstract Explore whether the axillary outcomes differ among HER2 positive subgroups receiving standard dual-targeted therapy, aiming to identify subgroups exhibiting enhanced sensitivity to NAT among HER2-positive/node-positive breast cancer patients. HER2 positive female patients with biopsy-proven node-positive disease from April 2020 to May 2023 were included. All patients underwent standard Neoadjuvant HER2-targeted dual therapy and axillary lymph node dissection (ALND) at Breast Surgery Center of Sichuan Cancer Hospital. Univariate and multivariate analyses were used to identify factors associate with axillary pathological complete response (ApCR). Statistical analysis and graphing were performed using SPSS 24.0 and GraphPad Prism 9.0 software. This study enrolled 215 HER2 positive patients with a total ApCR rate of 76.7%, which included 49 HER2 2+/FISH + and 166 HER2 3 + cases with approximate ApCR rates of 63.3% and 80.7% (P = 0.011). Univariate and multivariate analysis indicated that HER2 3 + disease (OR = 2.43, 95% CI 1.21–4.88, P = 0.012), Ki-67 ≥ 20% disease (OR = 3.00, 95% CI 1.26–7.13, P = 0.013) and NAC regimen of TCb (OR = 2.71, 95% CI 1.39–5.38, P = 0.004) were more likely to achieve ApCR. Further subgroup analysis revealed that HER2 3 + patients receiving TCb regimen showed the highest ApCR rate of 88% compared to other subgroups. HER2 3 + breast cancer had a higher ApCR rate than HER2 2+/FISH + breast cancer during Neoadjuvant HER2-targeted dual therapy. HER2 positive patients could benefit from NAC regimen of TCb in axillary response.

Abstract Background Today, breast cancer is the most diagnosed cancer worldwide. There are many different clinical presentations, radiological characteristics, and histological types of breast cancer. HER2 is overexpressed in a significant number of breast cancer cases reaching 20% of all breast cancers, and its overexpression is seen directly proportionate with a poor outcome and prognosis. Methods We started this cross-sectional research from January 2022–December 2023 on 202 breast cancer patients who had 220 lesions. The molecular subtypes of the different lesions were determined in all the included cases. Magnetic resonance imaging (MRI) studies were conducted in all included cases. The MRI parameters included conventional MRI, diffusion-weighted analysis, and dynamic post-contrast T1-weighted imaging. Results The prevalence of irregular margins (P 0.885 × 10–3 mm2/s, with 65.7% sensitivity and 60% specificity, with a statistically significant value (p = 0.005). Conclusions Magnetic resonance imaging of breast imaging is a promising noninvasive method for identifying breast tumors with the HER2 molecular subtype. Combining various radiological features by MRI may provide a conclusion for recognizing positive HER2 lesions.

Objective(s): to investigate the capability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) derived volumetric parameters to predict human epidermal growth factor receptor 2 (HER2) status in breast cancer patients.Methods: retrospective study enrolled 47 female patients with breast cancer. All patients had pretreatment [18F]-FDG PET/CT. Clinical data, pathology report and HER2 status were retrieved from medical records. In an attempt to assess the predictive value of the PET-derived metabolic parameters, Receiver operating characteristic (ROC) curve was constructed with area under curve analysis performed to detect best cutoff value of significant parameters for detection of HER2 positive.Results: No statistically significant difference was noted among both groups (HER2 positive and negative) in respect to age, menopausal status, histology, grade, T-stage, N-stage, or antigen Kiel 67 (Ki-67) index. ROC curve successfully marked cutoff point ≥42.35 for total lesion glycolysis (TLG) and ³12.75 for metabolic tumor value (MTV) that are capable to discriminate positive versus negative HER2 expression in breast cancer patients with area under curve (AUC) 0.728 and 0.723 and P-values 0.002 and 0.004 respectively. Such cutoff point was not deduced for standard uptake value (SUV) max. Primary tumor TLG cutoff correlated well with age where 77.8% of patients with TLG ³42.35 were older than 45 years old compared to 22.2% of them who were younger than 45 years, P-value=0.047. Also 70.3% of patients with TLG exceeds ³42.35 had T3 and 4 primary tumors while 65% of those with TLG

According to the World Health Organization in 2022, 2.3 million women were diagnosed with breast cancer. Investigating the interaction networks between Bcl‐2‐associated athanogene (Bag)‐1 and other chaperone proteins may further the current understanding of the regulation of protein homeostasis in breast cancer cells and contribute to the development of treatment options. The present study aimed to determine the interactions between Bag‐1 and heat shock proteins (HSPs); namely, HSP90, HSP70 and HSP27, to elucidate their role in promoting heat shock factor‐1 (HSF1)‐dependent survival of breast cancer cells. HER2‐negative (MCF‐7) and HER2‐positive (BT‐474) cell lines were used to examine the impact of Bag‐1 expression on HSF1 and HSPs. We demonstrated that Bag‐1 overexpression promoted HER2 expression in breast cancer cells, thereby resulting in the concurrent constitutive activation of the HSF1–HSP axis. The activation of HSP results in the stabilization of several tumor‐promoting HSP clients such as AKT, mTOR and HSF1 itself, which substantially accelerates tumor development. Our results suggest that Bag‐1 can modulate the chaperone activity of HSPs, such as HSP27, by directly or indirectly regulating the phosphorylation of HSF1. This modulation of chaperone activity can influence the activation of genes involved in cellular homeostasis, thereby protecting cells against stress.

Abstract Background With the development of novel anti-HER2 targeted drugs, such as ADCs, it has become increasingly important to accurately interpret HER2 expression in breast cancer. Previous studies have demonstrated high intra-observer and inter-observer variabilities in evaluating HER2 staining by human eyes. There exists a strong requirement to develop artificial intelligence (AI) systems to achieve high-precision HER2 expression scoring for better clinical therapy. Methods In the present study, we collected breast cancer tissue samples and stained consecutive sections with anti-Calponin and anti-HER2 antibodies. High-quality digital images were selected from immunohistochemical slides and interpreted as HER2 3+, 2+, 1+, and 0. AI models were trained and assessed using annotated training and testing sets. The AI model was trained to automatically identify ductal carcinoma in situ (DCIS) by Calponin staining and myoepithelial annotation and filter out DCIS components in HER2-stained slides using image-overlapping techniques. Furthermore, we organized two-phase validation studies. In phase one, pathologists interpreted 112 HER2 whole-slide images (WSIs) without AI assistance, whereas in phase two, pathologists read the same slides using the AI system after a washing period of 2 weeks. Results Our AI model greatly improved the accuracy of reading (0.902 vs. 0.710). The number of HER2 1 + patients misdiagnosed as HER2 0 was significantly reduced (32/279 vs. 65/279), and they benefitted from ADC drugs. In addition, the AI algorithm improved the intra-group consistency of HER2 readings by pathologists with different years of experience (intra-class correlation coefficient [ICC]: 0.872–0.926 vs. 0.818–0.908), with the improvement most pronounced among junior pathologists (0.885 vs. 0.818). Conclusions We proposed a high-precision AI system to identify and filter out DCIS components and automatically evaluate HER2 expression in invasive breast cancer.

Abstract 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. Graphical abstract

Xiaojuan Gao,&ast; Tiansheng Bu,&ast; Wenying Wang, Ying Xu Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Xu, Department of Traditional Chinese Medicine Management, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu, People’s Republic of China, Email 18009432685@163.comAbstract: Breast cancer remains the most prevalent malignancy among women globally, presenting significant challenges in therapeutic strategies due to tumor heterogeneity, drug resistance, and adverse side effects. Recent advances in targeted therapies, particularly antibody-drug conjugates (ADCs), have shown promise in addressing these challenges by selectively targeting tumor cells while sparing normal tissues. This study provides a comprehensive analysis of two innovative ADCs targeting HER2 and Trop-2, which are critical markers in various breast cancer subtypes. These conjugates combine potent cytotoxic drugs with specific antibodies, leveraging the antigens’ differential expression to enhance therapeutic efficacy and reduce systemic toxicity. Our comparative analysis highlights the clinical applications, efficacy, and safety profiles of these ADCs, drawing on data from recent clinical trials. In addition, the paper discusses the potential of these ADCs in treating other types of cancers where HER2 and Trop-2 are expressed, as well as the toxicity risks associated with targeting these antigens in normal cells. Additionally, the paper discusses novel synthetic drugs that show potential in preclinical models, focusing on their mechanisms of action and therapeutic advantages over traditional chemotherapy. The findings underscore the transformative impact of targeted ADCs in breast cancer treatment, noting significant advancements in patient outcomes and management of side effects. However, ongoing issues such as resistance mechanisms and long-term safety remain challenges. The conclusion offers a forward-looking perspective on potential improvements and the future trajectory of ADC research. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics, with particular attention to their broader applications and associated risks.Keywords: breast cancer, antibody drugs, HER2, Trop-2

Abstract Background The novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood. Methods The patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression. Results In this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P

ObjectiveTo compare the efficacy of trastuzumab plus pertuzumab (HP) combined with either nab-paclitaxel plus carboplatin or docetaxel plus carboplatin as neoadjuvant therapy for HER2-positive breast cancer in real-world clinical practice. MethodsClinical data of HER2-positive breast cancer patients who received neoadjuvant therapy with either HP combined with nab-paclitaxel plus carboplatin or HP combined with docetaxel plus carboplatin and subsequently underwent surgery were retrospectively collected from 11 tertiary grade-A hospitals in Hebei Province from June 2019 to December 2021. The total pathological complete response (tpCR) rates of the two groups were compared. ResultsA total of 76 patients were included in the study, with 47 in the nab-paclitaxel group and 29 in the docetaxel group. The tpCR rate was significantly higher in the nab-paclitaxel group than that in the docetaxel group (72.3% vs. 48.3%, χ2=4.463, P=0.035). Subgroup analysis indicated that patients older than 40 years, with cN2-3, cTNM stage Ⅲ, hormone receptor-positive status, and Ki67>30% had significantly higher tpCR rates in the nab-paclitaxel group than those in the docetaxel group (P

Abstract Background Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a new subtype of tumor, for which novel antibody–drug conjugates have shown beneficial effects. Assessment of HER2 requires several immunohistochemistry tests with an additional in situ hybridization test if a case is classified as HER2 2+. Therefore, novel cost-effective methods to speed up the HER2 assessment are highly desirable. Methods We used a self-supervised attention-based weakly supervised method to predict HER2-low directly from 1437 histopathological images from 1351 breast cancer patients. We built six distinct models to explore the ability of classifiers to distinguish between the HER2-negative, HER2-low, and HER2-high classes in different scenarios. The attention-based model was used to comprehend the decision-making process aimed at relevant tissue regions. Results Our results indicate that the effectiveness of classification models hinges on the consistency and dependability of assay-based tests for HER2, as the outcomes from these tests are utilized as the baseline truth for training our models. Through the use of explainable AI, we reveal histologic patterns associated with the HER2 subtypes. Conclusion Our findings offer a demonstration of how deep learning technologies can be applied to identify HER2 subgroup statuses, potentially enriching the toolkit available for clinical decision-making in oncology.

Abstract Breast cancer is among the highest morbidity and mortality rates in women around the world. In the present investigation we aimed to synthesis novel nanosystem combining two naturally important anticancer agents with different mechanism of action namely Moringa oleifera and caffeine. Firstly, chemical analysis of Moringa oleifera extract and caffeine was done by gas chromatography-mass spectroscopy (GC–MS) in order to assess the main chemical compounds present and correlate between them and the possible anticancer effect. The novel nanosystem was characterized through dynamic light scattering techniques which revealed the stability and homogeneity of the prepared M. oleifera leaves extract/Caffeine loaded chitosan nanoparticles, while FTIR and transmission electron microscope (TEM) proved the shape and the successful incorporation of M. oleifera leaves extract/Caffeine onto the nanochitosan carrier. Our initial step was to assess the anticancer effect in vitro in cancer cell line MCF-7 which proved the significant enhanced effect of M. oleifera leaves extract/Caffeine nanosystem compared to M. oleifera leaves extract or caffeine loaded nanoparticles. Further studies were conducted in vivo namely tumor biomarkers, tumor volume, bioluminescence imaging, molecular and histopathological investigations. The present study proved the potent anticancer effect of the synthesized M. oleifera leaves extract/Caffeine loaded chitosan nanoparticles. Mo/Caf/CsNPs exhibited a large number of apoptotic cells within the tumor mass while the adipose tissue regeneration was higher compared to the positive control. The prepared nanoparticles downregulated the expression of Her2, BRCA1 and BRCA2 while mTOR expression was upregulated. The aforementioned data demonstrated the successful synergistic impact of Moringa and caffeine in decreasing the carcinoma grade.

Abstract Background Tucatinib (TUC), a HER2-directed tyrosine kinase inhibitor, is the first targeted drug demonstrating intracranial efficacy and significantly prolonged survival in metastatic HER2-positive breast cancer (BC) patients with brain metastases. Current treatments for brain metastases often include radiotherapy, but little is known about the effects of combination treatment with TUC. Therefore, we examined the combined effects of irradiation and TUC in human HER2-overexpressing BC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) cell lines. For the latter two, a standard therapy successfully targeting HER2 is yet to be established. Methods Nine HER2-overexpressing (BC: BT474, ZR7530, HCC1954; CRC: LS411N, DLD1, COLO201; NSCLC: DV90, NCI-H1781) and three control cell lines (BC: MCF7, HCC38; NSCLC: NCI-H2030) were examined. WST-1 assay (metabolic activity), BrdU ELISA (proliferation), γH2AX assay (DNA double-strand breaks (DSB), Annexin V assay (apoptosis), and clonogenic assay (clonogenicity) were performed after treatment with TUC and/or irradiation (IR). The relevance of the treatment sequence was analyzed exemplarily. Results In BC, combinatorial treatment with TUC and IR significantly decreased metabolic activity, cell proliferation, clonogenicity and enhanced apoptotis compared to IR alone, whereby cell line-specific differences occurred. In the PI3KCA-mutated HCC1954 cell line, addition of alpelisib (ALP) further decreased clonogenicity. TUC delayed the repair of IR-induced DNA damage but did not induce DSB itself. Investigation of treatment sequence indicated a benefit of IR before TUC versus IR after TUC. Also in CRC and NSCLC, the combination led to a stronger inhibition of metabolic activity, proliferation, and clonogenic survival (only in NSCLC) than IR alone, whereby about 10-fold higher concentrations of TUC had to be applied than in BC to induce significant changes. Conclusion Our data indicate that combination of TUC and IR could be more effective than single treatment strategies for BC. Thereby, treatment sequence seems to be an important factor. The lower sensitivity to TUC in NSCLC and particularly in CRC (compared to BC) implicates, that tumor promotion there might be less HER2-related. Combination with inhibitors of other driver mutations may aid in overcoming partial TUC resistance. These findings are of high relevance to improve long-time prognosis especially in brain-metastasized situations given the intracranial activity of TUC.

Lifeng Tang,1,2 Wei Zhang,3 Long Chen2 1Department of Oncology, Liuzhou People’s Hospital, Liuzhou, Guangxi, 545006, People’s Republic of China; 2Department of Radiotherapy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People’s Republic of China; 3Department of Radiology, Liuzhou People’s Hospital, Liuzhou, Guangxi, 545006, People’s Republic of ChinaCorrespondence: Long Chen; Wei Zhang, Email clong6@126.com; holly2yang@126.comBackground: Research on the sequencing of brain radiotherapy and targeted chemotherapy after brain metastasis (BM) in HER2-positive breast cancer patients is limited and inconclusive. This study investigated the efficacy of sequential delivery of radiotherapy and targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with BM.Methods: Fifty-seven patients were categorized into two groups: the targeted-radiotherapy group (receiving 2– 8 cycles of anti-HER2-targeted therapy followed by radiotherapy after BM) and the radiotherapy-targeted group (undergoing radiotherapy first, followed by regular anti-HER2-targeted therapy). The study endpoints were intracranial progression-free survival (iPFS) and overall survival. Factors associated with intracranial progression and mortality were assessed by univariate and multivariate Cox proportional hazards analysis.Results: Patients in the radiotherapy-targeted group had better iPFS (P < 0.001), while there was no significant difference in overall survival between the two groups (P = 0.145). Multivariate Cox analysis showed that different sequential treatment groups were independent prognostic factors for iPFS. In patients with a modified breast graded prognostic assessment score of 3.5– 4.0, the median survival time was 26 months in the radiotherapy-targeted group and 22 months in the targeted-radiotherapy group (P = 0.019).Conclusion: Overall, radiotherapy followed by targeted therapy may improve survival in HER2-positive breast cancer patients with BM, particularly in those with a modified breast graded prognostic assessment score of 3.5– 4.0.Keywords: HER2, breast cancer, brain metastasis, craniocerebral radiotherapy, HER2-targeted drugs

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]

Background: The novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood. Methods: The patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression. Results: In this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P < 0.014), have more premenopausal patients (P < 0.001), a higher proportion of hormone receptor (HR) positive patients (P < 0.001), and less proportion of stage III V patients (P < 0.034). When NAT was finished, the pCR rate became 23.6% in the HER2-0 group while 22.1% in the HER2-low group, and there was also a higher pCR rate in HR- patients in comparison with that in HR + patients (P < 0.01). Considering HER2 expression inconsistency, the overall HER2 inconsistency rate was 30.4% (Kappa = 0.431, P < 0.01). Among patients initially diagnosed as HER2-0, 34% (N = 61) were re-diagnosed as HER2-low after NAT. After stratification by HR expression status, HR+/HER2-0 patients transformed to HER2-low after NAT in 37%, and 32% of HR- patients changed from HER2-0 to HER2-low. In this survival analysis, there were both better DFS rates (P = 0.009) and OS rates (P = 0.026) in the HR-/HER2-low patients in comparison with the HR-/HER2-0 patients, while the HER2-0 and HER2-low patients in the HR + group had no significant survival difference. Additionally, for non-pCR patients, there was better DFS (P = 0.029) and OS (P = 0.038) in the HER2-low group in comparison with that of the HER2-0 group, while no significant survival difference exists between pCR patients. Conclusion: After HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies. [ABSTRACT FROM AUTHOR]

Primary endometrial serous carcinoma, known for its aggressive nature and poor prognosis, shares similarities with breast and gastric cancers in terms of potential HER2 overexpression as a therapeutic target. Assessing HER expression is complicated by tumor heterogeneity and discrepancies between primary and metastatic sites. In this study, we retrospectively analyzed HER amplification and expression in 16 pairs of primary endometrial serous carcinoma resections and corresponding metastases. HER2 status was determined using immunohistochemistry (IHC), with criteria based on the percentage and intensity of tumor cell staining. Confirmatory techniques, such as dual in situ hybridization (DISH) and fluorescence in situ hybridization (FISH), were also employed. This study reports on the concordance rates and the presence and pattern of HER2 heterogeneity. Our results showed an 87.5% concordance rate in HER2 amplification status between primary and metastatic sites, with 33% of cases scored as 2+ being amplified. Heterogeneity was observed in 100% of amplified cases and 95% of non-amplified cases on in situ testing, with variations in heterogeneity patterns between techniques. In conclusion, our findings emphasize the importance of testing both primary and metastatic sites or recurrences, with a concordance rate of 87.5%. In addition, a review of the literature and combining the results showed a concordance rate of up to 68%. The presence and pattern of heterogeneity, particularly in cases of mosaic or clustered heterogeneity in the primary tumor, may serve as reliable indicators of concordance, predicting a non-amplified HER2 status in corresponding metastases. [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]

Objective To compare the efficacy of trastuzumab plus pertuzumab (HP) combined with either nab-paclitaxel plus carboplatin or docetaxel plus carboplatin as neoadjuvant therapy for HER2-positive breast cancer in real-world clinical practice. Methods Clinical data of HER2-positive breast cancer patients who received neoadjuvant therapy with either HP combined with nab-paclitaxel plus carboplatin or HP combined with docetaxel plus carboplatin and subsequently underwent surgery were retrospectively collected from 11 tertiary grade-A hospitals in Hebei Province from June 2019 to December 2021. The total pathological complete response (tpCR) rates of the two groups were compared. Results A total of 76 patients were included in the study, with 47 in the nab-paclitaxel group and 29 in the docetaxel group. The tpCR rate was significantly higher in the nab-paclitaxel group than that in the docetaxel group (72.3% vs. 48.3%, χ² =4.463, P=0.035). Subgroup analysis indicated that patients older than 40 years, with cN2-3, cTNM stage Ⅲ, hormone receptor-positive status, and Ki67>30% had significantly higher tpCR rates in the nab-paclitaxel group than those in the docetaxel group (P<0.05). Conclusion In real-world clinical practice, the efficacy of HP combined with nab-paclitaxel plus carboplatin as neoadjuvant therapy for HER2-positive breast cancer is superior to that of HP combined with docetaxel plus carboplatin. [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]

Aims: Over 50% of breast cancer cases are "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti‐HER2 antibody‐drug conjugates (ADCs) for treating HER2‐low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2‐low breast cancer. In this study we evaluated the performance of a deep‐learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2‐Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells' staining intensity and completeness of membrane staining. Methods and Results: We trained a DL model on a multicentric cohort of breast cancer cases with HER2‐IHC scores (n = 299). The model was validated on two independent multicentric validation cohorts (n = 369 and n = 92), with all cases reviewed by three senior breast pathologists. All cases underwent a thorough review by three senior breast pathologists, with the ground truth determined by a majority consensus on the final HER2 score among the pathologists. In total, 760 breast cancer cases were utilized throughout the training and validation phases of the study. The model's concordance with the ground truth (ICC = 0.77 [0.68–0.83]; Fisher P = 1.32e‐10) is higher than the average agreement among the three senior pathologists (ICC = 0.45 [0.17–0.65]; Fisher P = 2e‐3). In the two validation cohorts, the DL model identifies 95% [93% ‐ 98%] and 97% [91% ‐ 100%] of HER2‐low and HER2‐positive tumours, respectively. Discordant results were characterized by morphological features such as extended fibrosis, a high number of tumour‐infiltrating lymphocytes, and necrosis, whilst some artefacts such as nonspecific background cytoplasmic stain in the cytoplasm of tumour cells also cause discrepancy. Conclusion: Deep learning can support pathologists' interpretation of difficult HER2‐low cases. Morphological variables and some specific artefacts can cause discrepant HER2‐scores between the pathologist and the DL model. [ABSTRACT FROM AUTHOR]

Aims: Standard neoadjuvant endocrine therapy (NAET) is used for 6–9 months to downstage hormone‐receptor‐positive breast cancer. Bridging ET was introduced during the COVID‐19 pandemic to delay surgical intervention. There are no data in the literature on the effect of short course therapy on tumour response. We aimed to analyse the effect of bridging ET and validate the previously proposed neoadjuvant ET pathological reporting criteria. Methods and Results: This was a multicentre cohort of 256 patients who received bridging ET between March and October 2020. Assessment of paired pre‐ and post‐NAET hormone receptors and HER2 and posttherapy Ki67 expression was done. The median duration of NAET was 45 days. In all, 86% of cases achieved partial pathological response and 9% showed minimal residual disease. Histological response to ET was observed from as early as day 6 posttherapy. Central scarring was noted in 32.8% of cases and lymphocytic infiltrate was seen in 43.4% of cases. Significant changes associated with the duration of ET were observed in tumour grade (21%), with downgrading identified in 12% of tumours (P < 0.001), progesterone receptor (PR) expression with switch to PR‐negative status in 26% of cases (P < 0.001), and HER2 status with a switch from HER2‐low to HER2‐negative status in 32% of cases (P < 0.001). The median patient survival was 475 days, with an overall survival rate of 99.6%. Conclusions: Changes characteristic of tumour regression and significant changes in PR and HER2 occurred following a short course of NAET. The findings support biomarker testing on pretreatment core biopsies and retesting following therapy. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2)‐enriched breast cancer benefits significantly from anti‐HER2 targeted therapies. This highlights the critical need for precise HER2 immunohistochemistry (IHC) interpretation serving as a triage tool for selecting patients for anti‐HER2 regimens. Recently, the emerging eligibility of patients with HER2‐low breast cancers for a novel HER2‐targeted antibody–drug conjugate (T‐DXd) adds challenges to HER2 IHC scoring interpretation, notably in the 0–1+ range, which shows high interobserver and interlaboratory staining platform variability. In this review, we navigate evolving challenges and suggest practical recommendations for HER2 IHC interpretation. [ABSTRACT FROM AUTHOR]

Background: There are limited data on the role of multigene tests and their correlation with immunohistochemistry (IHC), especially on core biopsy. MammaTyper is a quantitative conformite Europeeanne (CE) marked, National Institute for Health and Care excellence (NICE) approved, in in vitro diagnostic quantitative real‐time polymerase chain reaction (RT‐qPCR) test for assessment of mRNA expression of four biomarkers (ESR1, PGR, ERBB2, MKI67). Methods: We evaluated the concordance of MammaTyper with oestrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 by IHC on 133 core needle biopsies of breast cancer. HER2 was positive if IHC 3+ or 2+ and fluorescence in situ hybridization (FISH)‐amplified. Global and hotspot Ki67 expression was analysed using a cutoff of ≥20% assessed manually and by digital image analysis. Agreements were expressed as overall percent agreement (OPA), positive percent agreement (PPA), negative percent agreement (NPA), and Cohen's kappa. Results: RT‐qPCR results of ESR1 were highly concordant with IHC with OPA of 94.7% using 1% cutoff and 91.7% when the low ER‐positive category was included. The PPA and NPA between RT‐qPCR and IHC for PR was 91.5% and 88.0%, respectively, when using the 1% cutoff. For ERBB2/HER2, the OPA was 95% and the PPA was 84.6%. 40 of 72 HER2 IHC score 0 tumours were classified as ERBB2 low. Best concordance between MKI67 by MammaTyper and Ki67 IHC was achieved using hotspot digital image analysis (OPA: 87.2%, PPA: 90.6%, NPA: 80%). Conclusion: RT‐qPCR‐based assessment of the mRNA expression of ESR1, PGR, ERBB2, and MKI67 showed high concordance with IHC, suggesting that the MammaTyper test on core needle biopsies represents a reliable, efficient, and reproducible alternative for breast cancer classification and refining HER2 low categorisation. [ABSTRACT FROM AUTHOR]

Circadian clocks, biochemical oscillators that are regulated by environmental time cues including the day/night cycle, have a central function in the majority of biological processes. The disruption of the circadian clock can alter breast biology negatively and may promote the development of breast tumors. The expression status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were used to classify breast cancer into different molecular subtypes such as triple-negative breast cancer (TNBC). Receptor status-dependent expression of circadian clock genes have been previously studied in breast cancer using relatively small sample sizes in a particular population. Here, using TCGA-BRCA data (n=1119), we found that the expressions of CRY1, PER1, PER2, PER3, BMAL1, CLOCK, RORA, RORB, RORC, NR1D1, NR1D2, and FBXL3 were higher in ER+ breast cancer cells compared with those of ER− status. Similarly, we showed that transcript levels of CRY2, PER1, PER2, PER3, BMAL1, RORA, RORB, RORC, NR1D1, NR1D2, and FBXL3 were higher in PR+ breast cancer cells than in PR− breast cancer cells. We report that the expressions of CRY2, PER1, BMAL1, and RORA were lower, and the expression of NR1D1 was higher, in HER2+ breast cancer cells compared with HER2− breast cancer cells. Moreover, we studied these receptor status-dependent changes in the expressions of circadian clock genes also based on the race and age of breast cancer patients. Lastly, we found that the expressions of CRY2, PER1, PER2, PER3, and CLOCK were higher in non-TNBC than in TNBC, which has the worst prognosis among subtypes. We note that our findings are not always parallel to the observations reported in previous studies with smaller sample sizes performed in different populations and organisms. Our study suggests that receptor status in breast cancer (thus, subtype of breast cancer) might be more important than previously shown in terms of its influence on the expression of circadian clock genes and on the disruption of the circadian clock, and that ER or PR might be important regulators of breast cancer chronobiology that should be taken into account in personalized chronotherapies. [ABSTRACT FROM AUTHOR]

According to the World Health Organization in 2022, 2.3 million women were diagnosed with breast cancer. Investigating the interaction networks between Bcl‐2‐associated athanogene (Bag)‐1 and other chaperone proteins may further the current understanding of the regulation of protein homeostasis in breast cancer cells and contribute to the development of treatment options. The present study aimed to determine the interactions between Bag‐1 and heat shock proteins (HSPs); namely, HSP90, HSP70 and HSP27, to elucidate their role in promoting heat shock factor‐1 (HSF1)‐dependent survival of breast cancer cells. HER2‐negative (MCF‐7) and HER2‐positive (BT‐474) cell lines were used to examine the impact of Bag‐1 expression on HSF1 and HSPs. We demonstrated that Bag‐1 overexpression promoted HER2 expression in breast cancer cells, thereby resulting in the concurrent constitutive activation of the HSF1–HSP axis. The activation of HSP results in the stabilization of several tumor‐promoting HSP clients such as AKT, mTOR and HSF1 itself, which substantially accelerates tumor development. Our results suggest that Bag‐1 can modulate the chaperone activity of HSPs, such as HSP27, by directly or indirectly regulating the phosphorylation of HSF1. This modulation of chaperone activity can influence the activation of genes involved in cellular homeostasis, thereby protecting cells against stress. [ABSTRACT FROM AUTHOR]

Background: In 2022, our team launched the pioneering national proficiency testing (PT) scheme for the pathological diagnosis of breast cancer, rapidly establishing its credibility throughout China. Aiming to continuously monitor and improve the proficiency of Chinese pathologists in breast pathology, the second round of the PT scheme was initiated in 2023, which will expand the number of participating institutions, and will conduct a nationwide investigation into the interpretation of HER2 0, 1+, and 2+/FISH- categories in China. Methods: The methodology employed in the current round of PT scheme closely mirrors that of the preceding cycle in 2022, which is designed and implemented according to the "Conformity assessment—General requirements for proficiency testing"(GB/T27043—2012/ISO/IEC 17043:2010). More importantly, we utilized a statistics-based method to generate assigned values to enhance their robustness and credibility. Results: The final PT results, published on the website of the National Quality Control Center for Cancer (http://117.133.40.88:3927), showed that all participants passed the testing. However, a few institutions demonstrated systemic biases in scoring HER2 0, 1+, and 2+/FISH- with accuracy levels below 59%, considered unsatisfactory. Especially, the concordance rate for HER2 0 cases was only 78.1%, indicating challenges in distinguishing HER2 0 from low HER2 expression. Meanwhile, areas for histologic type and grade interpretation improvement were also noted. Conclusions: Our PT scheme demonstrated high proficiency in diagnosing breast cancer in China. But it also identified systemic biases in scoring HER2 0, 1+, and 2+/FISH- at some institutions. More importantly, our study highlighted challenges in the evaluation at the extreme lower end of the HER2 staining spectrum, a crucial area for further research. Meanwhile, it also revealed the need for improvements in interpreting histologic types and grades. These findings strengthened the importance of robust quality assurance mechanisms, like the nationwide PT scheme conducted in this study, to maintain high diagnostic standards and identify areas requiring further training and enhancement. [ABSTRACT FROM AUTHOR]

Opinion Statement: This perspective underscores the evolution and significance of neoadjuvant therapy in breast cancer, tracing its history and efficacy in improving outcomes. It delves into the correlation between achieving complete response and long-term survival, emphasizing the predictive value of treatment response estimation. Neoadjuvant chemotherapy in HER2-positive early breast cancer, particularly with taxanes and anti-HER2 therapies, emerges as a cornerstone, offering enhanced breast conservation rates and prognostic insights. The focus on individualized care, tailored to treatment response, underscores the need for adaptive strategies. Additionally, the article discusses the ongoing debate surrounding anthracyclines' role and the benefits of dual HER2 blockade. Ultimately, advocating for a personalized approach, guided by treatment response assessment, ensures optimal outcomes in HER2-positive breast cancer management. [ABSTRACT FROM AUTHOR]

Purpose: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC. Methods: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR). Results: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3–7.7) and 7.3 (95% CI 7.1–7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3–4 anti-HER2 related toxicities were reported in six (1.9%) patients. Conclusion: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer (BC) is one of the leading causes of cancer and is the first cause of death from malignant tumors among women worldwide. New cancer therapies receive regulatory approval yearly and to avoid health disparities in society, the health systems are challenged to adapt their infrastructure, methodologies, and reimbursement policies to allow broad access to these treatments. In addition, listening to patients' voices about their therapy preferences is essential. We aim to investigate the administration route preferences [subcutaneous (SC) or intravenous (IV)] among patients diagnosed with HER2 positive BC and healthcare professionals (HCPs) and to investigate healthcare resources utilization (quality and quantity) for each route of administration (SC or IV) for treating those patients. Methods: We conducted a systematic literature review focused on clinical trials and observational and economic studies, using PubMed (MEDLINE), Cochrane Library, Virtual Health Library (VHL), Scientific Electronic Library Online (SciELO), and Latin American and Caribbean Health Sciences Literature (LILACS) databases based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Results: The literature review included 25 studies in the analysis. Studies have reported that patients and HCPs prefer the SC route of administration to IV because it saves time in terms of chair time, administration, and preparation and is less painful. In addition, SC administration might be a more cost-saving option when analyzing direct and indirect costs. Discussion: As BC stands as a significant global health concern and the leading cause of cancer-related deaths in women worldwide, understanding and incorporating patient and HCPs preferences in the choice of administration route become paramount. The observed preference for SC administration not only aligns with the imperative of adapting health systems to facilitate broad access to new cancer therapies but also underscores the importance of considering patient experiences and economic implications in shaping treatment strategies. These insights are crucial for healthcare policymakers, clinicians, and stakeholders in optimizing healthcare resources and enhancing the overall quality of BC care. [ABSTRACT FROM AUTHOR]

Tyrosine protein kinase HER2 plays an important role in carcinogenesis. In breast cancer (BC), the HER2 gene is amplified in approximately 20% of cases. Trastuzumab is used to treat BC with HER2 gene amplification. Trastuzumab is not effective in treating tumors with low HER2 expression, but trastuzumab deruxtecan was recently found to significantly improve prognosis in these patients. Nonetheless, there are still difficulties with accurate diagnosis of HER2-low BC, especially at the preoperative stage. In this study, when comparing the results between core needle biopsies and resection specimens using three immunohistochemistry scores (0, 1+, and 3+) of the HER2 protein level, we observed only moderate agreement (66.2%, κ = 0.486) in patients who did not undergo neoadjuvant therapy (n = 71). Other miRNA- or protein-coding genes regulated by HER2 signaling pathways may be additional markers for the scoring of the HER2 level. We measured levels of HER2-regulated miR-378a, -205, and -21 and mRNA levels of their target genes TRPS1, ITGA2, BCL6, and PTEN in BC surgical specimens. For estrogen receptor-positive BC (n = 64), we confirmed that the expression of miR-21, miR-378a, TRPS1, PTEN, and BCL6 is associated with the HER2 protein level. Moreover, the expression profile of miR-378a, BCL6, and PTEN differed between HER2 1+ and HER2 3+ tumors. TRPS1 expression was significantly higher in HER2 3+ tumors compared with HER2 0 tumors, but there was no difference in the amount of TRPS1 mRNA between HER2 1+ and HER2 3+ tumors. Thus, an analysis of the expression of miR-21, miR-378a, TRPS1, PTEN, and BCL6 may help to distinguish between HER2-negative, HER2-positive, and HER2-low BCs. [ABSTRACT FROM AUTHOR]

Data on rechallenges of HER2 targetted agents in breast cancer patients is limited. The goal of the study was to evaluate the effectiveness of trastuzumab-based therapy in patients who progressed under trastuzumab emtansine (TDM-1). The study was designed as a retrospective observational study. Survival plots were performed with the Kaplan–Meier method. Fifteen patients were involved in the study. The average age was 45 (range, 30–66). De novo metastatic patient number was six (40%), and the average number of metastatic sites was 2 (range, 1–4) at diagnosis. Fourteen patients (92.3%) had undergone breast surgery (lumpectomy or mastectomy). All patients previously had been treated with trastuzumab-based chemotherapy and TDM-1. Also, nine (60%) patients had received endocrine therapy, and nine (60%) patients had palliative radiotherapy. After progression under TDM-1, patients received trastuzumab with chemotherapy (73.3%) or alone (26.7%). The overall response ratio was 66.7%. Median progression-free survival was 9.4 months (95% CI, 3.4–15.3). The median OS duration was 24.2 (95% CI, 13.5–34.9) months. Toxicity in all grades was observed in ten (66.7%) patients, and grade 3–4 toxicity (anemia and neutropenia) in two patients (13.3%). This study showed that rechallenge trastuzumab-based therapy was effective and good-tolerated in heavily pretreated patients who had progressed under TDM-1. [ABSTRACT FROM AUTHOR]