Search

Purpose: This study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1. Methods: Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression. Results: JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors. Conclusion: The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC. [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]

Objective: To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to preoperatively predict human epidermal growth factor receptor 2 (HER2) status in bladder cancer (BCa) with multicenter validation. Methods: In this retrospective study, 207 patients with pathologically confirmed BCa were enrolled and divided into the training set (n = 154) and test set (n = 53). Least absolute shrinkage and selection operator (LASSO) regression was used to identify the most discriminative features in the training set. Five radiomics-based ML models, namely logistic regression (LR), support vector machine (SVM), k-nearest neighbors (KNN), eXtreme Gradient Boosting (XGBoost) and random forest (RF), were developed. The predictive performance of established ML models was evaluated by the area under the receiver operating characteristic curve (AUC). The Shapley additive explanation (SHAP) was used to analyze the interpretability of ML models. Results: A total of 1218 radiomics features were extracted from the nephrographic phase CT images, and 11 features were filtered for constructing ML models. In the test set, the AUCs of LR, SVM, KNN, XGBoost, and RF were 0.803, 0.709, 0.679, 0.794, and 0.815, with corresponding accuracies of 71.7%, 69.8%, 60.4%, 75.5%, and 75.5%, respectively. RF was identified as the optimal classifier. SHAP analysis showed that texture features (gray level size zone matrix and gray level co-occurrence matrix) were significant predictors of HER2 status. Conclusions: The radiomics-based interpretable ML model provides a noninvasive tool to predict the HER2 status of BCa with satisfactory discriminatory performance. Critical relevance statement: An interpretable radiomics-based machine learning model can preoperatively predict HER2 status in bladder cancer, potentially aiding in the clinical decision-making process. Key Points: The CT radiomics model could identify HER2 status in bladder cancer. The random forest model showed a more robust and accurate performance. The model demonstrated favorable interpretability through SHAP method. [ABSTRACT FROM AUTHOR]

What is this summary about? This is a summary of the publication about the DESTINY-Lung01 study, which was published in the New England Journal of Medicine in September 2021. The DESTINY-Lung01 study includes 181 adults with metastatic non-small-cell lung cancer (NSCLC) that could not be treated with surgery and who have had previous standard anticancer treatment. The publication includes information and results about 91 of the 181 study participants. These 91 participants had HER2-mutant NSCLC. Researchers wanted to learn if the drug trastuzumab deruxtecan (T-DXd) could help treat participants with HER2-mutant NSCLC. At the time of this publication, this study is ongoing. What are the key takeaways? Results from the study showed that 55% of participants responded to treatment with T-DXd. The median length of time participants continued to respond to T-DXd was 9.3 months. After receiving T-DXd, 92% of participants had disease control. After receiving T-DXd, half of the participants lived for at least 17.8 months. After receiving T-DXd, half of the participants lived for 8.2 months before their cancer got worse. During the study, 97% of participants had drug-related adverse events, with nausea being the most common. There were 20% of participants with serious drug-related adverse events. What were the main conclusions reported by the researchers? Based on these results, T-DXd could be a treatment option for people with HER2-mutant NSCLC that has been previously treated. Clinical Trial Registration:NCT03505710 (DESTINY-Lung01) (ClinicalTrials.gov) [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]

Anti‐HER2 therapy is indicated for erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2‐mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2‐mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor‐normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2‐amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2‐mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2‐amplified. Compared to ERBB2‐wildtype ECs (with or without ERBB2 amplification), ERBB2‐mutated/non‐amplified ECs were enriched for the microsatellite instability‐high (MSI‐H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2‐mutated/non‐amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2‐wildtype and ERBB2‐amplified ECs. [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]

There is limited research on the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) currently. The aim of this study is to summerize the clinicopathological factors and prognosis of cHCC-CCA, which could help us understand this disease. 72 cases of cHCC-CCA from West China Hospital of Sichuan University were collected. Tissue components were reviewed by pathologists. Immunohistochemistry was used to detect the status of mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) in cHCC-CCA, as well as the quantity and distribution of CD3+ T cells and CD8+ T cells. Fluorescence in situ hybridization was used to detect fibroblast growth factor receptor 2 (FGFR2) gene alteration. COX univariate and multivariate analyses were used to evaluate risk factors, and survival curves were plotted. 49 cases were classified as classic type cHCC-CCA and 23 cases as intermediate cell carcinoma. The cut-off value for diagnosing classic type was determined to be ≥ 30% for the cholangiocarcinoma component based on prognostic calculations. All tumors were MMR proficient. The rate of strong HER2 protein expression (3+) was 8.3%, and the frequency of FGFR2 gene alteration was 26.4%. CD3+ T cells and CD8+ T cells were mainly distributed at the tumor margin, and were protective factors for patients with cHCC-CCA. The overall survival of the 72 patients was 18.9 months, with a median survival of 12 months. Tumor size, TNM stage, and serum AFP level were prognostic factors for cHCC-CCA. The proportion of cholangiocarcinoma component reaching the threshold of 30%, may provide a reference for future pathology diagnosis. FGFR2 gene alteration was 26.4%, providing a clue for anti-FGFR2 therapy. However, more data is needed for further verification. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) is known for its oncogenic activities in diverse cancers, including non-small cell lung cancer (NSCLC). However, the prevalence of HER2 alterations in Malaysian NSCLC patients remains unreported. This study examined the prevalence and characteristics of HER2 mutations and amplification in a Malaysian cohort. Additionally, a systematic review was conducted to evaluate the global prevalence of HER2 alterations in NSCLC, as well as the efficacy of HER2-targeted therapies observed in clinical trials. NSCLC tumour samples received from October 2019 to December 2022 for next-generation sequencing diagnostics were included in the retrospective analysis. In this patient cohort, HER2 alteration was present in 5.8% of patients; 3.9% had HER2 mutations, 1.5% had HER2 amplifications and 0.4% were both HER2-mutated and amplified. HER2 exon 20 insertions were the most common HER2 variants, detected in 47/59 (79.7%) of HER2-mutated patients. Among cases with HER2 exon 20 insertions, the Y772&lowbar;A775dup variant was found in 34 patient samples. HER2-mutated patients were significantly younger than non-HER2-mutants (61 versus 64 years old; p = 0.046) and were inclined to be female and never-smokers, albeit not statistically significant. Patients with HER2 amplification were more likely to have progressed post-tyrosine kinase inhibitor therapy (p = 0.015). The systematic review highlighted a global variation in the prevalence of HER2 alterations in NSCLC, ranging from 0.3% to 9.1% for mutations and 0.2% to 19% for amplification. Finally, phase II clinical trials involving HER2-altered NSCLC patients demonstrated promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. In conclusion, the prevalence of HER2 alteration among Malaysian NSCLC patients falls within the global range. A systematic review of clinical trials revealed promising treatment outcomes and Malaysian NSCLC patients with HER2 alterations are anticipated to similarly benefit from HER2-targeted therapies. [ABSTRACT FROM AUTHOR]

The 25th Annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Winnipeg, Manitoba, on 26–27 October 2023. The WCGCCC is an interactive multidisciplinary conference that was attended by healthcare professionals from across Western Canada (British Columbia, Alberta, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; oncology nurses; pharmacists; and a family physician in oncology (FPO) participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of gastroesophageal cancers. [ABSTRACT FROM AUTHOR]

Purpose: Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Male breast cancer (MBC) is a rare condition, and the role of low HER2 expression (HER2 low) is not well understood. In this prospective study, 870 MBC patients treated between May 2009 and June 2023 were evaluated to investigate the prognostic significance of HER2 low status. After a median follow-up of 43 months, 659 patients were classified into three groups: 76% were HER2 low, 12.3% were HER2 zero, and 11.7% were HER2 positive. HER2 positivity was linked to younger age, higher tumor proliferation, and more aggressive cancer characteristics, but no differences were found between HER2 zero and HER2 low groups. Furthermore, HER2 low status did not influence disease-free or overall survival. However, HER2 low has a potential clinical impact on MBC as a treatment target. Background: Male breast cancer (MBC) is a rare disease, and the potential influence of low expression of human epidermal growth factor receptor 2 (HER2 low) remains unexplored. Methods: In this prospective cohort study, we evaluated 870 patients treated for MBC between May 2009 and June 2023 to assess HER2 low status and its prognostic implications. Results: With a median follow-up of 43 months (range 1–175 months), 659 eligible patients were categorized into three groups based on HER2 status: 501 (76%) HER2 low, 81 (12.3%) HER2 zero, and 77 (11.7%) HER2 positive. HER2 positivity correlated with younger age, higher proliferation index, non-specific type histology, lymphovascular invasion (LVSI), and low differentiation grade. Notably, all these parameters were equally distributed between the HER2 zero and HER2 low groups. Additionally, HER2 positivity was significantly associated with increased occurrences of regional and distant lymph nodes and pulmonary metastases. However, no statistically significant difference was observed between HER2 zero and HER2 low. Disease-free and overall survival showed no significant disparities between the groups. Conclusions: Our findings suggest that HER2 low status is frequently detected in MBC. Despite this, HER2 low did not correlate with clinical and pathological parameters, nor did it impact patients' survival. [ABSTRACT FROM AUTHOR]

Simple Summary: A review of the latest research at PubMed and major cancer conferences was conducted to find out the current treatments for advanced stomach and esophagogastric junction cancers. In the West, neoadjuvant and perioperative chemotherapy is preferred for localized tumors. In East Asia, adjuvant chemotherapy is preferred. Studies are looking at how well immunotherapy and other drugs work in the perioperative setting. To choose the best treatment for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is important to know biomarkers like HER2 expression, PD-L1 combined positive score (CPS), Claudin 18.2, and microsatellite instability (MSI). The standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The choice of chemotherapy with antibodies depends on the biomarker. This article reviews recent clinical trial results and looks at the future of systemic therapy. Background: The prognosis of patients diagnosed with locally advanced and metastatic gastric and esophago-gastric junction cancer is critical. The optimal choice of systemic therapy is essential to optimize survival outcomes. Methods: A comprehensive literature review via PubMed and analysis of major oncology congresses (European Society for Medical Oncology and American Society of Clinical Oncology websites) were conducted to ascertain the current status and latest developments in the systemic treatment of patients with localized or advanced gastric and esophago-gastric junction adenocarcinoma. Results: While neoadjuvant and perioperative chemotherapy for localized tumor stages is the preferred approach in the Western Hemisphere, adjuvant chemotherapy remains the preferred course of action in East Asia. The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care. Investigations are underway into the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI). In the present clinical context, the standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. Conclusions: This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2 is a well-known driver of worse outcomes for many types of cancer, including prostate cancer. While HER2 has been previously evaluated in prostate cancer bench studies and clinical trials, there has been a lack of diversity in the experimental designs and protocols. For this reason, it has only recently been reported that Black men with prostate cancer may have a higher prevalence of HER2 overexpression. To thoroughly address health inequities that exist for Black men with prostate cancer, it is critical to utilize diverse biospecimens and enroll diverse study participants into studies that evaluate genetic and molecular contributors to worse prognosis for high-risk populations. In this review, we reconsider the role of HER2 in prostate cancer with an approach that incorporates the effects of race and genetic ancestry. Human epidermal growth factor receptor 2 (HER2) is a major driver of disease progression, treatment resistance, and worse survival for patients with various types of cancers, including prostate cancer. However, key bench studies and clinical trials have failed to evaluate the role of HER2 in prostate cancer using racially diverse experimental designs and protocols. This lack of diversity represents what has been the status quo of cancer research in the United States for decades. In the case of prostate cancer, homogenic study designs are problematic as Black men are much more likely to be diagnosed and die from aggressive and incurable forms of the disease. Therefore, the strategic inclusion of biospecimens collected from Black patients as well as the recruitment and enrollment of Black men into prostate cancer clinical trials is necessary to comprehensively evaluate genetic and molecular factors that contribute to variable outcomes in this high-risk population. Additionally, a higher prevalence of HER2 expression in Black men was recently reported in a small cohort of prostate cancer patients and may contribute to worsened prognosis. In this review, we carefully consider the role of HER2 in prostate cancer while, for the first time, taking into account the influences of race and genetic ancestry. [ABSTRACT FROM AUTHOR]

Leptomeningeal carcinomatosis (LMC) is a devastating complication of advanced cancers, such as lung cancer and breast cancer, which is usually indicative of a poor prognosis. The current treatments for LMC include palliative care, with others aiming to prolong survival and relieve neurological symptoms. Traditional treatments for LMC include radiotherapy, systemic chemotherapy, and intrathecal injection. Furthermore, the application of molecularly targeted agents, such as antiepidermal growth factor receptor (anti‐EGFR), antihuman epidermal growth factor receptor 2 (anti‐HER2), and anti‐PD‐1 monoclonal antibody, have prolonged the survival of LMC patients. Targeted therapy with tyrosine kinase inhibitors has also been proven to be an effective treatment. Tyrosine kinases can be overactive or expressed at high levels in some cancer cells; therefore, the use of tyrosine kinase inhibitors may prevent the activation of tumor‐related pathways, preventing cancer cell growth. The EGFR family are cell surface receptors directly related to tumor occurrence with tyrosine kinase activity; it is the most widely used target for tyrosine kinase inhibitors in the treatment of LMC. In this review, we introduced the clinical manifestation and diagnostic criteria of LMC, clarified the treatment mechanism of tyrosine kinase inhibitors for LMC with mutations in EGFR, HER2, or anaplastic lymphoma kinase, reviewed the current application of various generation tyrosine kinase inhibitors in patients with LMC, and discussed new clinical trials and the future directions of tyrosine kinase inhibitor therapy. [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]

High-grade serous ovarian cancer (HGSOC) and ovarian clear cell carcinoma (CC), are biologically aggressive tumors endowed with the ability to rapidly metastasize to the abdominal cavity and distant organs. About 10% of HGSOC and 30% of CC demonstrate HER2 IHC 3 + receptor over-expression. We evaluated the efficacy of trastuzumab deruxtecan (T-DXd; DS-8201a), a novel HER2-targeting antibody-drug conjugate (ADC) to an ADC isotype control (CTL ADC) against multiple HGSOC and CC tumor models. Eleven ovarian cancer cell lines including a matched primary and metastatic cell line established from the same patient, were evaluated for HER2 expression by immunohistochemistry and flow cytometry, and gene amplification by fluorescence in situ hybridization assays. In vitro experiments demonstrated T-DXd to be significantly more effective against HER2 3 + HGSOC and CC cell lines when compared to CTL ADC (p < 0.0001). T-DXd induced efficient bystander killing of HER2 non-expressing tumor cells when admixed with HER2 3 + cells. In vivo activity of T-DXd was studied in HER2 IHC 3 + HGSOC and CC mouse xenograft models. We found T-DXd to be significantly more effective than CTL ADC against HER2 3 + HGSOC (KR(CH)31) and CC (OVA10) xenografts with a significant difference in tumor growth starting at day 8 (p = 0.0003 for KR(CH)31, p < 0.0001 for OVA10). T-DXd also conferred a survival advantage in both xenograft models. T-DXd may represent an effective ADC against primary and metastatic HER2-overexpressing HGSOC and CC. [ABSTRACT FROM AUTHOR]

Copyright of Medical Journal of Babylon is the property of Wolters Kluwer India Pvt Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A next generation multiscale quantitative systems pharmacology (QSP) model for antibody drug conjugates (ADCs) is presented, for preclinical to clinical translation of ADC efficacy. Two HER2 ADCs (trastuzumab-DM1 and trastuzumab-DXd) were used for model development, calibration, and validation. The model integrates drug specific experimental data including in vitro cellular disposition data, pharmacokinetic (PK) and tumor growth inhibition (TGI) data for T-DM1 and T-DXd, as well as system specific data such as properties of HER2, tumor growth rates, and volumes. The model incorporates mechanistic detail at the intracellular level, to account for different mechanisms of ADC processing and payload release. It describes the disposition of the ADC, antibody, and payload inside and outside of the tumor, including binding to off-tumor, on-target sinks. The resulting multiscale PK model predicts plasma and tumor concentrations of ADC and payload. Tumor payload concentrations predicted by the model were linked to a TGI model and used to describe responses following ADC administration to xenograft mice. The model was translated to humans and virtual clinical trial simulations were performed that successfully predicted progression free survival response for T-DM1 and T-DXd for the treatment of HER2+ metastatic breast cancer, including differential efficacy based upon HER2 expression status. In conclusion, the presented model is a step toward a platform QSP model and strategy for ADCs, integrating multiple types of data and knowledge to predict ADC efficacy. The model has potential application to facilitate ADC design, lead candidate selection, and clinical dosing schedule optimization. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common cancer in women and a leading cause of cancer-related mortality. Despite advances in screening and treatment, outcomes for advanced or recurrent BC remain poor, highlighting the need for new strategies. Recent research emphasizes the tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs), as key drivers of tumor growth, metastasis, and resistance to therapy. The presence of M2-like TAMs in the TME promotes immune evasion and tumor progression across BC subtypes. This review summarizes TAMs classification, their role in BC, and emerging therapies targeting TAMs, including depletion, inhibition of recruitment, and reprogramming from pro-tumoral M2 to anti-tumoral M1 phenotypes. Targeting TAMs offers a promising strategy to improve BC treatment outcomes.

Human epidermal growth factor receptor 2 (HER2) is one of the oncogenic drivers of breast cancer and is often used as a definitive therapeutic marker for breast cancer. This has led to significant improvements in both targeted therapy and prognosis for HER2-targeted breast cancer. Due to the differences in HER2 gene and protein expression levels, they are clinically classified into HER2 zero-expression breast cancer, low-expression breast cancer and high-expression breast cancer. Among them, HER2 low-expression is considered a special expression state, which is insensitive to conventional anti-HER2 therapy and has a poorer prognosis and thus has received attention from researchers. Some studies demonstrate that patients with HER2 low-expression can benefit from antibody-drug conjugates (ADC). Several studies are currently exploring the efficacy of various ADC drugs in breast cancer with HER2 low-expression, opening up new treatment avenues for patients with HER2 low-expression breast cancer. This review aims to summarize the clinical features of HER2 low-expression breast cancer and the recent advances in its therapeutic agents.

Objective: This review paper examines the effectiveness and prospects of monoclonal antibody therapies in oncology. The development of these therapies has revolutionized targeted cancer treatment due to the specificity and molecular precision of the antibodies. The article discusses their mechanisms of action, clinical applications and new trends, with a special focus on the role of personalized therapies. Materials and Methods: The review covers key studies on monoclonal antibody therapies, analyzing their mechanisms of action, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The paper also considers the integration of these therapies with other treatments, such as chemotherapy and immunotherapy. Main results: Monoclonal antibodies have shown high efficacy in the treatment of various cancers, including breast, ovarian and lung cancers, by targeting specific antigens such as HER2 and PD-1/PD-L1. Advances in bispecific antibodies, drug-antibody conjugates and personalized biomarkers are further improving treatment outcomes. Challenges such as resistance and side effects are being addressed through genetic engineering and innovative drug delivery systems. Conclusions: Monoclonal antibody therapies have revolutionized cancer treatment, offering precise and personalized therapeutic approaches. Further research into combination therapies and new antibody technologies promises to overcome current limitations and expand their therapeutic potential.

Antibody-drug conjugates (ADCs) offer targeted cancer therapy by delivering cytotoxic agents directly to tumor cells. However, challenges such as relapse, resistance, and diverse patient needs drive ongoing innovation in ADC development. Exploration of new small-molecule toxins with unique antitumor and toxicity profiles is crucial. Tub114, a novel Tubulysin B analog with a hydrophilic ethylene glycol moiety, has been conjugated to the anti-HER2 antibody DX-CHO9, forming the ADC DX126-262. This study examines the efficacy, pharmacokinetics, and safety profile of DX126-262, with a focus on Tubulysin-associated liver toxicity. In vivo efficacy was assessed using three HER2-positive tumor models, with dose-dependent tumor growth inhibition compared to established treatments. Pharmacokinetic studies were conducted in cynomolgus monkeys across a dosing range (3–30 mg/kg) to compare clearance and stability with Kadcyla and Enhertu. Acute toxicity assays were conducted in mice (75 and 150 mg/kg doses), and repeated-dose toxicity was evaluated over five doses, administered every 3 weeks in rats and cynomolgus monkeys. DX126-262 demonstrated significant and dose-dependent tumor growth inhibition across HER2-positive models, with superior antitumor efficacy compared to Kadcyla and comparable efficacy to Enhertu in vivo studies. In pharmacokinetic studies, DX126-262 exhibited a clearance rate similar to Enhertu and enhanced stability compared to Kadcyla. Acute toxicity assays revealed reduced hepatotoxicity at doses of 75 and 150 mg/kg in mice, with improved tolerance. In repeated-dose toxicity studies, DX126-262 was well tolerated in rats at doses up to 200 mg/kg, with the highest non-severely toxic dose (HNSTD) established at 100 mg/kg. In cynomolgus monkeys, DX126-262 demonstrated superior hepatotoxic tolerability without significant bone marrow suppression, with an HNSTD of 30 mg/kg. DX126-262, incorporating Tub114, a novel Tubulysin B analog, effectively mitigates the inherent hepatotoxicity associated with Tubulysin compounds while maintaining strong antitumor efficacy. These findings suggest that DX126-262 could serve as a safer and more effective option for HER2-targeted cancer therapy, warranting further clinical studies to confirm its therapeutic potential.

Abstract Trastuzumab (TZM) is a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) and is clinically used for the treatment of HER2‐positive breast tumors. However, the tumor microenvironment can limit the access of TZM to the HER2 targets across the whole tumor and thereby compromising TZM's therapeutic efficacy. An imaging methodology that can non‐invasively quantify the binding of TZM‐HER2, which is required for therapeutic action, and distribution within tumors with varying tumor microenvironments is much needed. Near‐infrared (NIR) fluorescence lifetime (FLI) Forster Resonance Energy Transfer (FRET) is performed to measure TZM‐HER2 binding, using in vitro microscopy and in vivo widefield macroscopy, in HER2 overexpressing breast and ovarian cancer cells and tumor xenografts, respectively. Immunohistochemistry is used to validate in vivo imaging results. NIR FLI FRET in vitro microscopy data show variations in intracellular distribution of bound TZM in HER2‐positive breast AU565 and AU565 tumor‐passaged XTM cell lines in comparison to SKOV‐3 ovarian cancer cells. Macroscopy FLI (MFLI) FRET in vivo imaging data show that SKOV‐3 tumors display reduced TZM binding compared to AU565 and XTM tumors, as validated by ex vivo immunohistochemistry. Moreover, AU565/XTM and SKOV‐3 tumor xenografts display different amounts and distributions of TME components, such as collagen and vascularity. Therefore, these results suggest that SKOV‐3 tumors are refractory to TZM delivery due to their disrupted vasculature and increased collagen content. The study demonstrates that FLI is a powerful analytical tool to monitor the delivery of antibodydrugs both in cell cultures and in vivo live systems. Especially, MFLI FRET is a unique imaging modality that can directly quantify target engagement with the potential to elucidate the role of the TME in drug delivery efficacy in intact live tumor xenografts.

Breast cancer is the most frequently diagnosed cancer in the UAE and a leading cause of cancer-related mortality. Although early diagnosis contributes to favorable prognoses, novel treatment modalities like antibody-drug conjugates (ADCs) have significantly broadened the therapeutic landscape for patients in metastatic settings. The recognition of “HER2-low” expression as a targetable category has caused a paradigm shift in the management of breast cancer. Although initially developed to target HER2-positive breast cancer, trastuzumab deruxtecan (T-DXd), an ADC, has now also been approved to treat metastatic or unresectable HER2-low breast cancers. Despite the inherent specificity of an ADC, the risk of off-site toxicity exists and is an essential component while assessing the risk-benefit ratio of the treatment. Developing strategies to balance efficacy and safety is crucial, especially for newly approved therapies like T-DXd. Regional perspectives, cultural beliefs, and demographic factors influence treatment decisions and outcomes. The objective of this paper is to establish a UAE-specific consensus among oncologists on practical T-DXd treatment considerations and management of associated side effects. Establishing a consensus on monitoring and managing T-DXd side effects among experts can promote informed decision-making.

BackgroundIn the realm of breast cancer diagnosis and treatment, accurately discerning molecular subtypes is of paramount importance, especially when aiming to avoid invasive tests. The updated guidelines for diagnosing and treating HER2 positive advanced breast cancer, as presented at the 2021 National Breast Cancer Conference and the Annual Meeting of the Chinese Society of Clinical Oncology, highlight the significance of this approach. A new generation of drug-antibody combinations has emerged, expanding the array of treatment options for HER2 positive advanced breast cancer and significantly improving patient survival rates. Triple-negative breast cancer (TNBC), on the other hand, may indicate survival outcomes following multi-agent adjuvant chemotherapy. DISCO is a more recent DCE MRI technique that has achieved high spatial and temporal resolution and minimized image artifacts in cases like malignant focal liver lesions, enhanced focal breast lesions, and intracranial aneurysms.ObjectiveTo employ the method mentioned above to differentiate between triple-negative and non-triple-negative as well as HER2 positive and HER2 negative cancer lesions, and to assess the value of quantitative and semi-quantitative parameters in molecularly typing breast cancer.MethodsAll participants were scanned with a 3.0-T MR scanner (GE SIGNA™ Premier) using a 16-channel phased-array body coil. Each participant underwent a DISCO DCE-MRI with a scan time of approximately 1 minute and 40 seconds. The ROIs were outlined with the GenIQ software, avoiding regions with blood vessels, susceptibility artifacts, hemorrhage, and necrosis. We evaluated four quantitative parameters (Ktrans, kep, ve, vp) and four semi-quantitative parameters (TTP, MAX Conc, AUC, MAX Slope). The carcinomas were segregated into respective subgroups (HER2+ vs HER2-, TNBC vs non-TNBC, HER2+ vs TNBC) and we compared the eight parameters across these groups. The AUC of the models was compared using DeLong’s test as per the ROC analysis.ResultsWe analyzed a total of 96 female patients, revealing significant differences in the semi-quantitative parameters such as TTP, MAX Conc, AUC, and MAX Slope among different groups. HER2-positive versus HER2-negative exhibited significant differences in quantitative parameters (Ktrans: 0.22 min-1 vs. 0.43 min-1, kep: 0.11 min-1 vs. 0.35 min-1, vp: 0.01 vs. 0.04, all P < 0.05). TNBC versus non-TNBC revealed statistical variations in quantitative parameters (Ktrans: 1.03 min-1 vs. 0.15 min-1, kep: 0.61 min-1 vs. 0.19 min-1, vp: 0.18 vs. 0.01, all P < 0.05). Additionally, HER2-positive compared to TNBC demonstrated significant differences in quantitative parameters (Ktrans: 0.22 min-1 vs. 1.03 min-1, kep: 0.11 min-1 vs. 0.61 min-1, vp: 0.01 vs. 0.18, all P < 0.05). As per ROC analysis, Ktrans, kep, vp, TTP, and MAX Conc effectively differentiated TNBC from non-TNBC, with TTP being the strongest determinant for TNBC. Furthermore, these parameters successfully distinguished between HER2 positive and HER2 negative, with kep being particularly effective in identifying HER2. Importantly, Ktrans, kep, vp, TTP, and MAX Conc were effective in discriminating HER2 positive from TNBC, with kep and TTP exhibiting notable efficacy in this context.ConclusionOur study suggests that DISCO DCE-MRI derived parameters could serve as reliable quantitative biomarkers for differentiating between TNBC and HER2 positive breast cancer.

BackgroundPatients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable.MethodsThe design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care.ResultsDZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.ConclusionsDZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.Clinicaltrialsgov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

Abstract 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.

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 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

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

Salivary gland cancers (SGC) are rare tumours with limited availability of systemic therapies. Some SGC subtypes overexpress HER2, and this represents a potential therapeutic target, but the evidence base is limited. This study sought to analyse real-world data on the efficacy of HER2-directed therapies in SGC. This is a retrospective observational study using anonymised data from commercial compassionate-use access registrations and a privately funded pharmacy prescribing register. Treatment duration was defined as the time from drug initiation to treatment discontinuation. Kaplan–Meier analysis of treatment duration was performed using R for Windows (v4.3.2). A case report is also provided of an exceptional responder. Eighteen patients were identified who received HER2-directed therapies for HER2-positive recurrent/metastatic SGC, and complete data on treatment duration was available for 15/18. Histology was salivary duct carcinoma in 13/18 patients, adenocarcinoma NOS in 4/18, and carcinoma ex pleomorphic adenoma in 1/18. The median treatment duration was 8.3 months (95% CI: 6.41-not reached), and the range was 1.0–47.0 months. Choice of HER2-directed therapy varied, with ado-trastuzumab emtasine being the most common (9/18). At the time of analysis, HER2-directed therapy was ongoing for 9/15, discontinued due to disease progression for 4/15, discontinued due to toxicity for 1/15, and 1/15 was discontinued for an unspecified reason. An exceptional responder experienced a complete response with a treatment duration of 47.0 months. These real-world data are comparable to the median PFS observed with HER2-directed therapies in phase II trials and support the use of HER2-directed therapies in this group.

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 Gastric cancer is the fifth most common cause of cancer-related deaths globally, with a decreasing but still high number of cases. Although there have been improvements in treatment choices, the expected survival rates have not yet been achieved. In addition to the challenges associated with developing effective therapies, there is an urgent need to establish diagnostic and predictive biomarkers to guide treatment selection. Therefore, this review summarizes key aspects of gastric cancer, including its epidemiology, associated risk factors, and underlying pathogenesis. It also discusses the main biomarkers involved in this disease, such as PD-L1, HER − 2, Epstein-Barr virus (EBV), Claudin 18.2, FGFR2, and the current standard and targeted therapies. Molecular testing for these changes is gaining significance in the context of gastric cancer. By incorporating detailed biomarker analysis into clinical practice, we can provide more effective and personalized treatment options, ultimately improving clinical management and enhancing survival rates for gastric cancer patients.

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

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.

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 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.

Abstract Background Human epidermal growth factor receptor 2 (HER2) plays an important role in the progression of multiple solid tumors and induces resistance to epidermal growth factor receptor (EGFR) target treatment. However, the expression status and the clinical significance of HER2 in oral squamous cell carcinoma (OSCC) is still controversial. Pyrotinib (PYR) is a promising novel EGFR/HER2 dual inhibitor, whose efficacy in OSCC has not been determined. Methods 57 locally advanced de novo OSCC patients were included in this study to investigate the relationship between the HER2 expression levels and the prognosis by the tissue microarray analysis (TMA). In vitro and in vivo experiments were performed to retrieve the efficacy of PYR in OSCC. The main downstream of HER2 was evaluated by western blotting in OSCC cell lines and xenograft tumors to explore the potential mechanism of PYR. Results This study revealed the primary tumor of OSCC had higher HER2 expression levels. Patients with HER2 overexpression had poor overall survival (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.

Aim: Human epidermal growth factor receptor-2 (HER2) is a well-established prognostic and predictive biomarker. It is an FDA-approved therapeutic target for HER2 positive breast, gastroesophageal, and more recently, lung and colon cancers. It is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancers. The emergence of new indications warrants further characterization of HER2 expression in diverse cancer populations. This study investigated HER2 expression in solid tumour samples and the feasibility of obtaining these results. Methods: Prospective consent was obtained at a Canadian tertiary academic cancer center from adult oncology patients who were referred for molecular genetic testing of malignant tissue samples. Standard HER2-targeted malignancies were considered breast and gastroesophageal, and were excluded from this study. Between July 2020 and November 2023, 499 samples of solid tumors underwent immunohistochemistry (IHC) HER2 staining. A median turnaround time (TAT) of 14 days would be considered feasible for clinical decision making. Results: The mean age (± SD) of participants was 67 ± 12.5 years, with 270 (54%) male and 229 (46%) female. HER2 protein expression was measured in 42 unique cancer types. IHC levels of 0, 1+, 2+, and 3+ were reported and were 43%, 12%, 35%, and 10% of all analyzable samples respectively (tissue inadequate in 3% of samples). The median TAT for HER2 expression results from time of request to result in release was 18 (interquartile range, 11 to 30) days. Conclusions: HER2 protein expression varies widely between different cancer types. TAT for HER2 IHC results was a median of 18 days, which is close to our feasibility cut-off.

Abstract In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients.