Greatly isolated heterogeneous circulating tumor cells using hybrid engineered cell membrane-camouflaged magnetic nanoparticles.

BACKGROUND: Circulating tumor cells (CTCs) are considered as a useful biomarker for early cancer diagnosis, which play a crucial role in metastatic process. Unfortunately, the tumor heterogeneity and extremely rare occurrence rate of CTCs among billions of interfering leukocytes seriously hamper the sensitivity and purity of CTCs isolation. METHODS: To address these, we firstly used microfluidic chips to detect the broad-spectrum of triple target combination biomarkers in CTCs of 10 types of cancer patients, including EpCAM, EGFR and Her2. Then, we constructed hybrid engineered cell membrane-camouflaged magnetic nanoparticles (HE-CM-MNs) for efficient capture of heterogeneous CTCs with high-purity, which was enabled by inheriting the recognition ability of HE-CM for various CTCs and reducing homologous cell interaction with leukocytes. Compared with single E-CM-MNs, HE-CM-MNs showed a significant improvement in the capture efficiency for a cell mixture, with an efficiency of 90%. And the capture efficiency of HE-CM-MNs toward 12 subpopulations of tumor cells was ranged from 70 to 85%. Furthermore, by using HE-CM-MNs, we successfully isolated heterogeneous CTCs with high purity from clinical blood samples. Finally, the captured CTCs by HE-CM-MNs could be used for gene mutation analysis. CONCLUSIONS: This study demonstrated the promising potential of HE-CM-MNs for heterogeneous CTCs detection and downstream analysis.

Comparison of anthracycline-containing and anthracycline-free regimens in neoadjuvant HER-2 positive breast cancer treatment.

While some clinics have adopted abbreviated neoadjuvant treatment for HER2-positive breast cancer, there remains a shortage of comprehensive clinical data to support this practice. This is a retrospective, multicenter study. A total of 142 patients were included in the study who are HER2-positive breast cancer, aged ≤ 65 years, with left ventricular ejection fraction ≥ 50%, received neoadjuvant chemotherapy and underwent surgery at 10 different oncology centers in Türkiye between October 2016 and December 2022. The treatment arms were divided into 4-6 cycles of docetaxel/trastuzumab/pertuzumab for arm A, 4 cycles of adriamycin/cyclophosphamide followed by 4 cycles of taxane/TP for arm B. There were 50 patients (35.2%) in arm A and 92 patients (64.8%) in arm B. The median follow-up of all of the patients was 19.9 months (95% CI 17.5-22.3). The 3-year DFS rates for treatment arms A and B were 90.0% and 83.8%, respectively, and the survival outcomes between the groups were similar (p = 0.34). Furthermore, the pathologic complete response rates were similar in both treatment arms, at 50.0% and 51.1%, respectively (p = 0.90). This study supports shortened neoadjuvant treatment of HER2-positive breast cancer, a common practice in some clinics.

Association between pathologic complete response and biochemical indicators after neoadjuvant therapy for HER2-positive breast cancer.

PURPOSE: This study investigated the changes in the fasting blood glucose (FBG), fasting triglyceride (FTG), and fasting total cholesterol (FTC) levels during neoadjuvant therapy (NAT) for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) and the association with pathologic complete response (pCR). METHODS: Relevant data from Sichuan Cancer Hospital from June 2019 to June 2022 were collected and analyzed, and FBG, FTG, and FTC were divided into baseline, change, and process groups, which were grouped to analyze the changes after receiving NAT and the association with pCR. RESULTS: In the estrogen receptor (ER)-negative subgroup, patients with low levels of FTG in the process group were more likely to achieve pCR compared to high levels, and in the progesterone receptor (PR)-negative subgroup, patients with lower FTG compared to higher FTG after receiving NAT was more likely to achieve pCR. CONCLUSIONS: Patients with HER2-positive BC undergoing NAT develop varying degrees of abnormalities (elevated or decreased) in FBG, FTG, and FTC; moreover, the status of FTG levels during NAT may predict pCR in ER-negative or PR-negative HER2-positive BC.Early monitoring and timely intervention for FTG abnormalities may enable this subset of patients to increase the likelihood of obtaining a pCR along with management of abnormal markers.

Neoadjuvant radiotherapy in ER+, HER2+, and triple-negative -specific breast cancer based humanized tumor mice enhances anti-PD-L1 treatment efficacy.

Pre-operative radiation therapy is not currently integrated into the treatment protocols for breast cancer. However, transforming immunological "cold" breast cancers by neoadjuvant irradiation into their "hot" variants is supposed to elicit an endogenous tumor immune defense and, thus, enhance immunotherapy efficiency. We investigated cellular and immunological effects of sub-lethal, neoadjuvant irradiation of ER pos., HER2 pos., and triple-negative breast cancer subtypes in-vitro and in-vivo in humanized tumor mice (HTM). This mouse model is characterized by a human-like immune system and therefore facilitates detailed analysis of the mechanisms and efficiency of neoadjuvant, irradiation-induced "in-situ vaccination", especially in the context of concurrently applied checkpoint therapy. Similar to clinical appearances, we observed a gradually increased immunogenicity from the luminal over the HER2-pos. to the triple negative subtype in HTM indicated by an increasing immune cell infiltration into the tumor tissue. Anti-PD-L1 therapy divided the HER2-pos. and triple negative HTM groups into responder and non-responder, while the luminal HTMs were basically irresponsive. Irradiation alone was effective in the HER2-pos. and luminal subtype-specific HTM and was supportive for overcoming irresponsiveness to single anti-PD-L1 treatment. The treatment success correlated with a significantly increased T cell proportion and PD-1 expression in the spleen. In all subtype-specific HTM combination therapy proved most effective in diminishing tumor growth, enhancing the immune response, and converted non-responder into responder during anti-PD-L1 therapy. In HTM, neoadjuvant irradiation reinforced anti-PD-L1 checkpoint treatment of breast cancer in a subtype -specific manner. According to the "bench to bedside" principle, this study offers a vital foundation for clinical translating the use of neoadjuvant irradiation in the context of checkpoint therapy.

Application of quantitative protein mass spectrometric data in the early predictive analysis of membrane-bound target engagement by monoclonal antibodies.

Model-informed drug discovery advocates the use of mathematical modeling and simulation for improved efficacy in drug discovery. In the case of monoclonal antibodies (mAbs) against cell membrane antigens, this requires quantitative insight into the target tissue concentration levels. Protein mass spectrometry data are often available but the values are expressed in relative, rather than in molar concentration units that are easier to incorporate into pharmacokinetic models. Here, we present an empirical correlation that converts the parts per million (ppm) concentrations in the PaxDb database to their molar equivalents that are more suitable for pharmacokinetic modeling. We evaluate the insight afforded to target tissue distribution by analyzing the likely tumor-targeting accuracy of mAbs recognizing either epidermal growth factor receptor or its homolog HER2. Surprisingly, the predicted tissue concentrations of both these targets exceed the Kd values of their respective therapeutic mAbs. Physiologically based pharmacokinetic (PBPK) modeling indicates that in these conditions only about 0.05% of the dosed mAb is likely to reach the solid tumor target cells. The rest of the dose is eliminated in healthy tissues via both nonspecific and target-mediated processes. The presented approach allows evaluation of the interplay between the target expression level in different tissues that determines the overall pharmacokinetic properties of the drug and the fraction that reaches the cells of interest. This methodology can help to evaluate the efficacy and safety properties of novel drugs, especially if the off-target cell degradation has cytotoxic outcomes, as in the case of antibody-drug conjugates.

Health-state utility of patients with HER2-positive breast cancer in Vietnam: A multicenter cross-sectional study.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer may have poor prognoses and short overall and disease-free survival. Most previous studies focused on assessing the quality of life and health-state utility of the general population of breast cancer patients. The number of studies for HER2-positive breast cancer patients is negligible. This study investigated the health-state utility and its associated factors among Vietnamese patients with HER2-positive breast cancer. METHODS: We conducted face-to-face interviews with 301 HER2-positive breast cancer patients to collect data. Their health-state utility was measured via the EQ-5D-5L instrument. The Mann-Whitney U and Kruskal-Wallis tests were employed to compare the differences in utility scores between two groups and among three groups or more, respectively. Factors associated with patients' heath-state utility were identified via Tobit regression models. RESULTS: Pain/discomfort (56.1%) and anxiety/depression (39.5%) were the two issues that patients suffered from the most, especially among metastatic breast cancer patients. The severity of distress (depression, anxiety, and stress) in patients was relatively mild. Of 301 patients, their average utility score was 0.86±0.17 (range: 0.03-1.00), and the average EQ-visual analogue scale (VAS) score was 69.12±12.60 (range: 30-100). These figures were 0.79±0.21 and 65.20±13.20 for 102 metastatic breast cancer patients, significantly lower than those of 199 non-metastatic cancer patients (0.89±0.13 and 71.13±11.78) (p<0.001), respectively. Lower health-state utility scores were significantly associated with older age (p = 0.002), lower education level (p = 0.006), lower monthly income (p = 0.036), metastatic cancer (p = 0.001), lower EQ-VAS score (p<0.001), and more severe level of distress (p<0.001). CONCLUSIONS: Our findings showed a significant decrement in utility scores among metastatic breast cancer patients. Patients' health-state utility differed by their demographic characteristics (age, education level, and income) and clinical characteristics (stage of cancer and distress). Their utility scores may support further cost-effectiveness analysis in Vietnam.

Efficacy and safety of pyrotinib combined with albumin-bound paclitaxel as first-line treatment for HER2-positive metastatic breast cancer in patients previously treated with adjuvant and/or neoadjuvant trastuzumab therapy: The stage 1 results of a single-arm, phase 2 prospective clinical trial.

OBJECTIVE: It has been observed that the prognosis of patients with HER2-positive metastatic breast cancer has improved significantly with HER2-targeted agents. However, there is still a lack of evidence regarding first-line anti-HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti-HER2 treatment in these patients. METHODS: Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer were enrolled. Pyrotinib plus albumin-bound paclitaxel were used as first-line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. RESULTS: From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow-up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand-foot syndrome (3.7%). Toll-like receptor 3 (TLR3) and Proto-oncogene tyrosine-protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. CONCLUSIONS: This study demonstrates that pyrotinib plus albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.

Cancer-stromal cell interactions in breast cancer brain metastases induce glycocalyx-mediated resistance to HER2-targeting therapies.

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.

[In vitro and in vivo validation of cytotoxicity of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells].

Objective To evaluate the toxicology of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells and to provide a safety basis for the clinical evaluation of HER2-CAR-T cell therapy. Methods The recombinant lentiviral vector was used to generate HER2-CAR-T cells. Soft agar colony formation assay was used to observe the colony formation of HER2-CAR-T cells, and the colony formation rate was statistically analyzed. The HER2-CAR-T cell suspension was co-incubated with rabbit red blood cell suspension, and the hemolysis of red blood cells was evaluated by direct observation and microplate reader detection. The HER2-CAR-T cell preparation was injected into the ear vein of male New Zealand rabbits, and the stimulating effect of HER2-CAR-T cells on the blood vessels of the animals was observed by staining of tissue sections. The vesicular stomatitis virus envelope glycoprotein (VSV-G) gene of pMD 2.G vector was used as the target sequence, and the safety of the lentiviral vector was verified by real-time fluorescence quantitative PCR. The heart, liver, lung, and kidney of mice receiving HER2-CAR-T cell infusion were collected, and the lesions were observed by HE staining. Results The HER2-CAR-T cells were successfully prepared. These cells did not exhibit soft agar colony formation ability in vitro, and the HER2-CAR-T cell preparation did not cause hemolysis in New Zealand rabbit red blood cells. After the infusion of HER2-CAR-T cells into the ear vein of New Zealand rabbits, no obvious vascular stimulation response was found, and no specific amplification of VSV-G was detected. No obvious lesions were found in the heart, liver, lung and kidney tissues of the treatment group. Conclusion The prepared HER2-CAR-T cells have reliable safety.

Incidence and survival of primary metastatic breast cancer in Denmark; implication of breast cancer screening, classification, and staging practice.

BACKGROUND: Primary metastatic breast cancer (pMBC) accounts for 5-10% of annual breast cancers with a median survival of 3-4 years, varying among subtypes. In Denmark, the incidence of breast cancer increased until 2010, followed by a stabilisation. Several factors influencing pMBC incidence and survival, including screening prevalence, staging methods, and classification standards, remain pivotal but inadequately documented. MATERIAL AND METHOD: This retrospective observational study involving pMBC patients diagnosed between 2000 and 2020 encompassed all Danish oncology departments. Data from the Danish Breast Cancer Group database and the National Patient Register included diagnosis specifics, demographics, treatment, and follow-up. RESULTS: Between 2000 and 2020, 3,272 patients were diagnosed with pMBC, a rise from 355 patients in 2000-2004 to 1,323 patients in 2015-2020. The increase was particularly observed in patients aged 70 years or older. Changes in tumour subtypes were observed, notably with a rise in human epidermal growth factor receptor 2 (HER2)-positive cases but a steady distribution of estrogen receptor (ER) status. Diagnostic practices changed over the two decades, with 6% evaluated with PET/CT (positron emission tomography-computed tomography) or CT (computed tomography) with a bone evaluation in 2000-2004 and 65% in 2015-2020. Overall survival (OS) improved from 23 months in 2000-2004 to 33 months in 2015-2020. In patients with ER-positive and HER2-positive disease, the multivariable model showed improved survival by year of diagnosis, and further, patients with ER-negative/HER2-negative disease fared worse the first 2 years after diagnosis. INTERPRETATION: Our study delineates changes in the treatment and survival of pMBC over two decades. Stage migration, screening introduction, and changes in registration practice, however, prevent a valid assessment of a possible causal relationship.

Radiological Features for Predicting the Status of CD8-Positive Lymphocytes in HER2 Positive Breast Cancer.

Background: The level of tumor-infiltrating lymphocytes (TILs) in human epidermal growth factor receptor type 2 (HER2)-positive breast cancer (BC) is positively correlated with pathological complete response. Aims: To investigate the relationship between ultrasound (US) and magnetic resonance imaging (MRI) features and the level of CD8-positive TILs (CD8+-TILs) in patients with HER2-positive BC. Study Design: Retrospective cohort study. Methods: This retrospective study included 155 consecutive women with HER2-positive BC. Patients were divided into two groups: CD8+-TILlow (< 35%) and CD8+-TILhigh (≥ 35%) groups. US and MRI features were evaluated using the BI-RADS lexicon, and the apparent diffusion coefficient (ADC) value was calculated using RadiAnt software. Univariate and multivariate analyses revealed the optimal US and MRI features for predicting CD8+-TIL levels. Receiver operating characteristic analysis and the Delong test were used to compare the diagnostic performance of US and MRI features. Furthermore, implementing a nomogram will increase clinical utility. Results: Univariate analysis of US features showed significant differences in shape, orientation, and posterior echo between the two groups; however, there were no significant differences in margins, internal echo, and microcalcification. Multifactorial analysis revealed that shape, orientation, and posterior echo were independent risk factors, with odds ratios of 11.62, 2.70, and 0.16, respectively. In terms of MRI features, ADC was an independent predictor of CD8+-TIL levels. These three US features and the ADC performed well, with area under the curve (AUC) values of 0.802 and 0.705, respectively. The combination of US and ADC values had higher predictive efficacy (AUC = 0.888) than either US or ADC alone (p = 0.009, US_ADC vs. US; p < 0.001, US_ADC vs. ADC). Conclusion: US features (shape, orientation, and posterior echo) and ADC value may be a valuable tool for estimating CD8+-TIL levels in HER2-positive BC. The nomogram may help clinicians in making decisions.

[Efficacy analysis of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 inhibitor treatment in hormone receptor positive/human epidermal growth factor receptor 2-low metastatic breast cancer].

Objective: To evaluate the efficacy of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment in hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer. Methods: Patients with metastatic breast cancer diagnosed with HR positive/HER2 low expression at the Fifth Medical Center of PLA General Hospital from October 1, 2018 to September 30, 2023 were retrospectively included. All patients received sequential chemotherapy or sequential endocrine therapy combined with targeted drugs after progression on CDK4/6 inhibitor treatment.The median follow-up was 9 months, and the follow-up ended on October 31, 2023. The patients were divided into chemotherapy group (receiving sequential chemotherapy) and endocrine therapy group (receiving sequential endocrine therapy combined with targeted drugs), according to the treatment plan. Information on demographic data, clinical and pathological diagnosis, treatment regimen, and efficacy evaluation was collected. The basic conditions of patients who may affect the curative effect of different treatment schemes were preset as stratified subgroups, including age, progesterone receptor (PR) status, HER2 status, disease-free survival, number of previous endocrine therapy and chemotherapy, and visceral metastasis. The primary endpoint was progression-free survival (PFS), the secondary endpoints were objective response rate (ORR), clinical benefit rate(CBR) and PFS based on stratification factors. The survival curve was plotted by Kaplan-Meier method, the comparison of PFS between groups was performed by log-rank test, and the comparison of ORR and CBR between groups were performed by χ2 test. Results: A total of 188 patients were included, including 126 patients in the chemotherapy group [all females, aged 29-74 (51±10) years] and 62 patients in the endocrine therapy group [1 male and 61 female, aged 29-77 (51±12) years]. ORR of chemotherapy group was 23.0% (29/126), higher than that of endocrine treatment group [3.2% (2/62)] (P<0.001); The CBR of chemotherapy group and endocrine therapy group were 46.8% (59/126) and 33.9% (21/62), respectively, with no statistical significance (P=0.091). The median PFS of chemotherapy group and endocrine therapy group were 5.0 (95%CI: 4.3-5.7) and 4.0 (95%CI: 1.6-6.4) months, respectively, with no statistical significance (P=0.484). In the preset stratified subgroups, the median PFS of chemotherapy [6.0 (95%CI: 5.4-6.6) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 1.8-2.2) months] (P<0.001) in PR negative patients; In patients who had progressed on over 2 previous endocrine treatments, the median PFS of chemotherapy [5.0 (95%CI: 3.8-6.2) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 0.6-3.4) months] (P=0.045). Conclusions: After progression on treatment with CDK4/6 inhibitors for HR-positive/HER2-low expression metastatic breast cancer, both chemotherapy and endocrine therpy combined with targeted drugs are viable treatment options. However, for patients with PR negative or ≥2 lines of endocrine therapy previously, priority should be accorded to chemotherapy.

Development of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy.

The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca2+/(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.

Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.

Introduction: The 21-gene analysis (OncotypeDX) is validated test for pT1-3, pN0-1 with hormone receptor (HR) positive and normal expression of human epidermal growth factor receptor-2 (HER2) breast cancer (BC) to determine the aggressiveness of the disease based on the calculation of Recurrence Score (RS). Methods: In this retrospective study the authors correlated pathological characteristics and Recurrence Score (RS) by traditional statistical methods and Observed Oriented Modeling (OOM) in a realistic cohort of BC patients. Results: OncotypeDX tests were performed in 94 tumour specimens of 90 BC patients. >83% of node-negative (pN0) and >72% of node-positive (pN1) cases could avoid chemotherapy. For pN0 cases, non-parametric correlation and tests demonstrated significant association in eight types of characteristics [progesterone receptor (PR) expression, Ki-67 value, Ki-67 group, PR group, grade, estrogen receptor (ER) expression, Nottingham Prognostic Index (NPI) and Clinical Risk]. For pN1 cases, parametric correlation and tests showed significant association in six characteristic types (number of positive nodes, ER and PR expression, PR group, Ki-67 group and NPI). Based on OOM for pN0 cases, significant associations were established in three characteristics (Ki-67 group, grade and NPI group). For pN1 cases OOM found significant associations in seven characteristics (PR group, PNI, LVI, Ki-67 group, grade, NPI group and number of positive nodes). Conclusion: First in oncology, OOM was applied, which found some other significant characteristics associated with RS than traditional statistical methods. There were few patients, where no clinical associations were found between characteristics and RS contrary to statistically significant differences. Therefore, the results of these statistical analyses can be neither applied for individual cases nor able to provide the bases for screening patients, i.e., whether they need for OncotypeDX testing or not. OncotypeDX still provides a personalised approach in BC.

Clinicopathological characteristics and prognosis of Epstein-Barr virus-associated gastric cancer.

OBJECTIVE: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS). METHODS: A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis. RESULTS: Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%. CONCLUSION: EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.

Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer: Real-life data from the temporary use authorization program in France.

BACKGROUND: Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T-DXd) in France based on DESTINY-Breast01 trial which demonstrated its efficacy and safety in HER2-positive metastatic/unresectable breast cancer after ≥2 anti-HER2-based regimens received at metastatic stage. METHODS: This multicenter real-world early access program included HER2-positive metastatic/unresectable breast patients pretreated with at least two lines of anti-HER2 regimens who received T-DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. RESULTS: Four hundred and fifty-nine patients (median age, 58 years; hormone receptor-positive, 67%; brain metastases, 28.1%) received T-DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2-22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow-up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T-DXd treatment was 3.4 (range, 0-7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD-related death. CONCLUSIONS: In this early access program in patients with heavily pretreated HER2-positive metastatic/unresectable breast cancer, T-DXd had antitumor activity with a similar response to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed.