OBJECTIVE:To evaluate the impact of primary tumor resection (PTR) on overall survival (OS) and cancer-specific survival (CSS) in women with de novo bone-only metastatic breast cancer (MBC). METHODS:Women diagnosed with de novo bone-only metastatic breast cancer between 2010 and 2017 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were included if they had bone metastasis at diagnosis but no lung, liver, or brain involvement. Primary tumor resection was defined as any cancer-directed breast surgery. Propensity scores were calculated using multivariable logistic regression incorporating demographics, tumor features, and treatment factors, followed by 1:1 nearest-neighbor matching (caliper = 0.2 SD). Kaplan-Meier, Cox proportional hazards, and restricted mean survival time (RMST) analyses assessed overall survival (OS) and cancer-specific survival (CSS). Time-dependent ROC curves (timeROC) evaluated model discrimination. Determinants of PTR were examined using multivariable logistic regression. RESULTS:A total of 3296 women with de novo bone-only metastatic breast cancer were included (1252 with PTR; 2044 without). After 1:1 matching, 2002 well-balanced patients remained (1001 per group). Median OS and CSS were significantly longer among patients undergoing surgery (OS: 69 vs. 39 months; CSS: 76 vs. 41 months; both p < 0.0001). PTR remained an independent predictor of improved OS (HR = 0.54, 95% CI 0.48-0.60, p < 0.001), with consistent benefit across subgroups. RMST differences (surgery - no surgery) increased with time, reaching 9.05 months for OS and 8.79 months for CSS at 60 months. Model discrimination was acceptable (AUCs for OS: 0.753, 0.734, 0.717 at 1-, 3-, and 5-years). Radiation therapy was positively associated with PTR (OR = 1.37, 95% CI 1.12-1.68, p = 0.002), whereas well/moderate grade predicted lower odds (OR = 0.80, 95% CI 0.66-0.99, p = 0.036). CONCLUSIONS:In this large SEER-based propensity-matched analysis, primary tumor resection was associated with significantly improved overall and cancer-specific survival among women with de novo bone-only metastatic breast cancer. These findings suggest that selected patients with isolated bone metastasis may benefit from locoregional surgery, warranting further prospective validation.

Abstract The multicenter, noninterventional, observational MMY4032 study is a large-scale, real-world study exploring daratumumab (DARA) in Chinese patients (n = 212) with multiple myeloma (MM) who have received ≤ 3 prior lines of therapy. In the first interim analysis (median follow-up, 10.5 months), DARA was often initiated in second-line therapy, often given in combination with a proteasome inhibitor and/or immunomodulatory drug, and induced high response rates (overall response rate [ORR], 71.8%) and acceptable safety. Here, we report treatment patterns, efficacy, and safety from the second interim analysis with a longer median follow-up of 16.2 months. At the time of this analysis, median duration of DARA exposure was 8.2 months. Among 189 response-evaluable patients, the ORR was 74.1% and the very good partial response or better rate was 55.6%. Minimal residual disease–negativity rate was 60.0% among tested patients. Median progression-free and overall survival were 32.8 months and not reached, respectively; 12-month rates were 77.9% and 87.8%. Response and survival rates were higher with DARA initiation in earlier lines of therapy. Median time to next treatment was not reached with most DARA-based regimens. Adverse drug reactions and serious adverse events were reported in 20.3% and 15.6% of patients, respectively. Overall, with longer follow-up of the MMY4032 study, responses deepened, and survival rates remained high with DARA-based regimens, with more favorable outcomes observed with earlier DARA initiation. No new safety concerns were observed. These real-world data continue to support early use of DARA-based regimens as a standard of care for Chinese patients with MM.

Photodynamic therapy (PDT) has emerged as a promising local treatment for breast cancer, with emerging evidence highlighting its potential to modulate the immune response. However, its effects on tumor microenvironment (TME) metabolism remain poorly understood. In this study, we introduce a novel photosensitizer, DTP, which efficiently generates reactive oxygen species and induces apoptosis in breast cancer cells in vitro. In vivo, DTP preferentially accumulates in tumors, significantly inhibiting tumor growth and reducing Ki-67 expression upon 650 nm irradiation. Untargeted metabolomics revealed significant alterations in the tryptophan metabolism pathway following DTP-PDT. Further targeted metabolomic analysis identified a specific reduction in kynurenine (Kyn), an immunosuppressive metabolite, within the tumor. Mechanistically, DTP-PDT reduced indoleamine 2,3-dioxygenase 1 (IDO1)-dependent Kyn production, diminished AhR nuclear localization and decreased AhR transcriptional activity in tumor-infiltrating T cells. This metabolic reprogramming alleviated the immunosuppressive TME, as evidenced by increased infiltration of CD8+ T cells and a reduction in regulatory T cells. Notably, exogenous Kyn partially restored the Kyn–AhR axis and attenuated the immune remodeling induced by DTP-PDT. Building on these immune-activating effects, we combined DTP-PDT with PD-L1 blockade, which significantly suppressed pulmonary metastasis and enhanced central memory T-cell generation, resulting in durable systemic antitumor immunity.

RATIONALE:Most patients with hormone receptor-positive breast cancer (BC) prefer endocrine therapy and chemotherapy. However, some HR+ BC patients often exhibit resistance to CDK4/6 inhibitors and even undergo molecular subtyping changes during disease progression. Therefore, precise detection and treatment of these patients after disease progression are crucial. PATIENT CONCERNS:In October 2021, a 51-year-old Chinese female (Han ethnicity) with a palpable mass in her left breast was diagnosed with HR+ BC. After endocrine therapy and CDK4/6 inhibitor treatment, the patient's disease still progressed and transformed into triple-negative BC. DIAGNOSES:Peripheral blood circulating tumor cells were isolated from the patient and performed targeted sequencing by using next-generation sequencing, revealing the presence of a PIK3CA mutation in the patient. INTERVENTIONS:The patient's condition was effectively controlled after treatment with PI3K inhibitors. OUTCOMES:The patient's progression free survival was prolonged to 7 months after treatment with the PI3K inhibitor. All adverse reactions were tolerated after symptomatic treatment. Her adverse reactions remained tolerable until further progression. LESSONS:Our case fully demonstrates the importance of the early detection of PIK3CA mutations in treatment strategies. In addition, circulating tumor cells-targeted sequencing technology could be used for the concomitant diagnosis of advanced BC and evaluate gene mutations under treatment pressure.

Recurrence related to poor prognosis is a leading cause of mortality in patients with breast cancer (BC). The MammaPrint (MP) genomic assay is designed to stratify recurrence risk and evaluate chemotherapy benefits for early-stage HR+/HER2- BC patients. However, MP fails to reveal spatial tumor morphology and is limited by high costs. In this study, a BC MP cohort is established and CPMP is developed, a weakly supervised agent-attention transformer model, to predict MP recurrence risk from annotation-free BC histopathological slides. CPMP achieves an AUROC of 0.824 ± 0.03 in predicting MP risk groups. CPMP is further leveraged for spatial and morphological analyses to explore histological patterns associated with MP risk groups. The model reveals tumor spatial localization at the whole-slide level and highlights distinct intercellular interaction patterns of MP groups. It also characterizes the diversity in tumor morphology and uncovers MP high-specific, low-specific, and colocalized morphological phenotypes that differ in quantitative cellular composition. Prognostic evaluation in the external cohort exhibits significant stratification of distant metastasis risk (HR: 3.14, p-value = 0.0014), underscoring the prognostic power of CPMP. These findings demonstrate the capability of CPMP in MP risk prediction, offering a flexible supplement to genomic risk assessment in early-stage BC.

PURPOSE:To raise awareness of radiation recall dermatitis (RRD) in the context of radiotherapy combined with abemaciclib, and to explore its potential mechanisms, characteristics, and treatment options. METHODS:We conducted a case series study reporting the first instances of RRD induced by abemaciclib in two women with locally advanced luminal breast cancer. Both patients experienced skin reactions in previously irradiated areas following abemaciclib administration. Additionally, a comprehensive literature review was performed to analyze the potential mechanisms of RRD, characteristics of radiotherapy, triggering drugs, and available treatments. RESULTS:The case series demonstrated that abemaciclib can induce RRD in patients who have undergone radiotherapy. Both patients experienced significant skin reactions, which were successfully managed and resolved upon rechallenge with abemaciclib. The literature review highlighted the importance of recognizing RRD as a potential adverse effect of cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), emphasizing the need for careful monitoring and appropriate management strategies. CONCLUSION:Radiation recall dermatitis is a potential adverse effect of abemaciclib in patients receiving radiotherapy for breast cancer. Our findings underscore the importance of awareness and vigilance in managing patients on CDK4/6is.

ObjectiveWe aimed to evaluate the clinicopathological characteristics and survival outcomes of patients with second primary ovarian carcinomas after a breast cancer diagnosis.Materials and methodsWe reviewed the medical reports of 23 patients at Sichuan Cancer Hospital between May 2002 and October 2021. We analyzed demographic and clinicopathologic characteristics, the time interval between diagnoses, and survival time. Kaplan-Meier and Cox proportional hazards regression tests were used to determine survival outcomes.ResultsThe median age of patients at the time of diagnosis of breast cancer (BC) and ovarian cancer (OC) was 46 and 49 years, respectively. Among them were 6 cases of synchronous OC and 17 instances of metachronous OC. The average interval between diagnoses of the two cancers was 62.48 months. The median OS after the second primary OC diagnosis was 38 months. According to Kaplan-Meier’s analysis, the advanced stage at presentation of BC (p=0.023) resulted in a significantly shorter interval between BC and OC diagnosis. On univariate Cox regression analysis, only BC Scarff-Bloom-Richardson (SBR) 3 Grade resulted in a considerably worse PFS (HR 0.187, p=0.048) and OS (HR 0.190, p=0.048), respectively.ConclusionWe should strengthen the follow-up management of breast cancer patients.The later the stage of breast cancer, the shorter the time interval of diagnosis of OC was. Early control of ovarian tumors and active comprehensive treatment for synchronous and metachronous breast and ovarian cancer can achieve good results.

Background: MMY 4032 (ChiCTR2200055491) is a multicenter, non-interventional, observational registry study that evaluated the real-world efficacy and safety of daratumumab-based regimens in Chinese multiple myeloma patients, which enrolled Chinese patients with multiple myeloma (MM) aged ≥18 years and with a history of ≤3 prior lines of therapy prior to initiating daratumumab-based regimens. All patients had either (1) started daratumumab after 1st Aug 2019 and were expected to continue ongoing daratumumab-based therapy at the time of study initiation on 3rd Nov 2021 or (2) started daratumumab after study initiation. Interim analyses of MMY4032 study demonstrated the favorable response and progression-free survival (PFS) without new safety concerns in Chinese patients treated with daratumumab-based regimens (Wang L et al., 2025, BMC Cancer). In the current analysis, health-related quality of life (HRQoL) was assessed. Methods: MMY 4032 enrolled Chinese patients with multiple myeloma (MM) aged ≥18 years and with a history of ≤3 prior lines of therapy prior to initiating daratumumab-based regimens. All patients had either (1) started daratumumab after 1st Aug 2019 and were expected to continue ongoing daratumumab-based therapy at the time of study initiation on 3rd Nov 2021 or (2) started daratumumab after study initiation. In MMY4032, HRQoL was assessed based on European Organization for Research and Treatment of Cancer QoL questionnaire core 30 (EORTC QLQ-C30) and EuroQol 5-Dimension 5-Level (EQ-5D-5L) visual analog scale (VAS). The score range for each scale is from 0 to 100. Higher scores for the functional scales, global health status (GHS) scale, and VAS scale represent better HRQoL, while higher scores on symptom scales indicate worse symptoms. Questionnaires were encouraged to be completed by the patient at each applicable visit. Mixed model for repeated measures (MMRM) model is used to estimate the least square mean (LS mean) changes from baseline on the longitudinal data. Results: The median duration of follow-up from daratumumab initiation to study end was 23.7 months. The LS mean (95% CI) changes from baseline in EQ-5D-5L VAS were -0.1 (95% CI: -3.76 to 3.64; n=42) at Month 4, 4.4 (95% CI: -0.16 to 8.90; n=28) at Month 8, 5.4 (95% CI: 0.14 to 10.61; n=21) at Month 12, 10.2 (95% CI: 2.23 to 18.22; n=9) at Month 18, and 4.0 (95% CI: -3.62 to 11.56; n=10) at Month 24, showing an increasing trend over time until Month 18. As for EORTC QLQ-C30 GHS scale, the same increasing trend could be observed until Month 12, while the LS mean change decreased to -4.3 (95% CI: -14.43 to 5.87; n=9) at Month 18 because 2 out of 9 patients had extremely low scores. The LS mean change from baseline at Month 18 did not meet the clinically meaningful threshold (10 points). Physical and role functioning, disease symptoms including fatigue and pain, remained at baseline levels in two years. Improvements were seen at several time points, for instance, the mean changes of role functioning and fatigue at Month 18 were 15.2 (95% CI: 2.73 to 27.58; n=9) and -20.1 (95% CI: -30.71 to -9.55; n=9), respectively. Conclusion:These results suggested that Chinese MM patients' HRQoL remained stable after treated with daratumumab -based regimens, with improvements observed at several time points in some scales. The results complemented the favorable clinical outcomes observed in Chinese MM patients treated with daratumumab-based regimens in real world, and illustrated the clinical benefits observed were not at the expense of patients' HRQoL, which was consistent with the conclusions of daratumumab related pivotal trials (Terpos E et al., 2022, Am J Hematol; Plesner T et al., 2021, Br J Haematol).

BACKGROUND:Breast cancer is a highly heterogeneous disease with diverse phenotypes. At present, increasing evidence supports the role of ribosomal biogenesis in human diseases and tumorigenesis. PNO1, as a ribosome assembly factor, plays a key role in the biological synthesis of ribosomes and ribosomal protein mutations associated with human diseases and tumor development. This study explored PNO1's role as a prognostic biomarker for breast cancer. METHODS:Clinical samples and online datasets were used to determine PNO1 expression in breast cancers with different molecular phenotypes and clinicopathological subtypes. CCK-8 assays, colony formation assays, wound healing, and transwell assays were performed to investigate tumor cell proliferation, migration, and invasion. Western blot, flow cytometry, and sphere-formation assays were used to assess the effect of PNO1 on breast cancer stemness. RNA-sequencing analysis was also performed to elucidate the underlying mechanism. RESULTS:Results showed that the expression level of PNO1 was upregulated in breast cancer samples. In addition, high PNO1 expression was positively correlated with poor survival in breast cancer patients with different molecular types. Moreover, PNO1 was associated with breast cancer heterogeneity by promoting its stem-like properties both in vitro and in vivo through the NF-κB signaling pathway, which can be suppressed by JSH-23. CONCLUSIONS:Our study found that PNO1 expression was positively correlated with poor survival in different molecular subtypes of breast cancer and that PNO1 promoted stem-like properties of breast cancer by activating NF-κB activity. Collectively, PNO1 is a potential prognostic biomarker that plays an important role in breast cancer progression.

BACKGROUND:Spleen tyrosine kinase inhibitors are potential treatment options for warm autoimmune haemolytic anaemia. This study aimed to assess the preliminary efficacy and safety of sovleplenib-an oral spleen tyrosine kinase inhibitor-in patients with warm autoimmune haemolytic anaemia in China. Here we report on the phase 2 results. METHODS:This randomised, double-blind, placebo-controlled, phase 2 part from the phase 2/3 study was conducted at 13 centres in China. Eligible patients, aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of no more than 2, had primary or secondary warm autoimmune haemolytic anaemia (stable underlying disease not requiring drug intervention) with no response to previous glucocorticoid treatment, haemoglobin of less than 100 g/L with active haemolysis, and a positive direct antiglobulin test. The study comprised two periods; patients were randomly assigned (3:1) to receive sovleplenib or placebo at 300 mg orally once a day in the 8-week double-blind period. Upon completion, all patients entered an open-label treatment period for at least 16 weeks and received sovleplenib 300 mg once a day until 24 weeks after the last patient was randomly assigned. The primary endpoint for phase 2 of the trial was overall haemoglobin response rate (haemoglobin ≥100 g/L with an increase of ≥20 g/L from baseline at least once, and haemoglobin not affected by rescue therapy, such as red blood cell transfusions, intravenous immunoglobulin, and glucocorticoids) by week 24. Efficacy analyses in the 0-8 week double-blind period included all patients who were randomly assigned, analysed by intention-to-treat. Safety analysis in the double-blind period included patients in the intention-to-treat population who received at least one dose of the study medication. This phase 2/3 study is registered with ClinicalTrials.gov, NCT05535933, and the phase 3 part is ongoing. FINDINGS:Between Sept 26, 2022, and May 9, 2023, 34 patients were screened and 21 patients (four [19%] male and 17 [81%] female) were enrolled in the study and randomly assigned to receive either sovleplenib (n=16) or placebo (n=5). All 21 patients completed the 0-8-week double-blind treatment and entered the open-label treatment period. The overall haemoglobin response rate was 67% (14 of 21 patients) by week 24, and durable haemoglobin response rate was 48% (ten of 21 patients) by week 24. During the 0-8-week double-blind treatment, 13 (81%) of 16 patients in the sovleplenib group versus five (100%) of five patients taking placebo reported treatment-emergent adverse events (TEAEs), and four (25%) of 16 patients versus four (80%) of five patients reported grade 3 adverse events. Although all 21 patients had a TEAE during the 24-week treatment with sovleplenib, only seven (33%) patients had grade 3 events. The most common grade 3 TEAE was anaemia (four [19%] patients), which was not related to treatment. There were no grade 4 or 5 TEAEs. INTERPRETATION:Sovleplenib treatment achieved an encouraging overall haemoglobin response in Chinese patients with warm autoimmune haemolytic anaemia and was well tolerated. The phase 3 part of the study (ESLIM-02) is currently ongoing to further substantiate the efficacy and safety of sovleplenib in this setting. FUNDING:HUTCHMED.

Breast cancer is a leading cause of cancer morbidity and mortality among young women, who often experience more aggressive disease, which may impact their treatment responses and long-term prognoses. Understanding the effectiveness of neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) in this specific population is critical for optimizing treatment strategies and improving prognoses. This research was conducted to compare the prognoses of young women (≤35 years old) with early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, who were treated with NAC versus those treated with AC. This study retrospectively analyzed data from young women with HR+/HER2- breast cancer, with complete follow-up information, sourced from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2018) and the Tianjin Medical University Cancer Institute and Hospital (TJMUCH) (2014-2018). Patients from both cohorts were allocated to NAC and AC groups based on their treatment regimens. Categorical variables were compared using chi-square, whereas the Kaplan-Meier method was utilized to generate survival curves; additionally, the log-rank test was employed for survival analysis. Propensity score matching (PSM) was employed to control baseline differences. Analysis of the SEER and TJMUCH cohorts revealed that patients treated with NAC had significantly worse overall survival (OS) compared to those treated with AC, as indicated by Kaplan-Meier curves both before and after PSM. The disease-free survival analysis of the TJMUCH cohort yielded similar results, indicating that patients treated with AC experienced longer periods without disease recurrence compared to their counterparts receiving NAC. Statistically significant differences were observed across both survival metrics, reinforcing the robustness of our findings. Overall, among young women (≤35 years old) with early-stage HR+/HER2- breast cancer, patients treated with AC exhibited a more favorable prognosis and improved survival outcomes compared to those treated with NAC. These findings could potentially influence clinical decision-making and treatment guidelines, advocating for a more tailored approach in managing young women with HR+/HER2- breast cancer.

Backgroud: Myelodysplastic neoplasms (MDS) are characterized by myelodysplasia and ineffective hematopoiesis leading to refractory cytopenia. Most of MDS patients had anemia at diagnosis requiring red blood cell (RBC) transfusion, which was an independent prognostic factor for poor overall survival of MDS. Therefore, improving anemia is one of the main goals of therapy in LR-MDS patients. Luspatercept, the transforming growth factor-β pathway inhibitor, showed good efficacy in low-risk MDS (LR-MDS) based on clinical trials. Aim: In this study, we analyzed the efficacy and safety of luspatercept in patients with low-blasts MDS (MDS-LB) compared to erythropoiesis-stimulating agents (ESA) in real world. Methods: The study planned to enroll MDS-LB patients newly diagnosed in the Department of Hematology, General Hospital of Tianjin Medical University from June 1st, 2022 to December 30th, 2024. The patients were divided into LR-MDS group (IPSS-R score ≤ 3.5) and HR-MDS group (IPSS-R score > 3.5) based on IPSS-R. The MDS patients in luspatercept group were received luspatercept treatment, as administered subcutaneously every 3 weeks. The starting dose of luspatercept was 1.0 mg per kilogram of body weight (mg/kg). If without erythroid response (HI-E, according to IWG 2018 criteria) and without disease progression after 2 cycles, patients could be received luspatercept with adjustment to a dose of 1.33 mg/kg and then to 1.75 mg/kg. The ESA group were received rhEPO ± roxadustat treatments. The primary end-point was the proportion of patients with HI-E. The key secondary end point was RBC transfusion independence (RBC-TI) for 8 weeks or longer. The adverse events (AE) were defined according to CTCAE 5.0. Results: The data-cutoff was June 30, 2024. A total of 48 MDS-LB were enrolled in this study (Luspatercept group n=27, ESA group n=21).(Table 1) Among luspatercept group, 11 (40.7%) had received treatments combined with ESA (including recombinant human EPO, roxadustat). The results showed that patients treated with luspatercept have a higher HI-E rate than those treated with ESA (73.9% vs. 55%), which might not be affected by SF3B1 mutation, serum erythropoietin level or transfusion burden. After 2 cycles of luspatercept treatment, the median Hb level increased significantly (P<0.05). The patients with first-line treatment, LR-MDS and combined treatments tended to have a higher response rate to luspatercept. The median time to achieve HI-E in luspatercept group was shorter than that of controls (1.5 vs. 5 months, P<0.01). (Table 1, Figure1) There was no serious AE observed. In luspatercept group, the median duration of response (mDOR) of patients received ≥ 3 cycle treatments was higher than that of < 3 cycles group (8 vs. 3 months, P<0.05). (Figure2) The HI-E group tend to have higher population of Treg, and lower concentrations of IL-2, IL-6, TNF-α and IFN-γ compared to non-HI-E group. The serum ferritin (SF), B-type natriuretic peptide (BNP) and C-reactive protein (CRP) levels in HI-E group tended to be lower than that of non-HI-E group. But there was no significant statistical difference between the two groups (all P>0.05). The BNP levels of patients with HI-E after luspatercept treatment were lower than the base-line (P <0.05). (Figure3) It indicated that inflammation factors might affect the response of luspatercept in MDS. Conclusions: This study showed that luspatercept was effective and tolerated well in MDS-LB patients. But inadequate treatments could affect the duration of response. It need to optimize the treatment of luspatercept in further. Key words: MDS-LB, luspatercept, EPO refractory, anemia, immune state

Objectives Myelodysplastic neoplasm (MDS) patients are at a high risk of infections, contributing significantly to morbidity and mortality. While neutrophil dysfunction is considered a primary factor, specific functional defects remain elusive.Methods We conducted a comprehensive study involving 90 participants, including controls and de novo MDS patients. We utilized the TAXIScan-FL system to evaluate neutrophil chemotaxis towards leukotriene B4 (LTB4). The global reactive oxygen species (ROS) production by neutrophils were measured by chemiluminescence assay, neutrophil alkaline phosphatase (NAP) was evaluated by enzymatic staining.Results MDS patients, irrespective of absolute neutrophil count (ANC) levels, exhibited elevated empirical antimicrobial therapy (EAT) rate compared to controls. Neutrophil migration towards LTB4 was notably impaired, demonstrating reduced velocity and directionality. Interestingly, MDS patients with high ANC still displayed poor directionality and slower migration. MDS patients also had compromised ROS and NAP activity. A noteworthy correlation was observed between EAT rate and chemotactic directionality parameters.Conclusion MDS patients face a heightened risk of infection, potentially attributed to impaired neutrophil chemotactic speed and directionality, alongside compromised ROS and NAP activity. Notably, chemotactic directionality emerged as a pivotal factor correlated with antimicrobial therapy. These insights hold significant clinical implications for managing infections in MDS patients, underscoring the importance of targeting specific neutrophil defects for more effective therapeutic strategies.

Young breast cancer (YBC) patients (age ≤ 40) exhibit aggressive features and poor prognosis, while facing complex needs including breast-conserving surgery and fertility preservation. Neoadjuvant therapy (NAT) is important for tumor downstaging and breast-conserving surgery in YBC treatment, but the NAT response mechanisms in YBC patients remain unelucidated. Here, we analyzed pre- and post-NAT samples from Chinese YBC patients using scRNA-seq and scATAC-seq. We found that NAT reshaped cellular heterogeneity in the tumor microenvironment (TME), reducing epithelial and T cells while increasing endothelial cells and fibroblasts. Residual cancer cells showed enriched epithelial-mesenchymal transition (EMT) and stromal remodeling programs. NAT responders had fewer luminal-like cells and retained basal-like cells in an early hybrid EMT state, whereas non-responders maintained both populations with late hybrid EMT. We identified therapy-resistant genes and motifs (e.g., VTCN1, PROM1, MZB1, Fox family) and linked CXCL13 upregulation to poor NAT response and tumor-specific T-cell expansion. Cell–cell communication analysis revealed NAT reprograms the TME by suppressing VEGF and TNF signaling in basal cells, while residual luminal cells transmit EGFR and CD47–SIRPA signals. ### Competing Interest Statement The authors have declared no competing interest.

e13670 Background: MammaPrint (MP) test has been used to evaluate the prognosis and chemotherapy benefit of hormonal receptor positive human epidermal receptor 2 negative (HR+/HER2-) breast cancer (BC). However, its application is constrained by specific clinical scenarios and the high cost of molecular testing. Given that pathological whole slide images (WSIs) provide cellular spatial and morphological information that may reflect phenotypic characteristics of molecular targets, the aim of this study was to identify morphological patterns associated with molecular MP results and to establish an AI model to predict the MP risk group of Chinese HR+/HER2- BC patients from WSIs. Methods: We collected a HR+/HER2- BC cohort from Tianjin Medical University Cancer Hospital (TJMUCH), comprising clinicopathologic features, digital WSIs, and MP results of 477 patients. A multi-instance weakly-supervised transformer model capable of aggregating morphological and spatial features was further developed to predict MP recurrence risk from annotation-free WSIs of BC. Specifically, our AI model was further leveraged for spatial and morphological analysis to explore histological patterns related to MP risk groups. Results: Our AI model shows promising robustness in clinical cohorts, which achieved an average AUC value of 0.825 (5-time 5-fold cross validation) in predicting MP risk group (Low vs. High) from WSIs. Key morphological features, such as dense tumor cellularity, tumor infiltrating lymphocytes, were identified as predictors of MP risk group. The distinct cellular spatial compositions in representative regions elucidate the spatial-morphological patterns associated with prognostic molecular MP testing. Conclusions: Overall, our work established a cost-effective AI model for HR+/HER2- BC patients to assess recurrence risk and guide treatment decisions. Future research will focus on external validation using larger cohorts, integrating this approach as a flexible supplement in routine clinical workflows.

Young women with breast cancer (YBC, age⩽40) are particularly prevalent in Asian. YBCs usually show more aggressive pathology and poorer outcomes than non-young patients. However, YBCs are underrepresented in current BC risk models, with their tumor intrinsic subtypes and microenvironments lacking a systematic elucidation at the single-cell level, thereby limiting the young-specific therapies. We established a single-cell Chinese YBC landscape baseline, including 246,659 cells, by applying scRNA-seq and scATAC-seq on untreated patients. We developed a cross-modal feature selection algorithm to construct a young-intrinsic subtype classifier ‘BCYtype’, outperforming existing classifiers in pseudobulk, cellular, and external cohorts. Comparative analyses with non-young samples revealed a direct differentiation trajectory from mammary stem cells to mature luminal cells. Pseudotemporal analysis also demonstrated that tumor cells in younger patients undergo earlier carcinogenesis. Mechanistically, we found that CDH1 interacts with pTex and NKT cells, serving as a young-specific marker and a potential therapeutic target for HR+ young patients. The interaction between exhausted T cells and antigen-presenting cells revealed NKG2A as a candidate therapeutic target for triple-negative breast cancer in young patients. ### Competing Interest Statement The authors have declared no competing interest. National Key Research and Development Program of China, 2020YFA0908700, 2020YFA0908702 National Natural Science Foundation of China, 62272246

Background: Hepatitis A virus cellular receptor 1 (HAVCR-1), first discovered as the entry factor for hepatitis A virus, has since been recognized as a tumor-associated antigen and is currently being intensively explored as a prognostic biomarker across multiple malignancies, including gastric and colorectal cancers. However, its contribution to breast cancer remains ambiguous. This study investigated the expression and clinical significance of HAVCR-1 in breast cancer. Methods: HAVCR-1 expression was evaluated via quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in a cohort of fresh-frozen normal and breast cancer tissues. Expression levels were correlated with clinicopathological parameters, including the Nottingham prognostic index, tumor stage, histological subtype, hormone receptor status (ER, PR, HER2), and survival outcomes. The prognostic and predictive value of HAVCR-1 was assessed via chi-square tests and receiver operating characteristic (ROC) analysis. The median follow-up period was 120 months. In vitro, HAVCR-1 was knocked down via siRNA in the MCF-7 and MDA-MB-231 cell lines, and the response to docetaxel was evaluated on the basis of the IC50 values. Additionally, ROC plotter analysis was used to assess the association between HAVCR-1 expression and therapeutic response in breast cancer patients. Results: Although qPCR revealed no statistically significant difference in HAVCR-1 mRNA levels between tumor and normal tissues (P=0.2697), IHC revealed increased protein expression in breast cancer tissues. Low HAVCR-1 expression was significantly associated with improved overall survival (OS, P < 0.01) and relapse-free survival (RFS, P=0.04). Subgroup analysis indicated that the survival benefit of low HAVCR-1 expression was particularly evident in ER-positive (P=0.046) and HER2-positive (P=0.004) subtypes but not in triple-negative breast cancer (TNBC). In vitro knockdown of HAVCR-1 conferred resistance to docetaxel in both MCF-7 (IC50: 0.86 nM vs. 1.75 nM) and MDA-MB-231 (IC50: 1.35 nM vs. 15.48 nM) cells. Clinically, patients with high HAVCR-1 expression are more likely to exhibit resistance to chemotherapy, particularly those with the luminal A, luminal B, and TNBC subtypes, but not those with HER2+/ER− tumors. Conclusion: HAVCR-1 is an independent prognostic factor for OS and RFS in breast cancer patients and may serve as a predictive biomarker for chemotherapy response. Its combination with ER, PR, and HER2 status could enhance prognostic stratification and therapeutic decision-making.