In this phase 2 trial (NCT05582499), patients with stage II-III hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer were categorized into endocrine-based and targeted-based groups based on previously proposed similarity network fusion (SNF) subtyping by digital pathology classification and were then randomly assigned in a 1:1 ratio to receive precision or control treatment. The primary endpoint was pathological complete response (pCR). Among 251 randomized patients, 49 were classified into an endocrine-based group and 202 into a targeted-based group. Patients receiving precision treatment had a significantly higher pCR rate (11.1% [90% confidence interval (CI), 6.8-16.8] vs. 4.0% [90% CI, 1.6-8.2]; p = 0.033), with the benefit mainly derived from the targeted-based group (13.9% in precision vs. 4.0% in control; p = 0.026). Toxicity was manageable. Our findings highlight that guiding neoadjuvant precision treatment by SNF subtyping in patients with HR+/HER2- breast cancer showed potential clinical benefits, with improvement of pCR in the targeted-based group and better tolerance in the endocrine-based group.

Breast cancer remains a leading cause of cancer-related morbidity and mortality worldwide, driven by therapeutic resistance, recurrence, and metastasis. Patient-derived organoids (PDOs) have emerged as a robust platform that preserves histopathological, genetic, and functional features of parental tumors, enabling translational research and precision oncology. However, the lack of standardized procedures across laboratories limits reproducibility and clinical applicability. Here, we present a consensus-oriented standard for the establishment, characterization, quality control and application of human breast cancer organoids derived from diverse clinical sources, including surgical tissues, biopsies, pleural effusion, ascites, and circulating tumor cells (CTCs). This document defines key terminologies, outlines standardized workflows, and introduces quantitative validation criteria for successful organoid establishment. In addition, it provides structured guidance for advanced models, including immune–tumor, neuro–tumor, and microbiota−tumor organoid systems, with defined functional validation endpoints. Standardized protocols for drug sensitivity testing are also proposed, including seeding density, exposure duration, and response metrics such as IC50 and AUC. Representative validation strategies, including histological, molecular and functional concordance with parental tumors, are incorporated to enhance reproducibility and translational relevance. This standard aims to harmonize methodologies, improve cross−study comparability, and accelerate the clinical implementation of breast cancer organoid-based precision medicine.

Background:Endocrine therapy (ET) is the primary treatment for hormone receptor (HR)-positive breast cancer. Based on the 2023 expert consensus, the Chinese Consensus Group on Breast Cancer Endocrine Therapy updated this consensus by integrating clinical research data and practical experiences. Methods:(I) Establishment of expert group: the expert group consists of experts from departments such as medical oncology, breast surgery, and pathology. (II) Literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) with a search cutoff date of Sep 30th 2025. (III) Assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines. Results:The 2026 consensus updated clinical research data on ET for both early and advanced breast cancer, defined the eligible population for neoadjuvant ET, and clarified the application of adjuvant cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy in moderate and high-risk patients. For advanced breast cancer, the consensus optimized the treatment strategy of first-line ET plus CDK4/6i, and recommended preferred post-CDK4/6i regimens for patients with distinct clinic-pathological characteristics. It also provides clear recommendations on the indication, optimal timing, and methodology of genetic testing. Conclusions:This consensus may provide clinical guidance for the standardized application of ET, thereby facilitating precise and individualized treatment for HR-positive breast cancer.

Neoadjuvant therapy (NAT) has emerged as a standard treatment strategy for locally advanced breast cancer (BC), yet robust biomarkers for response prediction remain elusive. Here, we established a real-world NAT cohort of 1,161 Chinese BC patients, including 1,145 cases with matched clinicopathological data and targeted sequencing, to systematically evaluate genomic features associated with NAT outcomes. We identified both cross-subtype and subtype-specific genomic associations with treatment response. PI3K-pathway alterations emerged as a consistent feature of resistance across subtypes, whereas mutations such as ERBB2 in HER2+ disease and MAP3K1 in triple-negative breast cancer were associated with subtype-specific response patterns. Regimen-level analyses further showed that some genomic associations were treatment-context dependent across chemotherapy-, endocrine-, anti-HER2-, and immunotherapy-containing regimens. Among patients with non-pathological complete response (non-pCR), genomic profiling further refined risk stratification for distant recurrence by revealing subtype-specific prognostic alterations, including TOP3B and SETD2. Furthermore, a machine-learning model integrating genomic and clinicopathological features showed favorable performance for NAT response prediction. Overall, our study provides a comprehensive genomic framework for response prediction and recurrence risk assessment, supporting more precise stratification and biomarker-guided treatment optimization in Asian breast cancer patients.

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Mitochondrial function is dysregulated frequently in cancer cells to allow for adaptation to a harsh tumor microenvironment. Targeting mitochondrial biogenesis and bioenergetics is, therefore, an attractive therapeutic strategy. In this study, we performed quantitative proteomic analyses in human parental and metastatic breast cancer cell lines to identify mitochondrial proteins involved in TNBC metastasis. We found that single-strand DNA-binding protein 1 (SSBP1) was downregulated in highly metastatic breast cancer cells. Moreover, SSBP1 downregulation promoted TNBC cell metastasis in vitro and in vivo. Mechanistically, SSBP1 loss decreased mitochondrial DNA copy number, thereby potentiating calcineurin-mediated mitochondrial retrograde signaling that induced c-Rel/p50 nuclear localization, activated TGFβ promoter activity, and TGFβ-driven epithelial-to-mesenchymal transition. Low SSBP1 expression correlated with tumor progression and poor prognosis in patients. Collectively, our findings identified SSBP1 as a novel metastasis suppressor and elucidated the mechanisms by which dysregulated mitochondrial signaling contributes to metastatic potential, providing potential new prognostic indicators for patients with TNBC. Cancer Res; 76(4); 952–64. ©2015 AACR.

Immune checkpoint blockade (ICB) has shown limited activity in HER2+ breast cancer, yet the mechanisms underlying this refractoriness remain unclear. Integrating single-cell transcriptomics from untreated human and murine HER2+ tumors with an anti-HER2 non-sensitive mouse model, a neoadjuvant non-pCR patient cohort, functional co-culture assays, and in vivo perturbations, we identify TIGIT signaling from malignant cells (via CD112) to CD8+T cells as a dominant immunosuppressive axis. High TIGIT and CD112 expression correlate with poor clinical outcomes and with the enrichment of TIGIT⁺CD8⁺T cells after anti-HER2 therapy. Therapeutically, combining anti-TIGIT with anti-HER2 reprograms the tumor microenvironment, expanding activated CD8+ T cells with enhanced effector function, increasing IFN-γ production, and restoring MHC-I on tumor cells. A central mechanistic node is the reinstatement of the costimulatory receptor CD226 on CD8+T cells. TIGIT blockade induces CD226, and CD8 dependence is required for efficacy. Neutralizing CD226 abrogates cytotoxicity and IFN-γ secretion. Multiplex tissue analyses further show that intratumoral CD8⁺CD226+T-cell density predicts improved overall and disease-free survival in HER2+ disease. Collectively, these data reveal that restoring CD226-mediated co-stimulation overcomes TIGIT-refractory immunity and sensitizes HER2+ tumors to anti-HER2 therapy, positioning CD226 as both a pharmacodynamic driver and a clinically actionable biomarker for patient selection and response monitoring.Anti-HER2 therapy fails in HER2⁺ breast cancer due to immunosuppression. This study shows tumor engagement of TIGIT on CD8⁺ T cells suppresses anti-tumor function. Combining anti-TIGIT with anti-HER2 blocks this suppression, reinvigorating CD8⁺ T cells via CD226 and enabling tumor clearance. This combination strategy overcomes therapeutic resistance.

Male breast cancer (MBC) accounts for less than 1% of all breast cancers, but the global incidence rate has increased in recent years. Compared to female patients, MBC typically presents at a later age and possesses distinct molecular biological characteristics. Histologically, MBC usually presents as hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Carcinoma in situ and invasive trait carcinoma are common, while special types of carcinoma are rare. In recent years, MBC has achieved significant progress in research on genomic mutation signatures and therapeutic approaches. Genomic profiling identifies abnormalities in DNA damage response pathways as a hallmark genetic feature of MBC, characterized by a high frequency of germline BRCA2 mutations as well as pathogenic variants in PALB2 and CHEK2. Additionally, dysregulation of the phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway offers potential targets for therapy. In contrast to female breast cancer, the frequency of TP53 somatic mutations is lower in MBC. Although precision oncology strategies, such as poly (ADP-ribose) polymerase inhibitors (PARPi) and PI3K pathway inhibitors, have demonstrated clear clinical benefits in female patients, high-quality prospective studies and robust evidence-based data specifically for MBC remain scarce. This article reviews the key molecular genetic features and clinical trial progress of MBC, aiming to provide a reference for precision treatment and the design of future clinical trials.

Background:Implant-based breast reconstruction (IBBR) has become the leading method for postmastectomy reconstruction worldwide. In China, growing patient demand has driven increased use of IBBR, but national trends in techniques and outcomes remain underreported. This study aimed to evaluate the evolution of IBBR practices and associated outcomes during a 13-year period at China's largest breast cancer center. Methods:We retrospectively analyzed 6088 patients who underwent breast reconstruction at Fudan University Shanghai Cancer Center from 2010 to 2023. We examined trends in surgical timing, reconstruction type (direct-to-implant [DTI] versus 2-stage tissue expander [TE]), mastectomy type, implant placement (prepectoral versus subpectoral), TiLOOP Bra use, postmastectomy radiotherapy, and unplanned reoperations. Logistic regression identified factors associated with DTI selection and reoperation risk. Results:The proportion of patients undergoing mastectomy receiving reconstruction rose from 5.3% in 2010 to 16.7% in 2023. IBBR became the predominant method after 2015, comprising 70%-80% of reconstructions since 2017. DTI surpassed TE in 2023, accounting for 73.4% of implant cases. DTI reconstruction was independently associated with nipple-sparing mastectomy, TiLOOP Bra use, and prepectoral placement. TiLOOP use significantly reduced reoperation risk (odds ratio = 0.63, P = 0.03), whereas TE use was associated with an increased risk (odds ratio = 1.58, P = 0.039). Conclusions:IBBR in China has rapidly evolved, with DTI and TiLOOP Bra use driving improved surgical outcomes. These findings support the growing role of surgical innovation, mesh support, and individualized planning in modern breast reconstruction.

1020 Background: Basal-like immune-suppressed (BLIS) triple-negative breast cancer (TNBC) is associated with a poor prognosis; however, prior analyses from the FUTURE and FUTURE-SUPER clinical trials indicated clinical responsiveness to anti-angiogenic therapy. We conducted this study to evaluate the safety and efficacy of combining bevacizumab with antibody–drug conjugates (ADCs) in patients with the BLIS subtype. Methods: The FUTURE 2.0 study (NCT05749588) is an ongoing, open-label, multi-arm phase II platform trial evaluating novel molecularly targeted agents in patients with histologically confirmed TNBC who progressed after ≥1 line of systemic therapy for recurrent or metastatic disease. This report presents results from the BLIS arms: arm C (HER2-low) and arm D (HER2-zero). In arm C, patients received either SHR-A1811 (anti-HER2 ADC, 4.8 mg/kg IV q3w) alone (C1) or with bevacizumab (15 mg/kg IV q3w) (C2). In arm D, patients received either SHR-A1921 (Trop2-targeted ADC, 3.0 mg/kg IV q3w) alone (D1) or with bevacizumab (7.5 mg/kg IV q3w) (D2). The primary endpoint was confirmed objective response rate (ORR). Safety was assessed in all treated patients with available safety data. Results: From April 2022 to October 2025, 100 women were enrolled: 60 assigned to bevacizumab-combination arms (C2 and D2) and 40 to ADC monotherapy arms (C1 and D1). All 100 patients completed at least one post-baseline assessment. Confirmed ORR was 40.0% (8/20; 95% CI: 21.9–61.3%) in C1, 86.7% (26/30; 95% CI: 70.3–94.7%) in C2, 40.0% (8/20; 95% CI: 21.9–61.3%) in D1, and 83.3% (25/30; 95% CI: 66.4–92.7%) in D2. All four arms met the protocol-specified ORR success criterion with high posterior probability. Median PFS was 9.2 months in the combination group versus 4.6 months in the monotherapy group (HR = 0.47; 95% CI: 0.30–0.74), indicating a clinically meaningful improvement. Grade ≥3 treatment-related adverse events occurred in 27.5% (11/40) of monotherapy patients and 33.3% (20/60) of combination patients. No treatment-related deaths occurred. Conclusions: This study provides preliminary evidence of synergy between bevacizumab and ADCs, supporting a promising new strategy—especially for basal-like, immune-suppressed TNBC. Phase III trials are ongoing to confirm the efficacy and safety of this combination. Clinical trial information: NCT05749588 . The efficacy table. ADC monotherapy ADC combined with bevacizumab A1811 N=20 A1921 N=20 Total N=40 A1811+ Bev N=30 A1921+ Bev N=30 Total N=60 ORR, n (%, 95% CI) 8 (40.0) 21.9 – 61.3 8 (40.0) 21.9 – 61.3 16 (40.0) 26.4 – 55.4 26 (86.7) 70.3 – 94.7 25 (83.3) 66.4 – 92.7 51 (85.0) 73.9 – 91.0 mPFS (mo, 95% CI) 4.9 4.1 – 5.7 4.4 3.7 – 5.1 4.6 3.9 – 5.3 9.1 7.2 – 11.1 9.3 8.2 – 10.5 9.2 7.3 – 11.0 HR in PFS, 95% CI 0.470.30 – 0.74 ( P =0.001)

The tumor microenvironment (TME) harbors diverse immune cell states that shape therapeutic outcomes in breast cancer. Here, we identify a conserved stress-programmed cellular module as a key responder to neoadjuvant therapies in breast cancer, characterized by coordinated heat shock gene expression across multiple immune cells, based on single-cell transcriptomic data from neoadjuvant chemotherapy-treated patients. We discover that this multicellular program enhances the effector fate of regulatory T cells (Tregs) via chronic and TME-wide TNF alpha signaling, compromising the efficacy of neoadjuvant chemotherapy. TNF alpha signaling, typically considered an antitumor cytokine, is paradoxically elevated in nonresponders both pre- and post-treatment, with a particularly prominent TNF alpha-TNFR2 interaction. Blocking this axis, with or without chemotherapy, significantly suppresses tumor growth without observable toxicities. Our findings highlight the immune-editing role of stress-programmed Effector regulatory T cells, Neoadjuvant chemotherapy, Stress-programmed immune states, TNF alpha -TNFR2 axis, breast cancercell states and support their therapeutic potential as a rational target in breast cancer.

e13054 Background: The combination of CDK4/6 inhibitors and endocrine therapy (ET) has become the first-line standard treatment for HR+/HER-2- advanced breast cancer (ABC). A certain number of patients who are not sensitive to endocrine therapy and progress rapidly during CDK4/6 inhibitor treatment 20% to 30% of the patients experienced disease progression within 12 months. Screening of those insensitive individuals and further exploration of the optimal treatment strategies is currently the greatest challenge faced by HR+ ABC. Methods: This is a randomize, open-labeled, multi-center phase Ib/II trial (NCT05759572). AI-assisted digital pathology classified of SNF4 subtype patients had pathologically confirmed hormone receptor-positive, HER2-negative with untreated ABC were enrolled. In safety lead-in phase, 9 patients were enrolled (following the 3+3+3 protocol) to receive oral apatinib (250 mg per day) with dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) and endocrine therapy to determine the safety and dose for subsequent phase II part. In pahse II patients were randomly assigned (1:1) to receive dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) and endocrine therapy with or without oral apatinib (250 mg per day). Randomisation was stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting. Safety was analyzed in all randomly assigned patients who received at least one dose of study treatment. Results: Between March 1, 2023, and August 1, 2024, 157 patients were screened and 145 were eligible and enrolled. In safety lead-in phase 9 patients were enrolled and the recommended phase 2 dose was determined as oral apatinib (250 mg per day) and dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) with endocrine therapy. In phase II part 136 patients were randomly assigned to the apatinib+dalpiciclib with ET ( precision group, n = 68) or dalpiciclib with ET (control group, n = 68). Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (27.8m vs 19.4m; stratified hazard ratio 0.57 [95% CI 0.36–0.91]; two-sided log-rank p = 0.017). Adverse events of grade 3 or 4 were reported in 72(93.5%) of 77 patients in the precision group and 62 (91.1%) of 68 patients in the control group. The most common adverse events of grade 3 or 4 were neutropenia (71 [92.2%] in the precision group vs 62 [91.1%] in the control group) and leukopenia (70 [91.0%] in the precision group vs 60 [88.2%]). Conclusions: AI-assisted digital pathology classification identified SNF4 patients who were resistant to ET combined with CDK4/6 inhibitor. The first-line treatment of apatinib combined with ET and CDK4/6 inhibitor, significantly improved the prognosis of these SNF4 patients with tolerated toxicity. Further prospective phase III trial has currently been conducted. Clinical trial information: NCT05759572 .

Axillary management in breast cancer has evolved toward de-escalation to reduce complications, particularly breast cancer-related lymphedema (BCRL). This study aimed to assess current practices and trends of axillary surgery and BCRL management in China. A nationwide survey was conducted across hospitals performing ≥ 200 breast cancer surgeries annually in 2022. The questionnaire evaluated institutional characteristics, clinical practices of axillary surgery and BCRL care. Data were compared with those from the 2017 national survey involving 110 hospitals to assess temporal changes in hospital-reported practice patterns. The 198 hospitals surveyed performed a total of 123,237 breast cancer surgeries in 2022. SLNB for cN0 patients was routine practice, with 59.6

Abstract The years 2024–2025 has marked a period of profound evolution in the management of breast cancer, characterized by the consolidation of established therapies and the emergence of transformative new strategies across all subtypes. The field of locoregional management is undergoing a paradigm shift towards surgical de-escalation, with landmark trials questioning the necessity of long-held axillary procedures. For hormone receptor-positive (HR +) breast cancer, the narrative has shifted from the initial adoption of CDK4/6 inhibitors (CDK4/6i) to refining their use in the adjuvant setting and, critically, defining the complex therapeutic landscape following their progression. The rise of antibody–drug conjugates (ADCs) continues to blur traditional subtype boundaries, particularly with the expansion of trastuzumab deruxtecan into the HER2-low and even “HER2-ultralow” populations. In HER2-positive (HER2 +) breast cancer, ADCs are challenging the long-standing first-line standards, while de-escalation strategies in early-stage disease are gaining robust evidence. For triple-negative breast cancer (TNBC), long-term data has solidified the role of immunotherapy, while molecular subtyping is finally translating into tangible clinical benefits in first-line precision trials. This commentary synthesizes the pivotal data from 2024–2025, exploring the clinical implications and future directions of these advancements.

LBA1003 Background: Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive biology and limited treatment options beyond first-line immunotherapy plus chemotherapy. Patients who progress after taxane-containing regimens face poor outcomes and have a high unmet need. Izalontamab brengitecan (iza-bren) is a first-in-class bispecific antibody–drug conjugate (ADC) targeting EGFRxHER3 with a potent topoisomerase I inhibitor payload. Here we report the results of a pre-planned interim analysis from a phase III study of iza-bren in patients with TNBC. Methods: This randomized, multicenter, open-label, phase III study enrolled patients with unresectable locally advanced or metastatic TNBC who had disease progression after 1–2 prior lines of systemic therapy for advanced disease—including prior taxanes. Patients were randomized 1:1 to receive iza-bren (2.5 mg/kg D1D8 Q3W) or treatment of physician’s choice (TPC) (eribulin, capecitabine, gemcitabine, or vinorelbine). Randomization was stratified by prior lines of therapy (1 vs. 2), prior anti-PD-(L)1 (yes vs. no), and HER2 IHC (0 vs. 1+/2+ ISH-). The dual-primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Results: A total of 418 patients were randomized (iza-bren/TPC: 207/211) and 412 were treated (iza-bren/TPC: 207/205). As of the data cutoff (Jan 13, 2026), median follow-up was 11.0 months. The median PFS by BICR was 8.5 months with iza-bren and 3.1 months with TPC (HR, 0.29 [95% CI, 0.22-0.38]; stratified log-rank P<0.0001). The median OS was 15.9 months with iza-bren and 12.5 months with TPC (HR, 0.60 [95% CI, 0.42-0.85]; stratified log-rank P=0.0019). The confirmed objective response rate (cORR) assessed by BICR was 51.7% with iza-bren and 20.5% with TPC (odds ratio, 4.28 [95% CI, 2.75-6.66]). Most common grade ≥3 TEAEs (iza-bren vs TPC) were neutrophil count decreased (58.0% vs 46.8%), white blood cell count decreased (56.0% vs 33.2%), platelet count decreased (52.7% vs 2.4%), and anemia (46.9% vs 3.9%). All-grade ILD was reported in 3 (1.4%) and 0 patients in the iza-bren and TPC arms, respectively. Treatment discontinuation due to TEAEs occurred in 4 (1.9%) patients in the iza-bren arm and 1 (0.5%) patient in the TPC arm. No new safety signals were observed. Conclusions: This pre-planned interim analysis met both dual-primary endpoints of PFS by BICR and OS. Iza-bren demonstrated a statistically significant and clinically meaningful improvement in both PFS and OS compared with chemotherapy, with a manageable safety profile in heavily pre-treated TNBC patients, supporting iza-bren as a new standard of care in this population. Clinical trial information: NCT06382142 .

Breast cancer exhibits marked clinical heterogeneity and dynamic epigenetic reprogramming during tumor progression, yet current subtyping approaches fail to capture molecular changes associated with metastasis. Here, we establish a comprehensive biobank of patient-derived organoids (PDOs) from matched primary tumors, adjacent normal tissues, and lymph node metastases. Integrated genomic, transcriptomic, and epigenetic analyses demonstrate that these PDOs preserve tumor-specific molecular signatures and recapitulate epigenetic remodeling during disease evolution. Epigenetic profiling defines four distinct clusters, characterized by unique transcription factor (TF) networks, pathway activities, and therapeutic vulnerabilities not fully represented by conventional classifications. The lymph node metastasis cluster, predominantly comprising metastatic PDOs, displays extensive chromatin remodeling driven by metastasis-enriched TFs, whose depletion markedly impairs spontaneous metastasis in vivo. Together, these findings establish PDO-based epigenetic characterization as a platform for elucidating regulatory mechanisms underlying breast cancer progression and for advancing precision therapeutic strategies.

TPS1144 Background: QLS1304 is a novel, highly-potent, and selective dual inhibitor of KAT6A/6B. KAT6A acetylates histone H3 at the 23rd lysine residue, thereby modulating gene transcription, and implicated in ER+/HER2- BC. QLS1304 showed potent efficacy in standard of care resistant, KAT6A-high and ESR1 -mutant ER+/HER2- BC patient-derived xenograft model, whether administered as a monotherapy or combination therapy ( Cancer Res (2025) 85 (8_Supplement_1): 457 ). In the ongoing phase 1 trial, QLS1304 monotherapy showed an acceptable safety profile and potential anti-tumor activity in pts with BC. This study aimed to evaluate the safety and preliminary efficacy of QLS1304 + ET combination (fulvestrant or QLC1401, a novel oral selective ER degrader) ± CDK4/6 inhibitor (CDK4/6i) in pts with ER+/HER2- locally advanced or metastatic (LA/M) BC. Methods: This multicenter, open-label, phase 1b/2 trial consists of phase 1b combination dose-escalation and phase 2 dose-expansion. The phase Ib study will enroll pts with LA/M ER+/HER2- BC, who have received prior ET plus CDK4/6i, utilizing the Rolling-Six design. There are 2 cohorts: Cohort 1A QLS1304 + fulvestrant and Cohort 1B QLS1304 + QLC1401. Three dose levels of QLS1304 are planned, which are 4 mg/d, 8 mg/d, and 12 mg/d. The dose of QLC1401 is 150 mg, which is the recommended phase 2 dose (RP2D) of monotherapy. Both QLS1304 and QLC1401 are orally administered in a 28-day cycle. A total of 12~18 pts per cohort are planned to be enrolled, which might be adjusted based on the occurrence of dose-limiting toxicities (DLTs) during the first cycle. The primary endpoints are safety, tolerability, and RP2D of QLS1304 combined with fulvestrant/QLC1401. In phase 2, 1~2 dose levels of QLS1304 will be explored in 5 cohorts. In Cohort 2A (QLS1304 + fulvestrant) and Cohort 2B (QLS1304 + QLC1401), pts with LA/M ER+/HER2- BC who received prior ET plus CDK4/6i will be enrolled. In Cohort 2C (QLS1304 + CDK4/6i + letrozole), pts with LA/M ER+/HER2- BC with no prior therapy will be enrolled. In Cohort 2D (QLS1304 + CDK4/6i + fulvestrant), adjuvant ET-resistant or ET+CDK4/6i pretreated LA/M ER+/HER2- BC pts will be enrolled in 2 subgroups. In Cohort 2E (QLS1304 + CDK4/6i + QLC1401), adjuvant ET-resistant, treatment naïve, or ET+CDK4/6i pretreated LA/M ER+/HER2- BC pts will be enrolled in 3 subgroups. Doublet combination will be firstly explored, which will support the dose selection of triplet combination. In triplet cohorts 2C–2E, 6 pts will be enrolled in a safety run-in to assess the preliminary safety profile in each cohort. Expansion will be started after safety confirmation. A total of 316~366 pts will be enrolled. The primary endpoint of phase 2 is ORR per RECIST v1.1. Patient enrollment is currently ongoing. Clinical trial information: NCT07235176 .

Abstract Neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy represents the current standard-of-care for HER2-positive breast cancer. However, treatment responses remain heterogeneous, underscoring the lack of clinically practical tools for predicting treatment efficacy and informing personalized therapy. Here, we developed HER2-LADDER (Layered AI-based Dual-targeteD anti-HER2 Recommendation), a spatially interpretable and clinically accessible artificial intelligence framework that integrates clinicopathological and spatial topological features from routine hematoxylin and eosin (H&E) and HER2 immunohistochemistry (IHC) slides. Using these spatially derived features, HER2-LADDER accurately predicted response to neoadjuvant TCbHP/PCbHP, achieving AUCs of 0.944 in the model construction cohort (N = 276), 0.917 in the temporal validation cohort (N = 82), and 0.869 in the trial-based validation cohort (N = 85). On the basis of HER2-LADDER scores, patients were stratified into Low (highly responsive), Medium (responsive), and High (resistant) groups, identifying candidates for treatment de-escalation (THP or TCbH/PCbH), standard-of-care (TCbHP/PCbHP), or alternative regimens (e.g., next-generation anti-HER2 antibody‐drug conjugates), respectively. Importantly, Xenium in situ profiling further revealed biological correlates underlying model predictions, including HER2-enriched tumor cell aggregation and neutrophil-helper T-cell interactions, thereby highlighting the mechanistic interpretability of the model. Collectively, HER2-LADDER unites digital pathology and high-resolution spatial profiling into a clinically accessible AI framework, offering a robust, transparent, and biologically grounded tool to tailor individualized HER2-targeted therapy optimization.

Objective:Age-associated molecular heterogeneity is well described in female breast cancer but remains insufficiently characterized in male breast cancer (MBC). We profiled age-stratified clinical and molecular differences between younger (≤55 years) male breast cancer (YMBC) and older (>55 years) male breast cancer (OMBC). Methods:We retrospectively analyzed 347 patients with MBC diagnosed at Fudan University Shanghai Cancer Center by integrating clinicopathological data, RNA sequencing, and whole-exome sequencing (WES). Survival, differential expression, and mutational signature analyses were performed. Tumor microenvironment features were inferred using xCell and ESTIMATE, and weighted gene co-expression network analysis (WGCNA) was conducted to identify age-associated co-expression modules. Candidate therapeutics were prioritized using the Genomics of Drug Sensitivity in Cancer (GDSC) resource and evaluated using patient-derived organoids (PDOs). Results:Compared with OMBC, YMBC more frequently had human epidermal growth factor receptor 2 (HER2)-positive status (14.91% vs. 4.02%) and triple-negative tumors (4.92% vs. 1.78%), and had worse 5-year recurrence-free survival (hazard ratio=2.19, P=0.018). Transcriptomic analyses indicated enrichment of neural-related programs and reduced immune-related signaling in YMBC, and xCell/ESTIMATE supported lower immune infiltration. Consistently, WGCNA identified age-associated modules linking neural-related programs with reduced immune infiltration. Immunohistochemistry supported increased perineural invasion and lower CD8+ T cell infiltration in YMBC. GDSC-guided prioritization with PDO testing nominated sepantronium bromide (YM155) as a candidate vulnerability in YMBC. WES showed a higher NBPF10 mutation frequency in YMBC (54.5% vs. 14.3%, P<0.05). Conclusions:Integrated multi-omics profiling revealed age-stratified clinical and molecular heterogeneity in MBC. YMBC patients demonstrated inferior recurrence-free survival, neural signaling enrichment, an immune-cold microenvironment, and enriched NBPF10 mutations. These findings support age as a meaningful stratification variable in MBC risk assessment and treatment planning, and highlight the need for caution when considering treatment de-escalation in younger patients, while nominating YM155 as a candidate agent for prospective evaluation.

Tumor metabolism is characterized by dynamic plasticity, but there is a lack of appropriate tools to detect metabolic changes across different tumor stages, limiting the application of metabolism-targeted therapies. Our study introduces a noninvasive liquid biopsy approach, utilizing exosomes to reflect the metabolic profile of primary tumors at the transcriptome level. We observed a significant correlation between cholesterol synthesis and the response to neoadjuvant chemotherapy in breast cancer, particularly with non-pathologic complete response (non-pCR). Methylsterol Monooxygenase 1 (MSMO1) was identified as a key factor influencing breast cancer chemosensitivity. MSMO1 regulates the metabolism of 14-demethyllanosterol (T-MAS), contributing to chemotherapy resistance via the PERK/eIF2α/ATF4/CHOP signaling pathway. Notably, plasma exosomal levels of MSMO1 may serve as a predictive biomarker for identifying patients who may benefit from T-MAS-mediated chemosensitization strategies, offering a promising approach for personalized breast cancer treatment.