Polymers play a crucial role in our daily lives; however, achieving a balance among mechanical performance, resistance to high and low temperatures, and mild shaping remains challenging. Here, we report a water-triggered supramolecular polymer composed of cellulose and polymethyl methacrylate. Following water-induced transformation of a stretchable supramolecular network into a densified cross-linked domain, the resulting polymer exhibits a remarkable increase in tensile strength from 2.7 MPa to 61.7 MPa, representing more than a 22-fold enhancement, and a flexural strength of 97 MPa, while maintaining structural integrity across a temperature range of -196 °C to 200 °C. In addition, the polymer enables scalable water-mediated shaping and reinforcement even in seawater, surfactant wastewater, and dye wastewater, while retaining high mechanical performance. Economic analysis and recycling assessment demonstrate that this polymer is amenable to scalable production and has considerable market potential. This study provides a biomimetic formulation for the fabrication of high-performance supramolecular polymers and broadens their potential applications across diverse fields.

Background:Existing neoadjuvant therapies for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer have not achieved optimal clinical outcomes, thus prompting the investigation of novel treatment strategies. Given the emerging significance of HDAC inhibitors in the management of advanced breast cancer, this study investigated the efficacy and safety of chidamide plus chemotherapy as neoadjuvant therapy for patients with HR+/HER2- breast cancer. Methods:This single arm, open-label, multicentre, phase 2 trial was conducted at three hospitals in China. Patients aged 18-75 years who had treatment-naïve, stage II-III HR+/HER2- breast cancer with an Eastern Cooperative Oncology Group performance status of 0-1 were enrolled. Patients received oral chidamide at a dose of 20 mg on days 1, 4, 8, and 11 of each 21-day cycle. The chemotherapy regimen consisted of four cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) administered every three weeks, followed by four cycles of docetaxel (100 mg/m2) administered every three weeks. The primary endpoint was the rate of residual cancer burden (RCB) 0-I. This study is registered with ClinicalTrials.gov, NCT05400993. Findings:Between May 23, 2022 and July 6, 2023, a total of 54 female patients (median age: 50 years [range, 26-75]) were recruited. The RCB 0-I rate was 35.2% (19 of 54, 95% confidence interval [CI], 22.7%-49.4%). The most frequent grade 3 or 4 adverse events were decreased neutrophil count (70%) and decreased white blood cell (67%). No treatment-related deaths occurred. Interpretation:The combination of chidamide and chemotherapy shows the potential to be an alternative neoadjuvant therapy option for patients with HR+/HER2- breast cancer. Funding:Shenyang Municipal Science and Technology Program (Grant No. 22-321-32-18), Shenzhen Chipscreen Biosciences Co., Ltd.

Antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) are widely used for HER2-positive metastatic breast cancer, but their efficacy in the neoadjuvant setting remains under investigation. The MUKDEN 06 trial (NCT05426486), a multicentre, randomised, phase 2b study, compared ARX788 (anti-HER2 ADC) plus pyrotinib (TKI) with the standard neoadjuvant regimen of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCbHP) in female patients with early or locally advanced HER2-positive breast cancer. The primary endpoint was the pathological complete response (pCR, ypT0/is, ypN0) rate, analyzed in the intention-to-treat population. pCR was achieved in 70.6% (48/68) of patients receiving ARX788 plus pyrotinib, compared to 51.5% (35/68) in the TCbHP group, with a significant absolute difference of 19.1% (95% CI, 2.7-34.6; p = 0.023). No treatment-related deaths occurred. The most common grade 3-4 adverse events were diarrhea and hepatic dysfunction in the ARX788 plus pyrotinib group, and fatigue, nausea and anorexia in the TCbHP group. Interstitial lung disease (ILD)/pneumonitis and ocular events were observed with ARX788 plus pyrotinib, indicating a distinct safety profile. These findings offer clinical insights into the potential of dual HER2-targeted blockade with an ADC and TKI as an optional neoadjuvant strategy for patients with early or locally advanced HER2-positive breast cancer.

e12593 Background: Hormone receptor (HR)-positive/ human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) exhibits lower rates of pathologic complete response and objective response rate (ORR) to neoadjuvant therapy, highlighting an urgent clinical need for more effective alternatives. Dalpiciclib is a novel CDK4/6 inhibitor, and chidamide is an orally selective histone deacetylase inhibitor. This study aims to explore the efficacy and safety of dalpiciclib plus chidamide and letrozole as neoadjuvant therapy for HR-positive/HER2-negative BC. Methods: This is a single-arm, open-label study that enrolled patients with early or locally advanced HR-positive/HER2-negative BC. After enrollment, patients received six 28-day cycles of dalpiciclib (100 mg, po, qd, d1-21) plus chidamide (20mg, biw, po, d1-21) and letrozole (2.5 mg, qd, po) as neoadjuvant therapy. Tumor response was assessed according to RECIST 1.1 by MRI examination every 2 cycles until surgery. Surgical treatment will be performed within 2-4 weeks after the end of neoadjuvant therapy, and subsequent adjuvant therapy will be carried out by the investigator according to the actual situation of the subject. The primary endpoint was residual cancer burden score of 0 or I (RCB 0/I), and the secondary endpoints were the total pathological complete response rate (tpCR; ypT0/is and ypN0), objective response rate (ORR) and safety analysis. This study is registered with China Clinical Trials Registry (ChiCTR2400081280). Results: From August 2023 to January 2025, 23 patients were enrolled in our study. All patients had ER expression ≥ 50%, and 74% (17/23) had Ki67 expression ≥ 20%. Among the 12 patients completed neoadjuvant therapy and underwent surgery, the postoperative RCB 0/I was 25% (95% CI, 5.5%-49.5%), tpCR was 25% (95% CI, 5.5%-49.5%), ORR was 92% (95% CI, 61.5%-100.0%). Among the 20 patients who completed the assessment after 2 cycles, the ORR was 75% (95% CI, 50.9%-94.0%). The most common adverse events (AEs) were decreased neutrophil count (100%) and decreased white blood cell count (86%), with grade ≥3 AEs occurring in 82% and 55% of patients, respectively. While other AEs were predominantly grade 1 or 2. Conclusions: Our results showed thatthe combination of dalpiciclib, chidamide and letrozole demonstrates an acceptable safety profile and promising clinical efficacy, suggesting its potential as an alternative fully oral, chemotherapy-free neoadjuvant treatment for HR-positive, HER2-negative early or locally advanced breast cancer. Further research is needed to validate these findings. Clinical trial information: ChiCTR2400081280 .

BACKGROUND:Minimal-access nipple-sparing mastectomy (NSM) with immediate prosthesis breast reconstruction results in better cosmetic outcomes than conventional operation. However, the impact of skin flap development techniques on postoperative complications and long-term oncologic safety is largely unknown. This report describes the surgical and oncologic outcomes of tumescence and sharp dissection compared with electrocautery dissection. METHODS:In this real-world retrospective cohort study, 5436 individuals undergoing NSM from 12 centers in China were identified. After exclusions and propensity score-matching, the study included 1252 patients who underwent minimal-access NSM with immediate prosthesis breast reconstruction between January 2016 and December 2022. Perioperative parameters, postsurgical complications, and long-term survival were analyzed. RESULTS:Of the 1252 patients, 313 (25 %) underwent tumescence and sharp dissection, and 939 (75 %) underwent electrocautery dissection. The patients in the tumescence and sharp dissection group had significantly lower rates of necrotic complications (5.8 % vs 13.0 %; p = 0.001), infection (2.6 % vs 5.6 %; p = 0.041), and implant loss (0.3 % vs 2.2 %; p = 0.025) than those receiving electrocautery dissection, with a significantly shorter operation time (median, 177 min; interquartile range [IQR], 132-219 min vs 201 min; IQR, 143-249 min; p < 0.001). The two groups did not differ significantly in 5-year overall survival (p = 0.938) or disease-free survival (p = 0.893). CONCLUSION:Tumescence and sharp dissection was associated with fewer postoperative complications and a shorter operation time than electrocautery dissection for breast cancer patients receiving minimal-access NSM with immediate prosthesis breast reconstruction, and showed no significant difference in long-term survival.

Background: Both neoadjuvant chemotherapy and endocrine therapy only result in trivial pathological complete response rates and moderate objective response rates (ORR) in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer, more promising alternatives are urgently needed. With proven synergistic effect of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and radiotherapy in preclinical studies, this pilot study aimed to explore the efficacy and safety of neoadjuvant stereotactic body radiation therapy (SBRT) followed by dalpiciclib and exemestane in HR-positive, HER2-negative breast cancer. Methods: This was a single-arm, non-controlled prospective pilot study. Treatment-naive patients with unilateral HR-positive, HER2-negative breast cancer received neoadjuvant radiotherapy (24 Gy/3 F) followed by dalpiciclib and exemestane for six cycles. The primary endpoint was the proportion of patients with residual cancer burden (RCB) score of 0-I. Key secondary endpoints included ORR, breast-conservation rate, biomarker analysis, and safety. Results: All 12 enrolled patients completed the study treatment and surgery. Two (16.7%) of them achieved the RCB 0-I with the ORR of 91.7% (11/12). Analyses of tumor specimens showed significant increase of infiltrating T cells rather than alteration of PD-L1 positive immune cells. The most common grade 3 adverse events (AEs) were neutropenia (66.7%) and leukopenia (25.0%), but no grade 4–5 AE or death occurred. Conclusions: Our results suggested neoadjuvant SBRT followed by dalpiciclib and exemestane is effective and tolerable and provides novel insights for the neoadjuvant treatment of HR+/HER2- breast cancer, which may be considered as a feasible option for patients with HR-positive, HER2-negative breast cancer. Funding: None. Clinical trial number: ClinicalTrials.gov: NCT05132790

CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2- breast cancer. However, their therapeutic effectiveness in triple-negative breast cancer (TNBC) remains controversial. Here, we observed that the expression level of fibrous sheath interacting protein 1 (FSIP1) could predict the treatment response of TNBC to CDK4/6 inhibitors. High FSIP1 expression level was related to a poor prognosis in TNBC, which was associated with the ability of FSIP1 to promote tumor cell proliferation. FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC. FSIP1 knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway. FSIP1 could form a complex with Nanog, protecting it from ubiquitination and degradation, which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors. Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.

Breast cancer is characterized by significant molecular heterogeneity; therefore, there are distinct clinical features, treatment modalities, and prognostic outcomes across its various molecular subtypes. In the era of precision medicine, liquid biopsy has emerged as a convenient and minimally invasive technique capable of dynamically representing the comprehensive tumor gene spectrum. This review systematically elaborates the clinical value of liquid biopsy as a breakthrough tool for precision diagnosis and treatment in breast cancer through dynamic detection of key biomarkers, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and non-coding RNA (ncRNA). Specific genetic mutations and methylation signatures in ctDNA can be applied to early breast cancer screening, minimal residual disease monitoring, and tracking drug resistance mechanisms. CTCs enumeration (≥1/7.5 mL in early-stage cancer or ≥ 5/7.5 mL in metastatic cancer) and PD-L1 expression levels demonstrate direct correlations with prognostic stratification and the efficacy of immunotherapy. As the specificity and sensitivity of liquid biopsy continue to improve, personalized treatment strategies, informed by biomarker analysis and targeted precision therapies, have unveiled new avenues of hope for patients with breast cancer. However, several challenges persist in the practical application of liquid biopsy. Despite persistent challenges, such as insufficient standardization and difficulties in resolving low-abundance variants, future advancements should focus on multi-omics integration and AI-driven technological breakthroughs to overcome bottlenecks in clinical translation. This review summarizes cutting-edge liquid biopsy technologies for identifying clinically significant molecular biomarkers, focusing on discussing critical challenges in the strategies to advance precision oncology applications for optimized treatment guidance and disease surveillance in breast cancer.

Significant heterogeneity exists in hormone receptor (HR)-positive/HER2-positive (HR+/HER2+) breast cancer, contributing to suboptimal pathological complete response rates with conventional neoadjuvant treatment regimens. Overcoming this challenge requires precise molecular classification, which is pivotal for the development of targeted therapies. We conducted molecular typing on a cohort of 211 patients with HR+/HER2+ breast cancer and performed a comprehensive analysis of the efficacy of various neoadjuvant treatment regimens. Our findings revealed four distinct molecular subtypes, each exhibiting unique characteristics and therapeutic implications. The HER2-enriched subtype, marked by activation of the HER2 signaling and hypoxia-inducible factor 1 (HIF-1) pathway, may benefit from intensified anti-HER2-targeted therapy. Estrogen receptor (ER)-activated subtype demonstrated potential sensitivity to combined therapeutic strategies targeting both ER and HER2 pathways. Characterized by high immune cell infiltration, the immunomodulatory subtype showed sensitivity to HER2-targeted antibody–drug conjugates (ADCs) and promise for immune checkpoint therapy. The highly heterogeneous subtype requires a multifaceted therapeutic approach. Organoid susceptibility assays suggested phosphoinositide 3-kinase inhibitors may be a potential treatment option. These findings underscore the importance of molecular subtyping in HR+/HER2+ breast cancer, offering a framework for developing precise and personalized treatment strategies. By addressing the heterogeneity of the disease, these approaches have the potential to optimize therapeutic outcomes and improve patient care.

The latest developments combining deep learning technology and medical image data have attracted wide attention and provide efficient noninvasive methods for the early diagnosis of breast cancer. The success of this task often depends on a large amount of data annotated by medical experts, which is time-consuming and may not always be feasible in the biomedical field. The lack of interpretability has greatly hindered the application of deep learning in the medical field. Currently, deep stable learning, including causal inference, make deep learning models more predictive and interpretable. In this study, to distinguish malignant tumors in Breast Imaging-Reporting and Data System (BI-RADS) category 3-4A breast lesions, we propose BD-StableNet, a deep stable learning model for the automatic detection of lesion areas. In this retrospective study, we collected 3103 breast ultrasound images (1418 benign and 1685 malignant lesions) from 493 patients (361 benign and 132 malignant lesion patients) for model training and testing. Compared with other mainstream deep learning models, BD-StableNet has better prediction performance (accuracy = 0.952, area under the curve = 0.982, precision = 0.970, recall = 0.941, F1-score = 0.955 and specificity = 0.965). The lesion area prediction and class activation map results both verify that our proposed model is highly interpretable. The results indicate that BD-StableNet significantly enhances diagnostic accuracy and interpretability, offering a promising noninvasive approach for the diagnosis of BI-RADS category 3-4A breast lesions. Clinically, the use of BD-StableNet could reduce unnecessary biopsies, improve diagnostic efficiency, and ultimately enhance patient outcomes by providing more precise and reliable assessments of breast lesions.

Intelligent and convenient human-computer interfaces realize efficient and close cooperation between people and the digital world. As windows of human-machine interaction (HMI), sensors directly determine the ability and quality of acquired signals and the utilization potential of HMI systems. However, it still remains challenging to develop antifreeze hydrogel sensors with freeze-resistant properties while avoiding the loss of other properties as much as possible to achieve stable HMI applications in low-temperature environments. Here, we present an Agar/PAAm dual-network hydrogel (Na+-Agar/PAAm-AFP) doped with both antifreeze protein (AFP) and sodium chloride (NaCl), which exhibits excellent antifreeze capability (-20 degrees C). The hydrogel integrates transparency (>90%), ultra stretchability (up to 2100%), good adhesion properties to metal, glass, and plastic, high electrical conductivity (3.41 S m(-1)), high sensitivity (GF = 10.23), and non-irritating to the skin. The hydrogel can be used for monitoring daily activities and glove-based HMI systems for intelligent control. In addition, based on this hydrogel, we have successfully developed an interactive system for real-time information transfer over long distances. It is expected to provide better health management monitoring in several fields and also help to advance the development of innovative and IoT technologies.

Abstract Triple‐positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan‐human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin‐dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II–III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%–84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0–I was 75% (95% CI, 46.8%–91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%–98.5%). Mean Ki‐67 level was significantly reduced from 45.0% (95% CI, 19.5%–70.5%) at baseline to 17.2% (95% CI, 0.7%–33.7%) after neoadjuvant therapy (p = 0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment‐related deaths occurred. This four‐drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.

Cancer lactate metabolic reprogramming induces an elevated level of extracellular lactate and H+, leading to an acidic immunosuppressive tumor microenvironment (TEM). High lactic acid level may affect the metabolic programs of various cells that comprise an antitumor immune response, therefore, restricting immune-mediated tumor destruction, and leading to therapeutic resistance and unsatisfactory prognosis. Here, we report a metal-phenolic coordination-based nanocomplex loaded with a natural polyphenol galloflavin, which inhibits the function of lactate dehydrogenase, reducing the production of lactic acid, and alleviating the acidic immunosuppressive TME. Besides, the co-entrapped natural polyphenol carnosic acid and the synthetic PEG-Ce6 polyphenol derivative (serving as a photosensitizer) could induce immunogenic cancer cell death upon laser irradiation, which further activates immune system and promotes immune cell recruitment and infiltration in tumor tissues. We demonstrated that this nanocomplex-based combinational therapy could reshape the TME and elicit immune responses in a murine breast cancer model, which provides a promising strategy to enhance the therapeutic efficiency of drug-resistant breast cancer.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been considered as a new immune checkpoint for tumor-induced immunosuppression. The role of CMTM6 in trastuzumab resistance remains unknown. Here, we uncover a role of CMTM6 in trastuzumab-resistant HER2+ breast cancer. CMTM6 expression was upregulated in trastuzumab-resistant HER2+ breast cancer cell. Patients with high CMTM6 expressing HER2+ breast cancer had worse overall and progression-free survival than those with low CMTM6 expression. In vitro, CMTM6 knockdown inhibited the proliferation and migration of HER2+ breast cancer cells, and promoted their apoptosis, while CMTM6 overexpression reversed these effects. CMTM6 and HER2 proteins were co-localized on the surface of breast cancer cells, and CMTM6 silencing reduced HER2 protein levels in breast cancer cells. Co-immunoprecipitation revealed that CMTM6 directly interacted with HER2 in HER2+ breast cancer cells, and CMTM6 overexpression inhibited HER2 ubiquitination. Collectively, these findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTM6 as a potential prognostic marker and therapeutic target for overcoming trastuzumab resistance in HER2+ breast cancer.

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients. V-ATPase, an ATP-driven proton pump positioned at lysosomal surfaces, is responsible for maintaining the stability of lysosome. Herein, we reported that the potassium voltage-gated channel subfamily J member 15 (KCNJ15) protein, which may bind to V-ATPase, can regulate the function of lysosome. The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy. The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase, contributing to the amelioration of drug resistance. Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading, advanced stages, more metastases of lymph nodes, and shorter disease free survival of patients with breast cancer. KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy. Moreover, we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes. In conclusion, KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer, which might guide the choice of therapeutic strategies.

e12603 Background: Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib plus dalpiciclib (cyclin dependent kinase 4/6 inhibitor) and letrozole in patients with triple-positive breast cancer (TPBC), but the efficacy still needs improvement. This pilot study explored the efficacy and safety of adding trastuzumab to this neoadjuvant regimen in TPBC. Methods: Patients received five 28-day cycles of pyrotinib (320 mg once daily), dalpiciclib (125 mg once daily on days 1-21) and letrozole (2.5 mg once daily), plus six 21-day cycles of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg maintenance dose on day 1), followed by surgery. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Secondary endpoints were objective response rate (ORR), breast pathological complete response (bpCR; ypT0/is) rate, residual cancer burden (RCB), change in Ki-67 level from baseline to surgery, and safety. Results: Between February 16, 2022 and June 2, 2022, 12 patients were enrolled. Seven (58%; 95% CI, 27.7-84.8) patients achieved tpCR and bpCR. The rate of RCB 0-I was 75% (95% CI, 46.8-91.1%). ORR was 92% (95% CI, 64.6-98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5% - 70.5%) at baseline to 17.2% (95% CI, 0.7% - 33.7%) after neoadjuvant therapy (P<0.05). The most common grade 3 adverse events were diarrhea (4 [33%]) and decreased neutrophil count (3 [25%]). No grade 4 events or treatment-related deaths occurred. Conclusions: This four-drug neoadjuvant regimen shows promising pathological response in patients with TPBC, with an acceptable safety profile. The results warranted further validation. Clinical trial information: NCT05228951 .