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Abstract As one of the most common tumors in women, the pathogenesis and tumor heterogeneity of breast cancer have long been the focal point of research, with the emergence of tumor metastasis and drug resistance posing persistent clinical challenges. The emergence of single-cell sequencing (SCS) technology has introduced novel approaches for gaining comprehensive insights into the biological behavior of malignant tumors. SCS is a high-throughput technology that has rapidly developed in the past decade, providing high-throughput molecular insights at the individual cell level. Furthermore, the advent of multitemporal point sampling and spatial omics also greatly enhances our understanding of cellular dynamics at both temporal and spatial levels. The paper provides a comprehensive overview of the historical development of SCS, and highlights the most recent advancements in utilizing SCS and spatial omics for breast cancer research. The findings from these studies will serve as valuable references for future advancements in basic research, clinical diagnosis, and treatment of breast cancer.

BackgroundKlebsiella pneumoniae is an opportunistic pathogen causing nosocomial infections, classified into carbapenem-sensitive and carbapenem-resistant strains. Understanding the virulence factors and antibiotic resistance of these strains is essential for effective clinical management.ObjectiveThis study compared the virulence genes and antibiotic resistance profiles of 50 CSKP and 50 CRKP strains, examining their expression under antibiotic pressure and the mechanisms contributing to their pathogenicity.MethodsVirulence genes (rmpA, rmpA2, iucA, iutA, Peg-344, ybts, iroB) were detected in both strains using polymerase chain reaction (PCR). Antibiotic susceptibility testing established minimum inhibitory concentrations (MICs) for key antibiotics. Gene expression analysis was performed with quantitative reverse transcription PCR (qRT-PCR) after 10 days of antibiotic exposure.ResultsCSKP strains exhibited significantly higher positivity rates for virulence genes compared to CRKP strains. CRKP strains predominantly expressed resistance genes KPC, SHV, and CTX-M3, whereas no resistance genes were found in CSKP. Antibiotic susceptibility tests showed increased MICs, particularly for ciprofloxacin and imipenem, following antibiotic induction. CSKP demonstrated elevated expression of rmpA and rmpA2, while CRKP showed increased expression of SHV, and KPC after antibiotic exposure.ConclusionThis study highlights the intricate relationship between virulence and resistance in Klebsiella pneumoniae. CSKP strains show strong virulence factor expression, while CRKP strains adapt to antibiotic pressure through altered gene expression patterns. These findings underscore the urgent need for continuous surveillance and innovative therapeutic strategies to combat multidrug-resistant Klebsiella pneumoniae infections.

Abstract Liquid–liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches.

Abstract Recently, mesoporous nanomaterials with widespread applications have attracted great interest in the field of drug delivery due to their unique structure and good physiochemical properties. As a biomimetic nanomaterial, mesoporous polydopamine (MPDA) possesses both a superior nature and good compatibility, endowing it with good clinical transformation prospects compared with other inorganic mesoporous nanocarriers. However, the subacute toxicity and underlying mechanisms of biomimetic mesoporous polydopamine nanoparticles remain uncertain. Herein, we prepared MPDAs by a soft template method and evaluated their primary physiochemical properties and metabolite toxicity, as well as potential mechanisms. The results demonstrated that MPDA injection at low (3.61 mg/kg) and medium doses (10.87 mg/kg) did not significantly change the body weight, organ index or routine blood parameters. In contrast, high-dose MPDA injection (78.57 mg/kg) is associated with disturbances in the gut microbiota, activation of inflammatory pathways through the abnormal metabolism of bile acids and unsaturated fatty acids, and potential oxidative stress injury. In sum, the MPDA dose applied should be controlled during the treatment. This study first provides a systematic evaluation of metabolite toxicity and related mechanisms for MPDA-based nanoparticles, filling the gap between their research and clinical transformation as a drug delivery nanoplatform.

Background: With our growing insight into the molecular heterogeneity and biological characteristics of breast cancer, individualized treatment is the future of cancer treatment. In this prospective Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study – neoadjuvant therapy (FASCINATE-N) trial, we classify breast cancer patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. Methods and design: The FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. After enrollment, patients will first be divided into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)−, HER2+, and HR−/HER2−. The HR+/HER2− patients are further stratified using fusion and clustering of similarity network fusion (SNF) algorithm into four subtypes; HER2+ patients are divided into HR+/HER2+ and HR−/HER2+ subtypes; and HR−/HER2− patients are stratified using the Fudan University Shanghai Cancer Center classification. For the assignment of drugs to patients, Bayesian methods of adaptive randomization will be used. The primary endpoint is pathological complete response rate; secondary endpoints include 3-year invasive disease-free survival, overall response rate, and toxicities according to common terminology criteria for adverse events (CTCAE) scale version 4.0 and the ratio of patients with complete cell cycle arrest (Ki67 < 2.7%) in HR+/HER2+ breast cancer. Discussion: The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets, and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients. Trial registration: ClinicalTrials.gov identifier: NCT05582499 ( https://classic.clinicaltrials.gov/ct2/show/NCT05582499 ).

Abstract Background The Organization for Economic Cooperation and Development emphasizes the importance of complex problem-solving (CPS) skills in the 21st century. CPS skills have been linked to academic performance, career development, and job competency training. Reflective learning, which includes journal writing, peer reflection, selfreflection, and group discussion, has been explored to improve critical thinking and problem-solving abilities. The development of various thinking modes and abilities, such as algorithmic thinking, creativity, and empathic concern, all affect problem-solving skills. However, there is a lack of an overall theory to relate variables to each other, which means that different theories need to be integrated to focus on how CPS skills can be effectively trained and improved. Methods Data from 136 medical students were analyzed using partial least square structural equation modeling (PLSSEM) and fuzzy set qualitative comparative analysis (fsQCA). A hypothesized model examining the associations between the CPS skills and influence factors was constructed. Results The evaluation of the structural model showed that some variables had significant influences on CPS skills, while others did not. After deleting the insignificant pathways, a structural model was built, which showed that mediating effects of empathic concern and critical thinking were observed, while personal distress only had a direct effect on CPS skills. The results of necessity showed that only cooperativity and creativity are necessary conditions for critical thinking. The fsQCA analysis provided clues for each different pathway to the result, with all consistency values being higher than 0.8, and most coverage values being between 0.240 and 0.839. The fsQCA confirmed the validity of the model and provided configurations that enhanced the CPS skills. Conclusions This study provides evidence that reflective learning based on multi-dimensional empathy theory and 21 stcentury skills theory can improve CPS skills in medical students. These results have practical implications for learning and suggest that educators should consider incorporating reflective learning strategies that focus on empathy and 21 stcentury skills to enhance CPS skills in their curricula.

Abstract Antibody‐drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer. Currently, there are two ADCs approved for the treatment of human epidermal growth factor receptor 2‐positive breast cancer, one for triple‐negative breast cancer, and multiple investigational ADCs in clinical trials. However, drug resistance has been noticed in clinical use, especially in trastuzumab emtansine. Here, the mechanisms of ADC resistance are summarized into four categories: antibody‐mediated resistance, impaired drug trafficking, disrupted lysosomal function, and payload‐related resistance. To overcome or prevent resistance to ADCs, innovative development strategies and combination therapy options are being investigated. Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.

To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor–negative (HR–) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase–relevant (TKR), and mesenchymal stem–like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR– breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab–drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.

Copy number alterations are pivotal genetic events in triple-negative breast cancer. Here the authors show the amplification of ENSA at the 1q21.3 region promotes the progression of TNBC via up-regulation of cholesterol biosynthesis.

Abstract Background Although long noncoding RNA HLA complex group 18 (lncRNA HCG18) has been suggested to regulate cell growth in several tumours, the function of HCG18 in epithelial ovarian cancer (EOC) and its mechanism are still unclear. Methods shRNAs were applied to reduce HCG18 and related genes. For overexpression of miRNA, a miRNA mimic was transfected into cells. Quantitative real-time PCR (qRT–PCR) was used to detect levels of HCG18, miR-29a/b, and mRNAs. MTT, colony formation, wound healing and Transwell assays were used to evaluate cell proliferation, migration and invasion, respectively. A luciferase reporter assay was utilized to evaluate NF-κB activity and the binding of miRNAs with HCG18 or TRAF4/5. BALB nude mice injected with cells stably expressing shHCG18 or shNC were used for in vivo modelling. Subcutaneous tumour growth was monitored in nude mice, and immunohistochemistry (IHC) was used to determine expression of the proliferation marker Ki67. Results Abnormal expression of HCG18 and miR-29a/b was observed in EOC tissues. Knockdown of HCG18 using shRNA inhibited proliferation, migration, EMT and the proinflammatory pathway in EOC cells. miR-29a/b mimics and TRAF4/5 knockdown exhibited effects similar to HCG18 knockdown. Further experiments suggested that HCG18 directly targets miR-29a/b and upregulates TRAF4/5 expression, which are inhibited by targeting miR-29a/b. Moreover, overexpression of TRAF4/5 antagonized the inhibitory effect of HCG18 knockdown, suggesting that they are involved in HCG18-mediated oncogenic effects. Silencing HCG18 reduced tumour size and levels of Ki67 and TRAF4/5 while increasing miR-29a/b levels in vivo. Conclusions Taken together, our data revealed an oncogenic signalling pathway mediated by HCG18 in ovarian cell lines, which functions as a ceRNA of miR-29a/b and thus derepresses expression levels of TRAF4/5, facilitating NF-κB pathway-mediated promotion of EOC cell proliferation and migration.

Abstract Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA‐seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.

Abstract Hormone receptor testing mainly serves the purpose of guiding treatment choices for breast cancer patients. Patients with estrogen receptor (ER)‐positive breast cancers show significant response to endocrine therapy. However, the methods to define ER status and eligibility for treatment remain controversial. Despite recent guidelines considering staining ≥1% of tumor nuclei by immunohistology as ER‐positive, it has raised concerns on the benefit of endocrine therapy for tumors with ER 1%‐10% expression, termed “ER‐low positive”. This subgroup accounts for 3% to 9% of all patients and is likely to have unique molecular features, and therefore distinct therapeutic response to endocrine therapy compared with ER‐high positive tumors. The latest guidelines did not provide detailed descriptions for those patients, resulting in inconsistent treatment strategies. Consequently, we aimed to resolve this dilemma comprehensively. This review discusses molecular traits and recent ER‐low positive breast cancer innovations, highlighting molecular‐targeted treatment rather than traditional unified endocrine therapy for future basic and clinical research.

Effects of dry grinding, wet grinding and wet grinding after fermentation on the physicochemical properties of mung bean were studied. The results indicated that the composition of wet ground mung bean after fermented flour (FWMB) changed the most, protein content decreased from 23.68% to 21.02%, the starch content decreased from 56.97% to 55.11%, and the amylose content increased from 14.48% to 19.72%.The analysis of pasting and hydration properties showed that wet ground mung bean flour (WMB) and FWMB had higher peak viscosity, minimum viscosity, attenuation value and final viscosity than dry ground mung bean flour (DMB), and water absorption index and swelling power were increased, but water solubility index was decreased. Particle size analysis found the average particle sizes of DMB, WMB and FWMB were 120.13, 105.21, 92.94 μm, respectively; scanning electron microscope observation showed that the ultrastructure of WMB and FWMB was relatively intact, while DMB had the greatest damage; damaged starch content confirmed WMB, FWMB and DMB were 9.92%, 5.99% and 6.07%, respectively. It indicated that wet grinding and wet grinding after fermentation can improve the pasting viscosity and hydration properties by reducing the damaged starch content and average particle size of mung bean

The novel coronavirus (COVID-19 or 2019-nCoV) is a respiratory virus that can exist in the mouth and saliva of patients and spreads through aerosol dispersion. Therefore, stomatological hospitals and departments have become high-infection-risk environments. Accordingly, oral disinfectants that can effectively inactivate the virus have become a highly active area of research. Hexadecyl pyridinium chloride, povidone-iodine, and other common oral disinfectants are the natural primary choices for stomatological hospitals. Therefore, this study investigated the inhibitory effect of hexadecyl pyridinium chloride on SARS-CoV-2 in vitro. Vero cells infected with SARS-CoV-2 were used to determine the disinfection effect; the CCK-8 method was used to determine cytotoxicity, and viral load was determined by real-time PCR. The results showed that hexadecyl pyridinium chloride has no obvious cytotoxic effect on Vero cells in the concentration range 0.0125–0.05 mg/mL. The in vitro experiments showed that hexadecyl pyridinium chloride significantly inhibits the virus at concentrations of 0.1 mg/mL or above at 2 min of action. Thus, the results provide experimental support for the use of hexadecyl pyridinium chloride in stomatological hospitals.

Objective To investigate the effects and mechanisms of ghrelin on plaque stability and endothelial funtion in ApoE-/- mice after myocardial infarction. Methods The ApoE-/- mice were divided into control group, double model group and ghrelin-treated group. All ApoE-/- mice were fed with a high-fat diet for 12 weeks to induce atherosclerotic vulnerable plaques. The atherosclerotic vulnerable plaque model was the control group.At the 8th week of this study, the double model group and the ghrelin group were subjected to acute myocardial infarction model(AMI). After modeling of AMI, the ghrelin group was administered with ghrelin (100 μg/kg,bid) until the end of the 12th week. Body weight and blood lipids were detected. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were recorded by echocardiography; NO level was measured by Griess method; the percentage of aortic sinus plaque area was evaluated by HE microscopy. The plaque content of lipid and collagen was observed by Oil Red 0 and Sirius red staining; The distribution of macrophages and smooth muscle cells in plaques were determined by RAM-11 and α-actin immunohistochemical staining and microscopy; And then the vulnerability index was calculated; Myocardial infarct size was measured by Masson staining and microscopy; The vascular endothelial growth factor (VEGF) was detected by quantitative real-time PCR and Western blot. Results Compared with the control group, the level of LVEF and LVFS and NO2-/NO3- concentration in the double model group were all decreased(P＜0.05), and the expression of VEGF was increased(P＜0.05), significantly. However, the ghrelin group had significantly reduced plasma TG level and also the myocardial infarct size(P＜0.05), LVEF, LVFS, NO2-/NO3- level, the expression of VEGF, and the plaque content of collagen and smooth muscle cells were all increased(P＜0.05), and reduced the percentage of aortic sinus plaque area, the distribution of lipid and macrophages(P＜0.05), and the vulnerability index as compared with the double model group(P＜0.05). Conclusions 1)Ghrelin may improve the endothelial function and improve heart function in ApoE-/- mice after myocardial infarction. 2)Ghrelin may stabilize vulnerable plaque and reduce the occurrence of reinfarction.

BackgroundThe optimal (neo)adjuvant regimen for human epidermal growth factor receptor-2 (HER2)-positive breast cancer regarding survival outcomes remains unclear.MethodsWe searched Web of Science, PubMed, and the Cochrane Central Register of Controlled Trials systematically to find out randomized controlled studies, up to January 2022, that compared different anti-HER2 regimens in the (neo)adjuvant setting. The primary endpoint was disease-free survival (DFS). We used a Bayesian statistical model to combine direct and indirect comparisons and used odds ratios (ORs) to pool effect sizes and performed the surface under the cumulative ranking area (SUCRA) curves to estimate the ranking probabilities of various regimens. For survival outcomes, we performed two parallel analyses, one based on data from both neoadjuvant and adjuvant studies and the other specific to adjuvant studies. All statistics were two-sided.ResultsFifteen studies were finally enrolled. Regarding DFS, the overall analysis indicated that the top two regimens for HER2-positive breast cancer were chemotherapy plus trastuzumab with lapatinib, and chemotherapy plus trastuzumab with pertuzumab (SUCAR of 81% and 79%, respectively), with the OR of 0.99 [95% confidence interval (CI), 0.59 to 1.54]; the parallel analysis specific to adjuvant trials indicated that the top two regimens were chemotherapy plus trastuzumab with sequential neratinib, and chemotherapy plus trastuzumab with pertuzumab (SUCRA of 80% and 76%, respectively), with the OR of 1.04 (95% CI, 0.63 to 1.73). The dual-target therapy that combines trastuzumab and pertuzumab showed the highest risk of inducing cardiac events, with an SUCRA of 92%.ConclusionsChemotherapy plus trastuzumab and pertuzumab might be the optimal regimen for HER2-positive breast cancer in improving the survival rate. However, the cardiotoxicity of this dual-target therapy should be taken care of.

In the contemporary digitalization landscape and technological advancement, the auction industry undergoes a metamorphosis, assuming a pivotal role as a transactional paradigm. Functioning as a mechanism for pricing commodities or services, the procedural intricacies and efficiency of auctions directly influence market dynamics and participant engagement. Harnessing the advancing capabilities of artificial intelligence (AI) technology, the auction sector proactively integrates AI methodologies to augment efficacy and enrich user interactions. This study delves into the intricacies of the price prediction challenge within the auction domain, introducing a sophisticated RL-GRU framework for price interval analysis. The framework commences by adeptly conducting quantitative feature extraction of commodities through GRU, subsequently orchestrating dynamic interactions within the model's environment via reinforcement learning techniques. Ultimately, it accomplishes the task of interval division and recognition of auction commodity prices through a discerning classification module. Demonstrating precision exceeding 90% across publicly available and internally curated datasets within five intervals and exhibiting superior performance within eight intervals, this framework contributes valuable technical insights for future endeavours in auction price interval prediction challenges. [ABSTRACT FROM AUTHOR]

Chinese breast cancer patients have not been well represented in clinical sequencing studies. Here the authors analyse the mutational landscape of 1,134 Chinese breast cancer patients, finding actionable targets and a higher prevalence of p53 and Hippo pathway mutations compared to Western cohorts.

Breast cancer has become the most commonly diagnosed cancer globally. The relapse and metastasis of breast cancer remain a great challenge despite advances in chemotherapy, endocrine therapy, and HER2 targeted therapy in the past decades. Innovative therapeutic strategies are still critically in need. Cancer vaccine is an attractive option as it aims to induce a durable immunologic response to eradicate tumor cells. Different types of breast cancer vaccines have been evaluated in clinical trials, but none has led to significant benefits. Despite the disappointing results at present, new promise from the latest study indicates the possibility of applying vaccines in combination with anti-HER2 monoclonal antibodies or immune checkpoint blockade. This review summarizes the principles and mechanisms underlying breast cancer vaccines, recapitulates the type and administration routes of vaccine, reviews the current results of relevant clinical trials, and addresses the potential reasons for the setbacks and future directions to explore.

Background: The microenvironment of triple-negative breast cancer (TNBC) can be divided into three clusters based on bioinformatics-based immunogenomic analysis: the “immune-desert” cluster, the “innate immune-inactivated” cluster, and the “immune-inflamed” cluster. The immune-inflamed cluster is considered as “hot tumor” while the other two are considered as “cold tumor”.Methods: To investigate the prognostic effect of microenvironment phenotypes on TNBC, we compared relapse-free survival (RFS) of different phenotypes in 100 patients with RNA sequencing-based expression data from the PATTERN trial (NCT01216111, published in JAMA Oncol 2020), which indicated a superior efficacy of adjuvant paclitaxel-plus-carboplatin regimen compared to the regimen of cyclophosphamide/epirubicin/fluorouracil followed by docetaxel for TNBC. We also analyzed the efficacy of the two regimens for different immune phenotypes to explore potential treatment strategies.Results: No significant difference in RFS was observed between the “hot tumor” and the “cold tumor” (hazard ratio [HR] = 0.68, 95% confidence interval [CI] 0.28–1.66, P = 0.40). However, the “hot tumor” subtype was associated with significantly longer RFS in node-positive patients (HR = 0.27, 95%CI 0.07–0.97, P = 0.03). Consistently, a similar trend to improved RFS of the “hot tumor” phenotype was detected in patients with stage pT2-3 tumors (HR = 0.29, 95%CI 0.06–1.30, P = 0.08). Furthermore, no significant difference in RFS between the two treatment arms was observed in patients with “hot tumor” (HR = 0.39, 95% CI 0.08–2.01, P = 0.24) or “cold tumor” (HR = 1.05, 95% CI 0.39–2.82, P = 0.92).Conclusion: The microenvironment phenotype in TNBC might have prognostic significance to patients with a high risk of recurrence. The association of the microenvironment phenotypes with the efficacy of adjuvant chemotherapy for TNBC remains to be further studied.

BackgroundLoco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis.MethodsTo delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype.ResultsWith a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery.ConclusionsLRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.

Background: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. Findings: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. Interpretation: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. Funding: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).