Advances in regional nodal management of early-stage breast cancer

With the continuous improvement of systemic treatment, reasonable local regional control of early-stage breast cancer can be translated into survival benefits. The optimization of regional nodal management in patients with limited sentinel lymph node(SLN) metastasis needs to be weighed by surgical complications, regional recurrence risk, and lymph node status, as well as other escalating treatment(systemic/radiotherapy) that may result from deescalating surgery. With the effective support and supplementation of systemic therapy and radiotherapy, the management of axillary surgery is developing in a de-escalating trend. The widespread application of neoadjuvant therapy has contributed to optimizing the management of patients with clinically node-negative/imaging nodepositive disease. In clinical practice, it is necessary to consider the residual tumor burden of regional lymph nodes when formulating the optimal irradiation fields in patients with limited positive SLN without axillary lymph node dissection. The combined application of genomic tests and American College of Surgeons Oncology Group Z0011/AMAROS criteria could provide patients with a better strategy of dual de-escalation treatment, which includes the de-escalation of both axillary surgery and systemic treatment. In the era of sentinel lymph node biopsy(SLNB), the regional nodal management of breast cancer should adhere to the concept of “updating ideas, making bold assumptions, and carefully seeking proof”, make full use of the benefits of systemic therapy and radiotherapy to reduce the scope of surgery and complications, and expand the “net benefit” of efficacy and quality of life. This review discusses the optimization of regional nodal management in the era of SLNB, in order to provide reference information for clinicians.

Provision of Fertility Preservation for Young Women with Early-Stage Breast Cancer

Breast cancer is the most common cancer in women worldwide, constituting 25% of all cancer diagnoses. Even though it is only affecting 4% - 6% of women under the age of 40, it remains the most common malignancy among younger patients. Advancement in the treatment and earlier detection gives excellent 5 years of survival. However, the standard treatment that comprises surgical-chemo radiation therapy or hormonal treatment often results in an increased incidence of treatment-induced infertility. Therefore, adding fertility preservation to primary cancer treatment may offer the best opportunity for future fertility. However, despite advancements in Assisted Reproductive Technology (ART), the uptake of fertility services in this group remains low. In this review, we highlighted the effect of all breast cancer treatments on women’s fertility, the effectiveness and safety of ART in breast cancer patients as well as the safety of pregnancy in breast cancer survivors. Our aim is to improve awareness of fertility preservation for breast cancer to ensure all women diagnosed with breast cancer have multidisciplinary approaches with early referral to fertility specialists to discuss regarding potential risks and benefits of fertility preservation to improve the uptake of fertility preservation among this group of patients.

Assessing the Clinical Efficacy and Effectiveness of Sentinel Lymph Node Biopsy Combined with Breast-Conserving Surgery for Early-Stage Breast Cancer

Objective:To analyze the impact of sentinel lymph node biopsy(SLNB)combined with breast-conserving surgery in the clinical treatment of early-stage breast cancer.Methods:80 patients with early-stage breast cancer admitted to the Second Department of Breast Surgery at Dezhou Second People’s Hospital from September 2020 to September 2022 were selected and randomly divided into a control group and an observation group using the random number table method,with 40 cases in each group.The control group underwent a modified radical mastectomy,while the observation group underwent SLNB combined with breast-conserving surgery.The surgical efficacy and prognosis between the two groups were compared.Results:The observation group exhibited shorter operation,hospitalization,and extubation times,as well as less intraoperative blood loss and drainage volume,all of which were significantly better than those in the control group(P<0.05).Additionally,the observation group demonstrated a higher rate of excellent breast cosmetology and quality of life,with lower complication incidence,significantly outperforming the control group(P<0.05).There was no statistical difference in the metastasis rate and recurrence rate between the two groups(P>0.05).Conclusion:The combination of SLNB and breast-conserving surgery proves highly effective for patients with early-stage breast cancer,presenting fewer complications and enhancing both breast cosmetic outcomes and quality of life.

Treatment patterns for adjuvant docetaxel-based chemotherapy in early-stage breast cancer in China：A pooled retrospective analysis of four observational studies

Objective：Adjuvant docetaxel-based chemotherapy is frequently used for operable early breast cancer（EBC）.This study investigated patterns of use of docetaxel（T）in real-life clinical practice in China.Methods：This was a retrospective pooled analysis of the Asia-Pacific Breast Initiatives（APBI）Ⅰ（2006–2008）and Ⅱ（2009–2011）registries,and two Chinese observational studies;BC STATE（2011–2014）and BC Local Registry（2007–2010）.Female Chinese adults（≥18 years）with operable breast cancer treated with docetaxel-based adjuvant chemotherapy were included in the analysis.Patients with metastatic disease were excluded.The primary endpoint was assessment of treatment patterns and patient profiles.A logistic regression analysis was conducted to identify factors associated with choice of adjuvant chemotherapy regimen.Results：Data from 3,020 patients were included.The most frequently used adjuvant regimen was docetaxel/anthracycline combination[n=1,421（47.1%）;of whom 52.0%received T/epirubicin（E）/cyclophosphamide（C）],followed by docetaxel/other[n=705（23.3%）;of whom 72.8%received TC],docetaxel/anthracycline sequential[n=447（14.8%）;of whom 40.9%and 39.6%received 5-Fu/EC-T and EC-T,respectively],and＂other＂[n=447（14.8%）;of whom 91.5%received T].A significant association was found between adjuvant therapy with docetaxel/anthracycline combination and patient weight,menopausal status and estrogen receptor status.Conclusions：Real-world data revealed that docetaxel/anthracycline combination is the most commonly used category of docetaxel-based adjuvant therapy for patients with operable breast cancer in China;of which TEC is the most frequently used regimen.

Clinicopathological analysis of early-stage breast cancer patients that meet indications for BRCA 1/2 genetic testing

Objective:To investigate the clinicopathological characteristics and prognostic factors of early-stage breast cancer patients with indications for breast cancer susceptibility genes 1/2(BRCA1/2)genetic testing in China.Methods:Based on the indication criteria for BRCA genetic testing specified in the National Comprehensive Cancer Network(NCCN)clinical practice guidelines in oncology,genetic/familial high-risk assessment:Breast and ovarian(Version 2.2019),a retrospective analysis was performed on patients with early-stage invasive breast cancer treated at Breast Disease Center,Peking University First Hospital between January 2008 and December 2016.Clinicopathological characteristics of all patients were analyzed,and prognoses were calculated using the KaplanMeier method and a Cox proportionate hazards model.Results:A total of 906 early-stage breast cancer patients who had indications for BRCA genetic testing and had complete clinicopathological data and follow-up information were included in the study group,accounting for34.7%of all breast cancer patients treated in Breast Disease Center,Peking University First Hospital during the study period.Compared with breast cancer patients without indications for BRCA genetic testing,the overall survival(OS)and disease-free survival(DFS)of patients with indications were not significantly different.In the study group,patients with premenopausal status,high T stage,lymph node positive,estrogen receptor(ER)negative,Ki-67>20%and presence of a vascular tumor thrombus had worse prognosis.There were more family histories of gastrointestinal cancer in patients with related indications than in patients without such indications.Conclusions:Single-center data showed that more than 30%of patients with early-stage breast cancer had indications for BRCA genetic testing.There was no prognostic difference in patients with or without indications for BRCA genetic testing.Premenopausal status,high T stage,lymph node positive,ER negative,Ki-67>20%,and presence of a vascular tumor thrombus were associated with poor prognosis.

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2(HER2)-positive early-stage breast cancer: A real-world retrospective study in Chinese patients

Objective: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2(HER2)-positive breast cancer in a real-world setting.Methods: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival(DFS) and overall survival(OS). Hazard ratios(HR) and 95% confidence intervals(95% CI) were calculated using the Cox regression model.Results: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group(DFS:HR=0.50, 95% CI, 0.37-0.68;P<0.001;OS: HR=0.53, 95% CI, 0.34-0.81;P=0.004) after adjusting for covariates.In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence,and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events(incidence ≥1%) were more common in patients receiving trastuzumab(54.44% vs.15.73%).Conclusions: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.

Presence of circulating tumor cells is associated with metabolic-related variables in postoperative patients with early-stage breast cancer

Objective：Although circulating tumor cells（CTCs）have been well-established as promising prognostic biomarkers in both early breast cancer and metastatic settings,little is known regarding the prognostic relevance of CTCs in the long-term postoperative monitoring of patients with non-metastatic breast cancer（non-MBC）.In this study,we investigated the associations of CTCs with clinicopathological features and metabolic-related variables,such as obesity and hyperglycemia.Methods：In this retrospective study,we recruited 264 patients with postoperative stage Ⅰ–Ⅲ breast cancer at Guangdong General Hospital from January 2009 to December 2015.The prevalence and number of CTCs were assessed using the Cell Search System at a median time of 19.0 months[interquartile range（IQR）,7.8–33.0]after surgery.The CTC assay results were correlated with the clinicopathological features and metabolic-related variables.A multivariate logistic regression analysis was performed to further determine the independent predictors of CTCs.Results：CTCs were detected in 10.6%of all patients.The positive rate of CTCs in patients with infiltrating ductal carcinoma was lower than that in patients with other pathological types（9.0%vs.28.6%,P=0.020）.More importantly,the presence of CTCs was correlated with blood glucose level（P=0.015）and high-density lipoprotein level（P=0.030）.The multivariate logistic regression analysis showed that the pathological type[odds ratio（OR）：1.757,95%CI：1.021–3.023;P=0.042]and blood glucose level（OR：1.218,95%CI：1.014–1.465;P=0.035）were independent predictors of the presence of CTCs.Conclusions：This study revealed potential associations between CTCs and metabolic-related factors in Chinese patients with non-MBC and supports the hypothesis that metabolic dysfunction in breast cancer patients might influence the biological activity of metastatic breast cancer,leading to a higher prevalence of CTCs.

Detection of the <i>PIK3CA</i>Mutation in Circulating Tumor DNA as a Possible Predictive Indicator for Poor Prognosis of Early-Stage Breast Cancer

Objectives: Circulating tumor DNA (ctDNA) is shown to provide the real-time genomic information of metastatic breast cancer. This study elucidates the clinico-pathological significance of ctDNA in early-stage breast cancer using the PIK3CA mutation as an indicator. Materials and Methods: Twenty-seven primary breast cancers without metastasis were surgically resected and pathologically diagnosed at the University of Tokyo Hospital, Japan. Genomic DNA of primary tumor was extracted from formalin-fixed and paraffin-embedded specimens. ctDNA was extracted from fresh-frozen plasma from patients. The PIK3CA mutations at E542K, E545K and H1047R were examined by Sanger sequencing or droplet digital PCR in 27 tumors and pre- and post-surgery plasma. Results: The PIK3CA mutations were detected in 13 (48%) of 27 primary tumors. These mutations did not significantly correlate with specific clinico-pathological characteristics of tumors. When ctDNA was examined, 4 (33%) of 12 cases carrying the mutated PIK3CA showed the identical mutation in pre-surgery plasma and 2 (50%) of them showed the identical mutations in post-surgery plasma. Interestingly, in these 2 cases in pathological stages IIIA and IA, fractional abundance of the mutated PIK3CA alleles to the total alleles in pre-surgery ctDNA was around 1% or more and was higher than that of the other two cases without PIK3CA mutations in post-surgery ctDNA. Conclusions: The PIK3CA mutation in ctDNA is detectable even in a subset of early-stage breast cancer. Furthermore, fractional abundance of the mutated PIK3CA in pre-surgery ctDNA could provide a possible predictive indicator for tumor burden and for choosing the appropriate adjuvant treatment of breast cancer.

Corrigendum to Clinicopathological analysis of early-stage breast cancer patients that meet indications for BRCA1/2 genetic testing

Xiang H,Xin L,Liu Q,Zhang H,Zhang S,Ye J,Cheng Y,Li T,Liu Y,Xu L.Clinicopathological analysis of early-stage breast cancer patients that meet indications for 5/?C47/2 genetic testing.ChinJ Cancer Res 2020;32(2):163-174.doi:10.21147/j.issn.1000-9604.2020.02.04.In this article,the funding source was not declared.The acknowledgements have been updated as follows.

VAB and MRI Following Percutaneous Ultra-Sound Guided Cryoablation for Primary Early-Stage Breast Cancer: A Pilot Study in Japan

Objective: This study aimed to evaluate the feasibility, safety, and cosmetic outcomes of percutaneous cryoablation (PCA) of breast intraductal carcinoma (IDC) lesions, as well as post-cryoablation magnetic resonance imaging (MRI) as a follow-up tool for detection of residual malignancies and local recurrences. Methods: Eight female patients underwent percutaneous ultrasound-guided cryoablation of breast IDC tumors under local anesthesia without subsequent resection. All patients received radiation- and endocrine therapies (RT, ET). The patients were followed using vacuum-assisted biopsy (VAB), mammography (MG), magnetic resonance imaging (MRI), and Moiré Topography for cosmetic outcomes. VAB was performed 6 months following cryoablation treatment for cases 1 and 2 (after starting radiation- and endocrine-therapies) or one month after PCA (cases 3, 4, 5, 6 and 7), prior to RT and ET. One patient declined VAB. Results: Mean age of the patients was 61.9 years, SD 7.7, ages range 53 - 72 years. Mean tumor size was 10.3 mm, SD 2.74, ranged 6.8 - 14.5 mm, median follow-up time was 28 months (range 13 - 34 months). No residual or recurrent malignancies were detected. One minor adverse event was observed: A skin redness in the ablated area;MRI at one-month post-cryotherapy showed various degrees of thermal burns in all patients in the pectoralis major muscle, which were not symptomatic and were resolved by 6 months following PCA. Decrease of fat necrosis areas in the vicinity of ablated ex-tumor was traced with MRI (mean size 54.9 mm, mean decrease after 2 years was 58%) and validated with VAB. Conclusions: Percutaneous cryoablation of early-stage low-risk breast cancer tumors smaller than 15 mm potentially presents a potential substitute for lumpectomy, offering encouraging short- to mid-term oncology results with good cosmesis outcomes. Patients would be able to benefit from local anesthesia in an outpatient setting and a shorter recovery period.

Association between high body mass index and prognosis of patients with early-stage breast cancer: A systematic review and meta-analysis

Background:A high body mass index(BMI)can indicate overweight or obesity and is a crucial risk factor for breast cancer survivors.However,the association between high BMI and prognosis in early-stage breast cancer(EBC)remains unclear.We aimed to assess the effects of high BMI on the prognosis of patients with EBC.Methods:The PubMed,Embase,and Cochrane Library databases and proceedings of major oncological conferences related to the effects of BMI on the prognosis of breast cancer were searched up to November 2021.Fixedand random-effects models were used for meta-analyses.Pooled hazard ratios(HRs)and 95%confidence intervals(CIs)for disease-free survival(DFS)and overall survival(OS)were extracted from the included literature.Results:Twenty retrospective cohort studies with 33,836 patients with EBC were included.Overweight patients had worse DFS(HR:1.16,95%CI:1.05-1.27,P=0.002)and OS(HR:1.20;95%CI:1.09-1.33,P<0.001).Obesity also had adverse effects on DFS(HR:1.17,95%CI:1.07-1.29,P=0.001)and OS(HR:1.30,95%CI:1.17-1.45,P<0.001).Likewise,patients with high BMI had worse DFS(HR:1.16,95%CI:1.08-1.26,P<0.001)and OS(HR:1.25,95%CI:1.14-1.39,P<0.001).In subgroup analyses,overweight had adverse effects on DFS(HR:1.11,95%CI:1.04-1.18,P=0.001)and OS(HR:1.18,95%CI:1.11-1.26,P<0.001)in multivariate analyses,whereas the relationship that overweight had negative effects on DFS(HR:1.21,95%CI:0.99-1.48,P=0.058)and OS(HR:1.39,95%CI:0.92-2.10,P=0.123)was not statistically significant in univariate analysis.By contrast,obesity had adverse effects on DFS(HR:1.21,95%CI:1.06-1.38,P=0.004 and HR:1.14,95%CI:1.08-1.22,P<0.001)and OS(HR:1.33,95%CI:1.15-1.54,P<0.001 and HR:1.23,95%CI:1.15-1.31,P<0.001)in univariate and multivariate analyses,respectively.Conclusions:Compared with normal weight,increased body weight(overweight,obesity,and high BMI)led to worse DFS and OS in patients with EBC.Once validated,these results should be considered in the development of prevention programs.

A multicenter study of the clinicopathological characteristics and a risk prediction model of early-stage breast cancer with hormone receptor-positive/human epidermal growth factor receptor 2-low expression

Background:In light of the significant clinical benefits of antibody-drug conjugates in clinical trials,the human epidermal growth factor receptor 2(HER2)-low category in breast cancers has gained increasing attention.Therefore,we studied the clinicopathological characteristics of Chinese patients with hormone receptor(HR)-positive/HER2-low early-stage breast cancer and developed a recurrence risk prediction model.Methods:Female patients with HR-positive/HER2-low early-stage breast cancer treated in 29 hospitals of the Chinese Society of Breast Surgery(CSBrS)from Jan 2015 to Dec 2016 were enrolled.Their clinicopathological data and prognostic information were collected,and machine learning methods were used to analyze the prognostic factors.Results:In total,25,096 patients were diagnosed with breast cancer in 29 hospitals of CSBrS from Jan 2015 to Dec 2016,and clinicopathological data for 6486 patients with HER2-low early-stage breast cancer were collected.Among them,5629 patients(86.79%)were HR-positive.The median follow-up time was 57 months(4,76 months);the 5-year disease-free survival(DFS)rate was 92.7%,and the 5-year overall survival(OS)rate was 97.7%.In total,412 cases(7.31%)of metastasis were observed,and 124(2.20%)patients died.Multivariate Cox regression analysis revealed that T stage,N stage,lymphovascular thrombosis,Ki-67 index,and prognostic stage were associated with recurrence and metastasis(P<0.05).A recurrence risk prediction model was established using the random forest method and exhibited a sensitivity of 81.1%,specificity of 71.7%,positive predictive value of 74.1%,and negative predictive value of 79.2%.Conclusion:Most of patients with HER2-low early-stage breast cancer were HR-positive,and patients had favorable outcome;tumor N stage,lymphovascular thrombosis,Ki-67 index,and tumor prognostic stage were prognostic factors.The HR-positive/HER2-low early-stage breast cancer recurrence prediction model established based on the random forest method has a good reference value for predicting 5-year recurrence events.Registritation:ChiCTR.org.cn,ChiCTR2100046766.

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase Ⅱ single-arm study

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Methanolic extract of Ephedra alata inhibits breast cancer cells in vitro and in vivo

Objective:To determine the anticancer potential of the methanolic extract from Ephedra alata against breast cancer both in vitro and in vivo.Methods:The effects of the methanolic extract of Ephedra alata on the viability,migration as well as apoptosis of breast cancer 4T1 cells were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,Transwell assay,and annexin V-FITC staining assay,respectively.Histological examination was also carried out.Moreover,a murine breast cancer model was established to evaluate the inhibitory effect of the extract.Biochemical parameters including hepatic and non-hepatic enzymes,malondialdehyde,and glutathione were investigated.Results:The methanolic extract of Ephedra alata showed a strong anti-proliferative and anti-migratory activity against 4T1 cells in a dose-dependent manner.It also induced apoptosis in 4T1 cells.In an in vivo mouse model,the extract markedly inhibited tumor growth,reduced malondialdehyde,and hepatic and non-hepatic enzymes as well as increased glutathione level.Conclusions:The methanolic extract of Ephedra alata inhibits breast cancer in vitro and in vivo,which may be a promising anticancer agent.

Microstrip Patch Antenna with an Inverted T-Type Notch in the Partial Ground for Breast Cancer Detections

This study designs a microstrip patch antenna with an inverted T-type notch in the partial ground to detect tumorcells inside the human breast.The size of the current antenna is small enough(18mm×21mm×1.6mm)todistribute around the breast phantom.The operating frequency has been observed from6–14GHzwith a minimumreturn loss of−61.18 dB and themaximumgain of current proposed antenna is 5.8 dBiwhich is flexiblewith respectto the size of antenna.After the distribution of eight antennas around the breast phantom,the return loss curveswere observed in the presence and absence of tumor cells inside the breast phantom,and these observations showa sharp difference between the presence and absence of tumor cells.The simulated results show that this proposedantenna is suitable for early detection of cancerous cells inside the breast.

Circular RNAs in breast cancer diagnosis,treatment and prognosis

Breast cancer has surpassed lung cancer to become the most common malignancy worldwide.The incidence rate and mortality rate of breast cancer continue to rise,which leads to a great burden on public health.Circular RNAs(circRNAs),a new class of noncoding RNAs(ncRNAs),have been recognized as important oncogenes or suppressors in regulating cancer initiation and progression.In breast cancer,circRNAs have significant roles in tumorigenesis,recurrence and multidrug resistance that are mediated by various mechanisms.Therefore,circRNAs may serve as promising targets of therapeutic strategies for breast cancer management.This study reviews the most recent studies about the biosynthesis and characteristics of circRNAs in diagnosis,treatment and prognosis evaluation,as well as the value of circRNAs in clinical applications as biomarkers or therapeutic targets in breast cancer.Understanding the mechanisms by which circRNAs function could help transform basic research into clinical applications and facilitate the development of novel circRNA-based therapeutic strategies for breast cancer treatment.

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men,respectively,worldwide.Although the antitumor activity of chalcones has been extensively studied,the molecular mechanisms of isoliquiritigenin analog 2',4',4-trihydroxychalcone(metochalcone;TEC)against carcinomas remain less well understood.In this study,we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner.TEC induced cell cycle arrest in the S-phase,cell migration inhibition in vitro,and reduced tumor growth in vivo.Moreover,transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways.TEC triggered the senescence-associated secretory phenotype(SASP)by repressing the JAK2/STAT3 axis.The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway,highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.

Apigenin is an anoikis sensitizer with strong anti-metastatic properties in experimental breast cancer

Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods.Among 19 tested dietary phytochemicals,the best results were obtained with apigenin,a natural component of celery.Phenotypically,apigenin sensitized breast cancer cells to anoikis,lowered the number of circulating tumor cells,and protected against breast cancer metastasis to lung in mice.Mechanistically,we demonstrated that the thromboxane A_(2)(TXA_(2))-TXA_(2)receptor(TP)axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway.Blockage of TXA_(2)signaling up-regulated p53 as well as its target gene p21,caused a G1 phase arrest,and finally led to apoptosis in breast cancer cells.TXA_(2)level was positively correlated with breast cancer cell anoikis rate,and apigenin significantly inhibited TXA_(2)biosynthesis in vitro and in vivo.Collectively,we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer,and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.

Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer

Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive.It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.Methods:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators.Then,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.Results:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific functions.We discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and CBX3.Moreover,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation.Notably,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.Conclusions:Our work deciphered the extensive regulation among hundreds of epigenetic regulators.The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.