Anti-PD1 antibody and not anti-LAG-3 antibody improves the antitumor effect of photodynamic therapy for treating metastatic breast cancer

Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

Needs and Opportunities for Information in Patients with Metastatic Breast Cancer Attending a Tertiary Hospital in Tanzania—A Qualitative Study

Background: The majority of breast cancer patients in Tanzania present with advanced disease, and a significant proportion has metastatic breast cancer (MBC) on presentation or develops it during the course of their follow-up. With few treatment options to choose from, such patients often benefit from empathic support and access to information to help them make treatment decisions based on their individual circumstances and needs. Patients with MBC have been shown to present with unique physical, social and psychological needs that require additional time, counselling and availability of health care providers in addition to the routine options available to other patients. In resource-limited settings, the needs of such patients are often unknown and unaddressed, which adds to the anxiety associated with the diagnosis and its treatment. Materials and methods: This descriptive qualitative study was conducted using 3 focus group discussions with a total of 17 participants with metastatic breast cancer (MBC) attending Ocean Road Cancer Institute in Dar es Salaam, Tanzania. Participants were purposively selected for the study from outpatient clinics and inpatient wards. A semi-structured FGD guide was used to moderate discussions and analysis was done using a thematic approach. Results: The median age of participants was 51 (range 33 - 81 years) with an average of 4 months (range 1 - 12 months) from diagnosis of BC to the interview. 4 (24%) were diagnosed with MBC on first presentation (denovo). Participants spoke about the importance of accurate BC-related information in allowing timely referral and treatment both in the community and within the health system. They recognized the role of mass and social media in increasing awareness about BC and identified myths surrounding cancer treatment especially mastectomy. Correct and timely information at points of care, through media platforms and via ambassadors/patient support groups was perceived as a means to avoiding delays and securing early and effective treatment. Conclusion: Patients with MBC in Tanzania have many unmet informational needs in relation to their disease. Accurate BC-related information is important in allowing early detection and diagnosis. At the community level, provision of information through established media platforms and the use of patient advocates may help to enable early referral and treatment of patients.

Significance of serum carcinoembryonic antigen in metastatic breast cancer patients:A prospective study

BACKGROUND Carcinoembryonic antigen(CEA)is an important serum tumour marker with a substantial role in diagnosis and monitoring of various solid tumours.About 36%-70%of breast cancers have elevated serum CEA.And the available studies show discrepancy in addressing the prognostic significance of CEA in advanced breast cancer.AIM To estimate the serum CEA level in our metastatic breast cancer patients and correlate it with response to treatment and clinical outcome.METHODS This was a prospective clinical study conducted on 50 metastatic breast cancer patients treated at breast clinic,with newly diagnosed metastatic breast cancer planned for palliative chemotherapy,targeted therapy,and hormonal treatment.We estimated the proportion of patients with elevated serum CEA level at baseline and after palliative treatment and also studied the association of serum CEA levels with known prognostic factors.The response to treatment was correlated with the serum CEA levels in the context of responders and nonresponders.RESULTS The median pre-treatment and post-treatment CEA levels were 7.9(1.8-40.7)ng/mL and 4.39(1.4-12.15)ng/mL,respectively,in the whole study population(P=0.032).No statistically significant difference was seen in baseline serum CEA between responders and non-responders.Even in the luminal group,pretreatment serum CEA was not a predictor of response,but post-treatment CEA was a significant predictor of tumour progression.In patients with liver and lung metastases,post-treatment CEA level difference was not statistically significant in both responders and non-responders though the values were higher in nonresponders.Among those with bone metastases,69.5%had elevated post-treatment serum CEA,and only 37.5%had elevated serum CEA in those with no bone metastases.CONCLUSION Elevated post-treatment serum CEA levels are associated with disease progression and poor response to therapy.Persistently elevated post-treatment serum CEA levels are significantly associated with bone metastases.Elevated serum CEA and hormonal status are significant predictors of treatment response.

Hormonal therapy might be a better choice as maintenance treatment than capecitabine after response to first-line capecitabine-based combination chemotherapy for patients with hormone receptor-positive and HER2-negative,metastatic breast cancer

Background:Both hormonal therapy(HT) and maintenance capecitabine monotherapy(MCT) have been shown to extend time to progression(TTP) in patients with metastatic breast cancer(MBC) after failure of taxanes and anthracycline?containing regimens.However,no clinical trials have directly compared the efficacy of MCT and HT after response to first?line capecitabine?based combination chemotherapy(FCCT) in patients with hormone receptor(HR)?positive and human epidermal growth factor receptor 2(HER2)?negative breast cancer.Methods:We retrospectively analyzed the charts of 138 HR?positive and HER2?negative MBC patients who were in non?progression status after FCCT and who were treated between 2003 and 2012 at the Cancer Institute and Hospital,Chinese Academy of Medical Sciences,in Beijing,China.The median number of first?line chemotherapy cycles was 6(range,4–8);combined agents included taxanes,vinorelbine,or gemcitabine.Of these 138 patients,79 received MCT,and 59 received HT.Single?agent capecitabine was administered at a dose of 1250 mg/m2 twice daily for 14 days,followed by a 7?day rest period,repeated every 3 weeks.Of the 59 patients who received HT,37 received aromatase inhibitors(AIs),8 received selective estrogen receptor modulators(SERMs),and 14 received goserelin plus either AIs or SERMs.We then compared the MCT group and HT group in terms of treatment efficacy.Results:With a median follow?up of 43 months,patients in the HT group had a much longer TTP than patients in the MCT group(13 vs.8 months,P ease?free surviv= 0.011).When TTP was adjusted for age,menopausal status,Karnofsky performance status score,disal,site of metastasis,number of metastatic sites,and response status after FCCT,extended TTP was still observed for patients in the HT group(hazard ratio:0.63;95% confidence interval:0.44–0.93;P = 0.020).We also observed a trend of overall survival advantage for patients in the HT group vs.patients in the MCT group,but the difference was not significant(43 vs.37 months,P tients in the MCT g= 0.400).In addition,patients in the HT group gen?erally tolerated the treatment well,whereas paroup experienced grades 3–4 adverse events,the most frequent of which were hand?foot syndrome(15.8%) and hematologic abnormalities(7.6%).Conclusion:For HR?positive and HER2?negative MBC patients,HT might be considered a treatment after response to FCCT but prior to MCT as a long?term administration.

Phase Ⅱ study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA

Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.

Efficacy of capecitabine-based combination therapy and singleagent capecitabine maintenance therapy in patients with metastatic breast cancer

Objective： The purpose of this study was to observe the efficacy and toxicities of capecitabine-based chemotherapy and capecitabine monotherapy as maintenance therapy in the treatment of metastatic breast cancer（MBC）.Patients and methods： A total of 98 MBC patients were treated with capecitabine combined with vinorelbine（NX）. Results： The median number of treatment was 6 cycles（1-7 cycles）. There were two cases of complete remission（CR）, 58 partial remission, 27 stable disease（SD）, 11 progression disease. The overall response rate（ORR）（CR ＋ PR） was 61.2%. The clinical benefit rate（CBR） was 75.5%. Fifty of effective patients received with capecitabine monotherapy as maintenance therapy. The ORR（CR ＋ PR） was 4%. The CBR was 48%. The median progression-free survival（PFS） was 12 months. In maintenance therapy or not, the median post metastasis survival rate（MSR） was 63 and 28 months, respectively. In the combination therapy group, the major grade 3/4 toxicities included hand-foot syndrome（3.1%）, skin pigmentation（2.0%）, diarrhoea and abdominal distension（5.1%）, stomatitis（1.0%）, and leukopenia（20.4%）.Conclusions： Capecitabine-based combination therapy and single-agent capecitabine maintenance therapy were well tolerated and effective to MBC.

Decrease of Peripheral Blood CD8+/CD28- Suppressor T Cell Followed by Dentritic Cells Immunomodulation among Metastatic Breast Cancer Patients

Objective： To explore the effects of dentritic cells on the peripheral blood lymphocyte subpopulations of metastatic breast cancer patients treated with chemotherapy. Methods： The current study involved 44 metastatic breast cancer patients treated with docetaxel-based chemotherapy. Among them, 25 cases were treated with dendritic cells derived from CD34＋ hematopoietic stem cells enriched autologous peripheral mononuclear cells after chemotherapy, and 19 cases received chemotherapy alone. Peripheral blood samples were collected from each patient before and after treatment, and lymphocyte subpopulations including CD3＋, CD3＋/CD4＋, CD3＋/CD8＋, CD3-/CD16＋56＋, CD3＋/CD16＋56＋, CD4＋/CD25＋, CD8＋/CD28-, CD8＋/CD28＋, CD4/CD8, DC1, DC2 and DC1/DC2 were analysed by a 3-color flow cytometric analysis. Results： The two treatment groups were well matched with regard to demographic and baseline disease characteristics. Comparing the changes of lymphocyte subpopulations between the two groups, it showed that the difference of the change of CD8＋/CD28-lymphocyte had statistic significance. The percentage of CD8＋/CD28-lymphocyte was lower in the chemotherapy＋DC group, but higher in the chemotherapy-alone group. Conclusion： As CD8＋/CD28-lymphocyte represent a kind of suppressive T lymphocyte, we conclude that dentritic cell therapy can relieve immunosuppression to some extent.

Effectiveness of second-line anti-HER2 treatment in HER2-positive metastatic breast cancer patients previously treated with trastuzumab:A real-world study

Objective:Several studies have demonstrated different benefits for patients whose disease progressed despite previous trastuzumab treatment.Due to limited real-world data,we evaluate the effectiveness of anti-human epidermal growth factor receptor 2(HER2)therapy(lapatinib or trastuzumab)plus chemotherapy or chemotherapy alone in patients who were previously treated with trastuzumab-containing regimens and investigate factors associated with effectiveness.And we further show the effectiveness of the two anti-HER2 therapy groups.Methods:A total of 342 HER2-positive metastatic breast cancer(MBC)patients whose disease progressed during prior anti-HER2(trastuzumab)and standard chemotherapy therapy from Department of Breast Oncology,the Fifth Medical Center of Chinese PLA General Hospital,from August 2010 to December 2016 were included.Seventy-eight patients received standard chemotherapy only,148 patients continued to receive trastuzumab and switched to other chemotherapy drugs,and 116 patients received tyrosine-kinase inhibitors(TKIs;lapatinib)and chemotherapy.The main outcome measures were progression-free survival(PFS),overall response rate(ORR),and clinical benefit rate(CBR).Subgroup analyses were conducted to identify patient characteristics associated with the greatest clinical benefit.Results:After a median follow-up of 26.2(range,2.0-56.0)months,PFS significantly improved with anti-HER2 therapy compared with chemotherapy alone:median 6.0 months with lapatinib[95%confidence interval(95%CI),4.53-7.47],4.5 months with trastuzumab(95%CI,3.99-5.01)vs.3.0 months with chemotherapy alone(95%CI,2.42-3.58);stratified hazard ratio(HR)=0.70,95%CI,0.60-0.81;P<0.0001.The ORR values were 33.6%,25.0%and 12.8%,respectively,the CBR values were 60.3%,48.6%and 26.9%,respectively.The effectiveness of lapatinib group and trastuzumab group were further analyzed.In multivariate analysis,lapatinib group was associated with a longer PFS,after controlling other potential confounders(HR=0.68,95%CI,0.52-0.90;P=0.006).Conclusions:The combination of TKIs and chemotherapy was effective in this cohort previously treated with trastuzumab treatment.Therefore,TKIs combined with chemotherapy is an option for Chinese HER2-positive MBC patients previously treated with trastuzumab treatment.

Prognostic tumor microenvironment gene and the relationship with immune infiltration characteristics in metastatic breast cancer

The aim of this study was to reveal genes associated with breast cancer metastasis,to investigate their intrinsic relationship with immune cell infiltration in the tumor microenvironment,and to screen for prognostic biomarkers.Gene expression data of breast cancer patients and their metastases were downloaded from the GEO,TCGA database.R language package was used to screen for differentially expressed genes,enrichment analysis of genes,PPI network construction,and also to elucidate key genes for diagnostic and prognostic survival.Spearman’s r correlation was used to analyze the correlation between key genes and infiltrating immune cells.We screened 25 hub genes,FN1,CLEC5A,ATP8B4,TLR7,LY86,PTGER3 and other genes were differentially expressed in cancer and paraneoplastic tissues.However,patients with higher expression of CD1C,IL-18 breast cancer had a better prognosis in the 10 years survival period,while patients with high expression of FN1,EIF4EBP1 tumors had a worse prognosis.In addition,TP53 and HIF1 genes are closely related to the signaling pathway of breast cancer metastasis.In this study,gene expression of ATP8B4 and CD1C were correlated with cancer tissue infiltration of CD8^(+)T lymphocytes,while GSE43816,GSE62327 and TCGA databases showed that CD8^(+)T lymphocytes were closely associated with breast cancer progression.Functional enrichment analysis of genes based on expression differences yielded key genes of prognostic value in the breast cancer microenvironment.

Efficacy, patterns of use and cost of Pertuzumab in the treatment of HER2+ metastatic breast cancer in Singapore: The National Cancer Centre Singapore experience

BACKGROUND Pertuzumab is a humanized anti-human epidermal growth factor receptor 2(HER2)monoclonal antibody found in a Phase III clinical trial to significantly improve median survival in HER2 positive metastatic breast cancer(MBC)when used in combination with a taxane and Trastuzumab,and its clinical efficacy has transformed the therapeutic landscape of HER2-positive breast cancer.There are currently few reports on the pattern of use and value of Pertuzumab in real world settings.Our study describes the clinical efficacy and treatment costs of Pertuzumab in HER2-positive MBC treated in a tertiary cancer centre in Singapore in a predominantly Asian population.AIM To investigate the clinical efficacy and treatment costs of Pertuzumab in HER2-positive MBC in an Asian population in Singapore.METHODS A retrospective study of 304 HER2-positive MBC patients seen at National Cancer Centre Singapore between 2011-2017 was conducted.Demographic and clinical data were extracted from electronic medical records.Clinical characteristics and billing data of patients who received Pertuzumab were compared with those who did not.RESULTS Thirty-one(62.0%)of the fifty(16.4%)patients who received Pertuzumab as firstline therapy.With a median follow-up of 21.5 mo,there was a statistically significant difference in the median overall survival between Pertuzumab and non-Pertuzumab groups[51.5(95%CI:35.8–60.0)vs 32.9(95%CI:28.1–37.5)mo;P=0.0128].Two(4.88%)patients in the Pertuzumab group experienced grade 3(G3)cardiotoxicity.The median treatment cost incurred for total chemotherapy for the Pertuzumab group was 130456 Singapore Dollars compared to 34523 Singapore Dollars for the non-Pertuzumab group.The median percentage of total chemotherapy costs per patient in the Pertuzumab group spent on Pertuzumab was 50.3%.CONCLUSION This study shows that Pertuzumab use in the treatment of metastatic breast cancer is associated with a significantly better survival and a low incidence of serious cardiotoxicity.However,the proportionate cost of Pertuzumab therapy remains high and further cost-effectiveness studies should be conducted.

Updates in endocrine therapy for metastatic breast cancer

Endocrine therapy(ET)remains the mainstay of treatment for steroid hormone receptor-positive,human epidermal growth factor 2(HER2)-negative metastatic breast cancer(MBC).Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations,transforming the landscape of MBC management.The options for ET are expanding,with promising agents in the pipeline.Although MBC remains incurable,many patients can enjoy years of survival with good quality of life by cycling through the many available agents.With the plethora of available agents and rapid approvals,clinicians look to evidencebased guidelines to assist in treatment selection to maximize patient well-being.In this review,we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive,HER2-negative MBC.We will discuss landmark trials and highlight their impact in reshaping treatment approaches.Finally,we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.

Abemaciclib, a Recent Novel FDA-Approved Small Molecule Inhibiting Cyclin-Dependant Kinase 4/6 for the Treatment of Metastatic Breast Cancer: A Mini-Review

Abemaciclib (Verzerio®) is a cell cycle inhibitor of both CDK4 and CDK6. In 2017, abemaciclib was approved by the Food and Drug Administration (FDA) and, in 2018 by the European Medicines Agency (EMA) for the treatment of postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced breast cancer. In this mini-review, we provide a series of information for respectively their targets and its selectivity, results on preclinical trial, clinical phase I, II and III trials, and some perspectives. We also describe the batch and flow steps used for the synthesis of this cancer drug.

Cardiac Safety with High Cumulative Dose of Pegylated Liposomal Doxorubicin in Patients with Metastatic Breast Cancer Previously Treated with Conventional Anthracyclines

Introduction: The treatment of metastatic breast cancer (MBC) is still challenging. Many studies documented the efficacy of pegylated liposomal doxorubicin (PLD) in patients with MBC, but there is a limited data about the cardiac safety with high cumulative dose (HCD) of PLD. Aim of the work: We conducted this trial to outline the cardiac safety of HCD of PLD in patients with MBC who previously received conventional anthracyclines. Methods: During the period of nine years (January 2011 to December 2019). We extracted the data of the patients with MBC receiving PLD at Medical Oncology Department, South Egypt Cancer Institute, Assiut University. These included patients’ demographics and therapeutic data including the full data of PLD, prior conventional anthracyclines, prior trastuzumab, and prior radiotherapy. Also, data about comorbidities as well as cardiac and other toxicities of PLD were obtained. The data was analysed using SPSS v. 21. Results: For all 81 eligible patients, the mean age was 43.9 years (±standard deviation (SD) 13.2). The mean cumulative dose of PLD was 378.4 mg/m2 (± SD of 250.2) and a range of 100 - 1200 mg/m2. About thirty-one (38.3%) patients received high cumulative dose (400 mg/m2 or more), while the remaining 50 patients did not. The decline in left ventricular ejection fraction (LVEF) was relatively rare;and of low grade. Grade 2 decline in LVEF occurred in only two patients who received high cumulative dose of PLD, and only one patient who did not reach HCD (p = 0.555). Grade 3 or 4 decline in LVEF did not occur in patients either with or without HCD. Regarding other toxicities, there was a significant increase in incidence of all grades palmar plantar erythrodysesthesia (PPE) in patients who received HCD of PLD when compared to those who did not reach the HCD (38.7% versus 16% respectively;p = 0.021). Conclusion: Our study concluded that the use of PLD seems to be a justified agent in the treatment of MBC who previously treated by conventional anthracyclines in the adjuvant, metastatic or both settings, even in patients reaching the cumulative dose of conventional anthracycline.

The efficacy and safety of thalidomide for treating metastatic breast cancer:a systematic review

Objective This systematic review was conducted to investigate the efficacy and safety of thalidomide in metastatic breast cancer(MBC).Methods Based on pre-defined inclusion and exclusion criteria,data were independently collected from different databases by three investigators.Overall,three studies were included.Results The included studies indicated that no patient achieved a partial or complete response from different thalidomide dose levels.Thalidomide was well-tolerated at doses of 100 mg,200 mg,and 400 mg.In all three studies,common side effects included constipation,somnolence,fatigue,peripheral neuropathy,and dry mouth.Circulating angiogenic factors were not significantly correlated with disease progression.Conclusion The available evidence indicates that single-agent thalidomide has little or no activity in patients with MBC.

The prognostic value of baseline circulating tumor cells in patients with metastatic breast cancer: a meta-analysis

Objective:The prognostic value of circulating tumor cells(CTCs)in metastatic breast cancer(MBC)patients was contentious.A meta-analysis was conducted to evaluate whether MBC patients’clinical outcomes could be predicted by CTCs detection.Methods:Relevant published studies were searched through electronic databases from January 1990 to February 2018,among which,those investigated the correlation between CTCs and clinical outcomes of progression-free survival and overall survival in MBC patients were involved.The hazard ratios(HR)and confidence intervals(CI)in the studies were extracted from the study using random or fixed effects model,and the meta-analysis was conducted.The prognostic value of tumor cells in patients with different subtypes was estimated by subgroup analysis.Results:Twenty-one eligible studies enrolling 3,837 patients were appropriate for pooled analysis.Progression-free survival(HR,1.66;95%CI,1.47–1.87;P=0.000)and overall survival(HR,2.51;95%CI,2.13–2.96;P=0.000)were worse in patients with CTCs-positive.Subtypes of hormone receptor(HorR)positive,human epidermal growth factor receptor-2(HER2)negative and triple negative with presence of CTCs showed a statistically significant worse PFS and OS.However,CTCs detection presented no prognostic value in patients with HorR-negative or HER2-positive subtypes.Conclusion:The enumeration of CTCs at baseline in patients with MBC subtypes of HorR-positive,HER2-negative and triple negative is connected with disease progression and poor survival,but inappropriate for HorR-negative and HER2-positive subtypes.

Personalized surgical recommendations and quantitative therapeutic insights for patients with metastatic breast cancer: Insights from deep learning

Background:The role of surgery in metastatic breast cancer(MBC)is currently controversial.Several novel statistical and deep learning(DL)methods promise to infer the suitability of surgery at the individual level.Objective:The objective of this study was to identify the most applicable DL model for determining patients with MBC who could benefit from surgery and the type of surgery required.Methods:We introduced the deep survival regression with mixture effects(DSME),a semi-parametric DL model integrating three causal inference methods.Six models were trained to make individualized treatment recommendations.Patients who received treatments in line with the DL models'recommendations were compared with those who underwent treatments divergent from the recommendations.Inverse probability weighting(IPW)was used to minimize bias.The effects of various features on surgery selection were visualized and quantified using multivariate linear regression and causal inference.Results:In total,5269 female patients with MBC were included.DSME was an independent protective factor,outperforming other models in recommending surgery(IPW-adjusted hazard ratio[HR]=0.39,95%confidence interval[CI]:0.19–0.78)and type of surgery(IPW-adjusted HR=0.66,95%CI:0.48–0.93).DSME was superior to other models and traditional guidelines,suggesting a higher proportion of patients benefiting from surgery,especially breast-conserving surgery.The debiased effect of patient characteristics,including age,tumor size,metastatic sites,lymph node status,and breast cancer subtypes,on surgery decision was also quantified.Conclusions:Our findings suggested that DSME could effectively identify patients with MBC likely to benefit from surgery and the specific type of surgery needed.This method can facilitate the development of efficient,reliable treatment recommendation systems and provide quantifiable evidence for decision-making.

Efficacy and clinical outcome of chemotherapy and endocrine therapy as first-line treatment in patients with hormone receptor-positive HER2-negative metastatic breast cancer

Background:Endocrine therapy(ET)and ET-based regimens are the preferred first-line treatment options for hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative metastatic breast cancer(HR+/HER2-MBC),while chemotherapy(CT)is commonly used in clinical practice.The aim of this study was to investigate the efficacy and clinical outcome of ET and CT as first-line treatment in Chinese patients with HR+/HER2-MBC.Methods:Patients diagnosed with HR+/HER2-MBC between January 1st,1996 and September 30th,2018 were screened from the Chinese Society of Clinical Oncology Breast Cancer database.The initial and maintenance first-line treatment,progression-free survival(PFS),and overall survival(OS)were analyzed.Results:Among the 1877 included patients,1215(64.7%)received CT and 662(35.3%)received ET as initial first-line treatment.There were no statistically significant differences in PFS and OS between patients receiving ET and CT as initial first-line treatment in the total population(PFS:12.0 vs.11.0 months,P=0.22;OS:54.0 vs.49.0 months,P=0.09)and propensity score matched population.For patients without disease progression after at least 3 months of initial therapy,maintenance ET following initial CT(CT-ET cohort,n=449)and continuous schedule of ET(ET cohort,n=527)had longer PFS than continuous schedule of CT(CT cohort,n=406)in the total population(CT-ET cohort vs.CT cohort:17.0 vs.8.5 months;P<0.01;ET cohort vs.CT cohort:14.0 vs.8.5 months;P<0.01)and propensity score matched population.OS in the three cohorts yielded the same results as PFS.Conclusions:ET was associated with similar clinical outcome to CT as initial first-line treatment.For patients without disease progression after initial CT,switching to maintenance ET showed superiority in clinical outcome over continuous schedule of CT.

Navigating breast cancer brain metastasis:Risk factors,prognostic indicators,and treatment perspectives

In this editorial,we comment on the article by Chen et al.We specifically focus on the risk factors,prognostic factors,and management of brain metastasis(BM)in breast cancer(BC).BC is the second most common cancer to have BM after lung cancer.Independent risk factors for BM in BC are:HER-2 positive BC,triplenegative BC,and germline BRCA mutation.Other factors associated with BM are lung metastasis,age less than 40 years,and African and American ancestry.Even though risk factors associated with BM in BC are elucidated,there is a lack of data on predictive models for BM in BC.Few studies have been made to formulate predictive models or nomograms to address this issue,where age,grade of tumor,HER-2 receptor status,and number of metastatic sites(1 vs>1)were predictive of BM in metastatic BC.However,none have been used in clinical practice.National Comprehensive Cancer Network recommends screening of BM in advanced BC only when the patient is symptomatic or suspicious of central nervous system symptoms;routine screening for BM in BC is not recommended in the guidelines.BM decreases the quality of life and will have a significant psychological impact.Further studies are required for designing validated nomograms or predictive models for BM in BC;these models can be used in the future to develop treatment approaches to prevent BM,which improves the quality of life and overall survival.

Eribulin in breast cancer:Current insights and therapeutic perspectives

Eribulin is a non-taxane synthetic analogue approved in many countries as thirdline treatment for the treatment of patients with metastatic breast cancer.In addition to its mitotic property,eribulin has non-mitotic properties including but not limited to,its ability to induce phenotypic reversal of epithelial to mesenchymal transition,vascular remodelling,reduction in immunosuppressive tumour microenvironment.Since approval,there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types,including hormone receptor positive,HER2 positive and triple negative breast cancer,many demonstrating promising activity.This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent,its toxicity profile,and potential future directions.

Albumin-based multidrug delivery system enriched in Golgi apparatus against metastatic breast cancer

Breast cancer and metastasis remain great challenges in clinical therapy.Compared with monotherapy,combination therapy,especially mediated by nanomedicine delivery strategy,significantly improves the therapeutic efficacy and reduces undesired toxicity.Cyclooxygenase-2(COX-2)inhibitors are widely used for adjuvant chemotherapy because COX-2 is overexpressed in virtually all cancer cell lines to regulate tumor progression by catalyzing prostaglandin E2(PGE2)synthesis.This drug combination strategy is still required to be improved due to some unsatisfactory clinical trial results.Intricate processes of tumor growth and metastasis are orchestrated by multiple proteins in addition to COX-2,which are modified and transported by Golgi apparatus.Hence,disrupting the structure and function of Golgi apparatus can inhibit the secretion of tumor-related proteins and further suppress carcinoma progression and metastasis.Since COX-2 is also enriched within Golgi apparatus in tumor cells,COX-2 inhibitors and Golgi disrupting agents can be co-delivered to Golgi apparatus to maximize the synergy.In this work,we developed a human serum albumin(HSA)nanoparticle encapsulating pirarubicin(THP),retinoic acid(RA),and indomethacin(IMC),called TIR-HSA,which was observed to be localized in Golgi complex of 4T1 cells.Owing to the synergistic effect of these three drugs,TIR-HSA inhibited the proliferation,migration,and invasion of tumor cells,enhanced the apoptotic rate,and improved the immunosuppressive tumor microenvironment,which remarkably regressed the tumor growth and metastasis and prolonged the survival period of 4T1-bearing mice.