| Background:Metastatic breast cancer remains an incurable disease and clinical benefit and prolongation of time to progression are the main end points in advanced setting.Targeted therapies have shown promising potentials in HER2(Human epidermal growth factor receptor-2)positive breast cancer,but with uncertain effects in HER2-negative breast cancer,especially when disease is progressing rapidly.The regimen of antiangiogenic therapy in combination with chemotherapy had been studied for years.Because of the toxicity and limited efficacy,it brought,this regimen was not widely recommended in advanced breast cancer.Apatinib is an oral,highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2).Phase ? clinical trials of Apatinib single agent had presented objective response and manageable toxicity in heavily pretreated,metastatic breast cancer.Oral vinorelbine represents a good choice for its toxicity and activity in anthracycline and taxane-pretreated breast cancer patients.This all-oral study aims to investigate the efficacy and safety of the oral vinorelbine-Apatinib combination in pre-treated metastatic breast cancer.In addition,we applied target hybrid capture deep sequencing to detect gene variants in circulating tumor DNA(ctDNA)to explore the therapeutic effect predictors.Methods:This study enrolled patients with HER2-negative advanced breast cancer,pretreated with anthracycline/taxanes,and who failed in the metastatic setting at least one prior chemotherapy or endocrine therapy when hormone receptor is positive.Patients were treated with apatinib 500mg/425mg daily plus oral vinorelbine 60mg/m2 day 1,8,15 every 3 weeks/cycle.Patients eligible were evaluated by CT or MRI scan at baseline and every 2 cycles(6 weeks)there after until disease progressed.The primary endpoint was progression-free survival(PFS).The secondary endpoints were objective response rate(ORR),clinical benefit rate(CBR),overall survival(OS),and safety.Patients eligible for ctDNA detection were evaluated in serial plasma samples before and during treatment.Plasma DNA was subjected to targeted hybrid capture next generation sequencing.Single nucleotide variants(SNV),small insertion and deletion(indel)and copy number variants(CNV)were detected to explore potential effect predictors and the relationship between gene variants and PFS as well as clinical benefit.Results:40 patients were enrolled with a median age of 55(30-70)years.First 17 patients started apatinib at the dose of 500mg/day.Considering safety issues,a lower dose of apatinib 425mg/day was subsequently started as the initial dose after these 17 patients recruited.26(65.0%)patients experienced treatment delay and 20(50.0%)patients experienced dose modification during treatment.Median follow-up time was 10.3 months.Of all 40 patients,median PFS was 5.4 months(95%CI,3.4m-7.3m).Median OS was not reached.32 patients were eligible for efficacy analysis.ORR was 15.6%(5/32).CBR was 46.9%(15/32).The most common adverse events of all grades included gastrointestinal reaction(70.0%),myelosuppression(67.5%),hypertension(62.5%),pain(60.0%),malaise(52.5%),anorexia(50.0%),elevated transaminase(47.5%),hand-foot reaction(47.5%),proteinuria(37.5%),and elevated bilirubin(32,5%).Proteinuria,treatment delay,and ECOG(Eastern Cooperative Oncology Group)performance status were independent predictive factors for PFS.A total of 20 patients were eligible for ctDNA detection.All the patients had baseline blood sample collected and 11 of them had at least one sample during treatment.A total of 47 blood samples were collected and 53 variant alterations were detected.the most frequently altered genes were TP53(35%),PIK3CA(25%).The median follow-up time was 10.5 months.There was a statistically significant difference in PFS for baseline total mutation number(TNM)<2 versus ?2(7.9m vs 1.9m,p=0.004).The distribution of maximum variant allele frequency(p=0.038),total mutation number(p=0.006)as well as total variant number(p=0.031)presented potential efficacy predicting value.Longitudinal follow up showed dynamic changes to mutations and copy number variants in ctDNA could reflect tumor burden and might indicate clonal response to treatment.The study also observed some alterations in gene were correlated with disease development in advance of image.Conclusions:(1)The all-oral therapy of antiangiogenic tyrosine kinase inhibitor apatinib plus vinorelbine presented objective efficacy in advanced HER2-negative breast cancer who failed from first-line therapy,with acceptable and manageable toxicity.Patients with better performance status before treatment could gain improved efficacy.Proteinuria presented during treatment might be a predictor for therapeutic efficacy.(2)The efficacy of antiangiogenic tyrosine kinase inhibitor and chemotherapy in advanced breast cancer could be predicted by total mutation number in ctDNA before treatment.Patients with less than 2 mutations at baseline could have longer PFS.There are correlations between therapeutic effectiveness and baseline variant frequency as well as mutation number.The higher the mutation frequency and number was,the less likely the benefit would gain.Dynamic changes to gene alterations had correlation with tumor burden,which contain potential value in detection of disease development in advance of image.Background:SPARC(secreted protein acidic and rich in cysteine)is a secreted glycoprotein that interacts with extracellular matrix protein and acts as a regulator of critical cellular functions such as proliferation and cell migration.An increasing number of studies have shown altered expression of SPARC in several malignancies.However,the role of this potential biomarker in breast cancer development and progression is controversial.Accounting for 10-17%of all breast carcinomas,Triple-negative breast cancer(TNBC)is known for its poor prognosis and high recurrence probability compared with other types of breast cancer.There is a need for prognostic biomarkers to guide treatment decisions for this subtype.Although SPARC expression was increased in TNBC tumor tissues compared with other breast cancer subtypes,the relationship between its level and TNBC prognosis is still uncertain.The aim of this study is to explore the association between SPARC and the prognosis of triple-negative breast cancer.Methods:In this study,a total of 211 samples of triple-negative breast lesions from 2004 to 2008 were collected in our hospital.SPARC expression was evaluated by immunohistochemistry using an immunoreactive score(IRS)from patients with up to 10 years clinical follow-up data.The current study set out to examine both the expression of SPARC in primary tumor tissue and to demonstrate if a link existed between the levels of SPARC and the clinical outcome.Results:High SPARC expression(IRS>3)was observed in 52.1%of all primary tumors of TNBC patients.Univariable analysis demonstrated that patients with high SPARC expression had worse 5-year disease-free survival(DFS)(56%vs 71.2%,HR=1.58,95%Cl:1.01-2.47,P = 0.044)and 5-year overall survival(OS)(71.8%vs 81.1%,HR=1.74,95%CI:1.06-2.85,P = 0.029)compared to those with low SPARC protein levels.In multivariable analysis,high SPARC expression was independently predictive for DFS(p=0.018)and OS DFS(p=0.014)in all TNBC patients.There was no significant correlation between cytoplasmic SPARC expression and clinicopathological parameters,including age,menopausal status,histopathologic grade,tumor size,lymph node metastasis,vascular invasion,or TNM staging.Conclusion:The presence of higher SPARC expression in tumor tissue is an independent risk factor for the prognosis of triple-negative breast cancer.The relationship between SPARC expression and TNBC prognosis should be further examined in larger prospective study.The method to evaluate SPARC expression should be standardized.Further studies should be conducted to clarify the association between SPARC expression and the efficacy of nab-paclitaxel. |
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