| Objective: Approximately 15% to 20% of patients with breast cancer have tumors that overexpress the human epidermal growth factor receptor-2(HER2)protein,which was characterized by poor prognosis.Anti-HER2 target drugs have demonstrated to be a clinical breakthrough for treating this subtype of breast cancer,substantially improving survival.However,there is still no consensus on the standard therapy for HER2-positive patients with optimal combination.Moreover,progression during or after anti-HER2 target drugs remains a therapeutic challenge in breast cancer.Several studies have demonstrated that HER2 mutations may be a predictive biomarker of resistance to HER2-directed therapy.Due to the limited data,we evaluate the effectiveness of first-line and second-line anti-HER2 treatment for HER2-positive metastatic breast cancer patients,and investigate factors associated with effectiveness.Further more,we detect the correlation between HER2 gene mutation and antiHER2 therapeutic response.Methods: Eligible patients were HER2-overexpressing metastatic breast cancer(MBC).HER2-positive MBC patients whose disease progressed during or after prior anti-HER2(trastuzumab)and standard chemotherapy therapy from our breast oncology department were included.The follow treatment were standard chemotherapy only,continued to receive trastuzumab and switched to other chemotherapy drugs,or tyrosine-kinase inhibitors(TKIs;lapatinib)and chemotherapy.To study the molecular basis underlying refractory MBC,we obtained the plasma cell free DNA(cfDNA)of 32 patients who received systemic anti-HER2 therapy,and used next-generation sequencing to investigate the mutational and transcriptional profiles of 230 genes.We focused on HER2 mutation to identify the roles of HER2 mutations in the refractoriness to anti-HER2 therapies.In addition,patients progressed despite taxane treatment,who were naive to trastuzumab and were treated with capecitabine plus trastuzumab or vinorelbine plus trastuzumab as first line were enrolled.Data were retrospectively obtained from computerized population-based databases at our department.Demographic and clinical data were examined for every one of the participants.The main outcome measures were progression-free survival(PFS),overall response rate(ORR),clinical benefit rate(CBR).Subgroup analyses were conducted to identify patient characteristics associated with the greatest clinical benefit.All statistical analyses were done with the software SPSS(version 21.0).Results: 1.Three hundred and forty-two HER2-positive MBC patients whose disease progressed during or after prior anti-HER2(trastuzumab)and standard chemotherapy therapy from our breast oncology department between August 2010 and December 2016 were included.PFS significantly improved with anti-HER2 therapy compared with chemotherapy alone(median 6.0 months with lapatinib [95% confidence interval(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.Multiple analysis was performed for adjusted PFS hazard ratio,and the lapatinib combination treatment was also found to be associated with a significantly better outcome compaired with trastumab group(HR,0.68[0.52-0.90],P=0.006).2.A total of 32 HER2-positive breast cancer patients were eligible in this study.The median age of the participants was 46 years(range 32–59).More than half of the patients(53.1%)were negative for hormone receptors.93.8% of the patients had visceral metastasis,and 56.3% had > 3 metastatic sites.For the therapy regimen after plasma collected,16 patients(50.0%)received Trastuzamab containing regimens,10 patinets(31.3%)received Lapatinib containing regimens,5 patients(15.6%)received ado-trastuzumab emtansine(TDM1).Somatic driver mutations in tumor DNA were identified by targeted sequencing in 230 cancer related genes panel.All the patients harboured at least one genetic alteration including copy number variations.A total of 79 genes were detected in the samples from the patients.Genes in which somatic alterations were detected frequently included ERBB2(20 cases,62.5%),PIK3CA(18 cases,56.3%),ALK(18 cases,56.3%),TP53(18 cases,56.3%),BCR(16 cases,50.0%),AR(16 cases,50.0%),FGFR1(10 cases,31.3%).HER2 mutations were found in 7 of the 32 patients(21.8%).Kaplan-Meier analysis revealed that patients with HER2 mutation worse PFS than none(HR 2.23,95%CI 0.9-5.5,P=0.084).3.A total of 161 patients treated at our breast oncology department from January 2010 to September 2017 were included.75 were treated with capecitabine,and 86 were treated with vinorelbine.The median PFS for patients treated with capecitabine and vinorelbine was 9.5 months and 7.0 months,respectively(hazard ratio [HR] 0.64;95% confidence interval [CI],0.46 to 0.93;P = 0.02).The ORRs were 34.7% and 46.5%(P=0.086),and the CBRs were 64.0% and 51.0%(P=0.63),for the capecitabine and vinorelbine groups,respectively.Vinorelbine group was associated with higher proportions of treatment-related grade 3 to 4 leucopenia(21.1% vs.9.0%)and neutropenia(18.4% vs.6.0%)than was capecitabine.However,capecitabine was associated with higher proportions of hand-foot syndrome than vinorelbine group.Additionally,more patients in the vinorelbine group discontinued therapy due to toxicity(15.1% vs.6.7%)or by choice(9.3% vs.1.3%).Conclusion: 1.PFS significantly improved with anti-HER2 therapy compared with chemotherapy alone.The combination of lapatinib and chemotherapy was effective in this cohort previously treated with trastuzumab treatment.In conclusion,lapatinib combined with chemotherapy is an option for HER2-positive MBC patients previously treated with trastuzumab treatment.Univariate and multiple analysis were performed for adjusted PFS hazard ratio,and the lapatinib regimens was an optimal treatment for the patients who were healthy enough to receive lapatinib,and available to it.2.Detection of Circulating-free DNA using next generation sequencing with high sensitivity may identify a predictive biomarker.HER2 gene mutation rate was higher in the patients previously treated with trastuzumab containing treatment.HER2 mutations may be a predictive biomarker of resistance to HER2-directed therapy.Functional validation is warranted.These data may help in the selection of treatment options in the clinical setting.3.Trastuzumab plus capecitabine or vinorelbine is active and tolerated in first-line treatment of metastatic with taxanes failure and naive to trastuzumab.Compared with vinorelbine,capecitabine combination therapy resulted in significant improvements in PFS.However,vinorelbine group resulted in higher ORR than did capecitabine group.Capecitabine group had mild toxicities and shoud be used as a first-line option,espacialy for the patients who were older than 50 years,had visceral involvement,or had ? 3 metastatic sites. |
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