BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proli...BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proliferation-related genes with prognosis in HER2+breast cancer(BC)patients is unclear.AIM To identify and evaluate fresh ferroptosis-related biomarkers for HER2+BC.METHODS First,we obtained the mRNA expression profiles and clinical information of HER2+BC patients from the TCGA and METABRIC public databases.A four gene prediction model comprising PROM2,SLC7A11,FANCD2,and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort.Patients were stratified into high-risk and low-risk groups based on their median risk score,an independent predictor of overall survival(OS).Based on these findings,immune infiltration,mutations,and medication sensitivity were analyzed in various risk groupings.Additionally,we assessed patient prognosis by combining the tumor mutation burden(TMB)with risk score.Finally,we evaluated the expression of critical genes by analyzing single-cell RNA sequencing(scRNA-seq)data from malignant vs normal epithelial cells.RESULTS We found that the higher the risk score was,the worse the prognosis was(P<0.05).We also found that the immune cell infiltration,mutation,and drug sensitivity were different between the different risk groups.The highrisk subgroup was associated with lower immune scores and high TMB.Moreover,we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses.HRisk-HTMB patients had the worst prognosis,whereas LRisk-LTMB patients had the best prognosis(P<0.0001).Analysis of the scRNAseq data showed that PROM2,SLC7A11,and FANCD2 were significantly differentially expressed,whereas FH was not,suggesting that these genes are expressed mainly in cancer epithelial cells(P<0.01).CONCLUSION Our model helps guide the prognosis of HER2+breast cancer patients,and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.展开更多
Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-neg...Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2−)breast cancer remain unclear.Methods:We retrospectively collected mammography records of an HR+/HER2−breast cancer cohort(n=316)with matched clinicopathological,genomic,transcriptomic,and metabolomic data.On the basis of mammographic images,we grouped tumors by calcification status into calcification-negative tumors,tumors with probably benign calcifications,tumors with calcification of lowmoderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy.We then explored the molecular characteristics associated with each calcification status across multiple dimensions.Results:Among the different statuses,tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores,estrogen receptor(ER)pathway activation,lipid metabolism,and sensitivity to endocrine therapy.Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes,elevated lymph node metastasis incidence,Ki-67 staining scores,genomic instability,cell cycle pathway activation,and may benefit from cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors.Conclusions:Our research established links between tumor calcifications and molecular features,thus proposing potential precision treatment strategies for HR+/HER2−breast cancer.展开更多
Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, ...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.展开更多
Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosph...Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.展开更多
Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with ...Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast cancer.Methods:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and safety.Results:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 months.The overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),respectively.Most adverse events reported were of grade 1/2,and none were of grade 4/5.Conclusions:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast cancer.The combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.展开更多
Human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer is an aggressive phenotype with a poor prognosis,and can easily metastasize and recur.Currently,chemotherapy plus HER2-targeted therapy is th...Human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer is an aggressive phenotype with a poor prognosis,and can easily metastasize and recur.Currently,chemotherapy plus HER2-targeted therapy is the standard systemic treatment for most of these patients.Given that neoadjuvant chemotherapy(NAC)has an efficacy equivalent to that of adjuvant chemotherapy and some additional benefits,many patients,especially those with more advanced tumors,prefer NAC and generally will not receive additional chemotherapy after surgery,irrespective of the pathological response.However,achieving pathological complete response to NAC is strongly correlated with prognosis,especially in triple-negative and HER2-overexpressing breast cancer.Therefore,postoperative treatment of these patients with residual diseases should be optimized to achieve favorable outcomes.The CREATE-X study has confirmed that additional chemotherapy can improve the outcomes of patients with HER2-negative residual disease after NAC.In addition,chemotherapy plays an indispensable role in the treatment of patients who receive surgery directly or who have recurrent lesions.Therefore,can additional chemotherapy improve prognosis of patients with HER2-overexpressing residual breast cancer?At present,no studies have compared the efficacy of additional chemotherapy plus trastuzumab with that of anti-HER2 therapy alone in residual cancer.The KATHERINE study revealed that trastuzumab emtansine(T-DM1)can reduce the risk of recurrence or death by 50%compared with trastuzumab in patients with HER2-positive residual invasive breast cancer after neoadjuvant therapy.T-DM1 is an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine,and thus,to an extent,T-DM1 is equivalent to simultaneous application of chemotherapy and targeted therapy.However,high cost and low accessibility limit its use especially in low-and middle-income countries and regions.Hence,we proposed this perspective that additional chemotherapy plus trastuzumab should be given to HER2-overexpressing breast cancer patients with residual disease after NAC to improve their prognosis by discussing that the efficacy of additional chemotherapy plus trastuzumab is superior to that of anti-HER2 therapy alone and not inferior to T-DM1.Additional chemotherapy plus trastuzumab-based HER2-targeted therapy can be used as an alternative regimen to T-DM1 when T-DM1 is unavailable.However,further clinical research on the selection of chemotherapeutic agents is warranted.展开更多
目的:利用监测、流行病学和最终结果(surveillance,epidemiology,and end results,SEER)数据库构建列线图来预测老年早期HER2阳性乳腺癌患者的生存概率。方法:SEER数据库中筛选的5220名(基于单靶向治疗时代)和1176名(基于双靶向治疗时代...目的:利用监测、流行病学和最终结果(surveillance,epidemiology,and end results,SEER)数据库构建列线图来预测老年早期HER2阳性乳腺癌患者的生存概率。方法:SEER数据库中筛选的5220名(基于单靶向治疗时代)和1176名(基于双靶向治疗时代)患者被随机分为训练组和内部验证组。采用COX比例风险回归筛选生存相关预测因素并建立列线图模型,利用一致性指数(C-index)、校准曲线、受试者工作特征曲线(receiver operating characteristic curve,ROC)检验模型的准确性及实用性。对接受化疗和非化疗的患者使用两组倾向评分匹配进行统计配对,并对筛选的变量进行亚组分析。结果:单靶治疗时代列线图是由七个变量构建:年龄、婚姻状态、T分期、N分期、手术、化疗、放疗。双靶治疗时代列线图由两个变量构建:化疗和放疗。亚组分析结果表明,接受化疗的老年HER2阳性乳腺癌患者有更好的总生存期(OS)。结论:基于SEER数据库,建立并验证了预测老年早期HER2阳性乳腺癌患者生存率的准确列线图。该研究表明,化疗能增加老年患者的生存获益。展开更多
Overexpression of human epidermal growth factor receptor-2(HER2) in metastatic breast cancer(MBC) is associated with poor prognosis.This single-arm open-label trial(EGF109491;NCT00508274) was designed to confirm the e...Overexpression of human epidermal growth factor receptor-2(HER2) in metastatic breast cancer(MBC) is associated with poor prognosis.This single-arm open-label trial(EGF109491;NCT00508274) was designed to confirm the efficacy and safety of lapatinib in combination with capecitabine in 52 heavily pretreated Chinese patients with HER2-positive MBC.The primary endpoint was clinical benefit rate(CBR).Secondary endpoints included progression-free survival(PFS),time to response(TTR),duration of response(DoR),central nervous system(CNS) as first site of relapse,and safety.The results showed that there were 23 patients with partial responses and 7 patients with stable disease,resulting in a CBR of 57.7%.The median PFS was 6.34 months(95% confidence interval,4.93-9.82 months).The median TTR and DoR were 4.07 months(range,0.03-14.78 months) and 6.93 months(range,1.45-9.72 months),respectively.Thirteen(25.0%) patients had new lesions as disease progression.Among them,2(3.8%) patients had CNS disease reported as the first relapse.The most common toxicities were palmar-plantar erythrodysesthesia(59.6%),diarrhea(48.1%),rash(48.1%),hyperbilirubinemia(34.6%),and fatigue(30.8%).Exploratory analyses of oncogenic mutations of PIK3CA suggested that of 38 patients providing a tumor sample,baseline PIK3CA mutation status was not associated with CBR(P = 0.639) or PFS(P = 0.989).These data confirm that the lapatinib plus capecitabine combination is an effective and well-tolerated treatment option for Chinese women with heavily pretreated MBC,irrespective of PIK3CA status.展开更多
Background： We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neo...Background： We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab. Methods： Women （n=372） with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paelitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core- biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy. Results： Eighteen percent （67/372） of patients achieved a pathologic complete response （pCR） in their breast. HER2-positive tumors had a significant higher pCR rate than HER2-negative tumors （33.0% versus 13.5%, P〈0.001） in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio （OR）, 2.26; 95% confidence interval （CI）, 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not （pCR, 27.2% versus 14.6%, P=0.005）. Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2- negative tumors in both anthracycline response group （40.5% versus 20.0%, P=0.025） and anthracycline non-response group （28.3% versus 11.3 %, P=0.002）. Conclusions： Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy.展开更多
基金The Science and Technology Commission of Shanxi province,No.201901D111428.
文摘BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proliferation-related genes with prognosis in HER2+breast cancer(BC)patients is unclear.AIM To identify and evaluate fresh ferroptosis-related biomarkers for HER2+BC.METHODS First,we obtained the mRNA expression profiles and clinical information of HER2+BC patients from the TCGA and METABRIC public databases.A four gene prediction model comprising PROM2,SLC7A11,FANCD2,and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort.Patients were stratified into high-risk and low-risk groups based on their median risk score,an independent predictor of overall survival(OS).Based on these findings,immune infiltration,mutations,and medication sensitivity were analyzed in various risk groupings.Additionally,we assessed patient prognosis by combining the tumor mutation burden(TMB)with risk score.Finally,we evaluated the expression of critical genes by analyzing single-cell RNA sequencing(scRNA-seq)data from malignant vs normal epithelial cells.RESULTS We found that the higher the risk score was,the worse the prognosis was(P<0.05).We also found that the immune cell infiltration,mutation,and drug sensitivity were different between the different risk groups.The highrisk subgroup was associated with lower immune scores and high TMB.Moreover,we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses.HRisk-HTMB patients had the worst prognosis,whereas LRisk-LTMB patients had the best prognosis(P<0.0001).Analysis of the scRNAseq data showed that PROM2,SLC7A11,and FANCD2 were significantly differentially expressed,whereas FH was not,suggesting that these genes are expressed mainly in cancer epithelial cells(P<0.01).CONCLUSION Our model helps guide the prognosis of HER2+breast cancer patients,and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.
基金supported by grants from the National Key Research and Development Project of China(Grant No.2020YFA0112304)the National Natural Science Foundation of China(Grant Nos.81922048,82072922,91959207,and 92159301)+3 种基金the Program of Shanghai Academic/Technology Research Leader(Grant No.20XD1421100)the Shanghai Key Laboratory of Breast Cancer(Grant No.12DZ2260100)the Clinical Research Plan of SHDC(Grant Nos.SHDC2020CR4002 and SHDC2020CR5005)the SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals(Grant No.SHDC12021103).
文摘Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2−)breast cancer remain unclear.Methods:We retrospectively collected mammography records of an HR+/HER2−breast cancer cohort(n=316)with matched clinicopathological,genomic,transcriptomic,and metabolomic data.On the basis of mammographic images,we grouped tumors by calcification status into calcification-negative tumors,tumors with probably benign calcifications,tumors with calcification of lowmoderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy.We then explored the molecular characteristics associated with each calcification status across multiple dimensions.Results:Among the different statuses,tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores,estrogen receptor(ER)pathway activation,lipid metabolism,and sensitivity to endocrine therapy.Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes,elevated lymph node metastasis incidence,Ki-67 staining scores,genomic instability,cell cycle pathway activation,and may benefit from cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors.Conclusions:Our research established links between tumor calcifications and molecular features,thus proposing potential precision treatment strategies for HR+/HER2−breast cancer.
基金supported by the National Natural Science Foundation of China (No. 82003311, No. 82061148016, No. 82230057 and No. 82272859)National Key R&D Program of China (No. 2022YFC2505101)+2 种基金Sun Yat-Sen Clinical Research Cultivating Program (No. SYS-Q202004)Beijing Medical Award Foundation (No. YXJL2020-0941-0760)Guangzhou Science and Technology Program (No. 202102010272 and No. 202201020486)。
文摘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.
基金The National Science and Technology Council of Taiwan funded this study.
文摘Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.
基金supported by grants from the National Key R&D Program of China(Grant No.2018YFC0115204)the National Natural Science Foundation of China(Grant No.81672634)+3 种基金the Chinese Society of Clinical Oncology Foundation(Grant No.Y-2019AZMS-0377)the Beijing Medical Award Foundation(Grant No.YXJL-2020-0941-0763)Beijing Hope Run Special Fund of Cancer Foundation of China(Grant No.LC2019B16)Beijing Xisike Clinical Oncology Research Foundation(Grant No.Y-pirrefabre202101-0008).
文摘Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast cancer.Methods:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and safety.Results:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 months.The overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),respectively.Most adverse events reported were of grade 1/2,and none were of grade 4/5.Conclusions:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast cancer.The combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.
文摘Human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer is an aggressive phenotype with a poor prognosis,and can easily metastasize and recur.Currently,chemotherapy plus HER2-targeted therapy is the standard systemic treatment for most of these patients.Given that neoadjuvant chemotherapy(NAC)has an efficacy equivalent to that of adjuvant chemotherapy and some additional benefits,many patients,especially those with more advanced tumors,prefer NAC and generally will not receive additional chemotherapy after surgery,irrespective of the pathological response.However,achieving pathological complete response to NAC is strongly correlated with prognosis,especially in triple-negative and HER2-overexpressing breast cancer.Therefore,postoperative treatment of these patients with residual diseases should be optimized to achieve favorable outcomes.The CREATE-X study has confirmed that additional chemotherapy can improve the outcomes of patients with HER2-negative residual disease after NAC.In addition,chemotherapy plays an indispensable role in the treatment of patients who receive surgery directly or who have recurrent lesions.Therefore,can additional chemotherapy improve prognosis of patients with HER2-overexpressing residual breast cancer?At present,no studies have compared the efficacy of additional chemotherapy plus trastuzumab with that of anti-HER2 therapy alone in residual cancer.The KATHERINE study revealed that trastuzumab emtansine(T-DM1)can reduce the risk of recurrence or death by 50%compared with trastuzumab in patients with HER2-positive residual invasive breast cancer after neoadjuvant therapy.T-DM1 is an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine,and thus,to an extent,T-DM1 is equivalent to simultaneous application of chemotherapy and targeted therapy.However,high cost and low accessibility limit its use especially in low-and middle-income countries and regions.Hence,we proposed this perspective that additional chemotherapy plus trastuzumab should be given to HER2-overexpressing breast cancer patients with residual disease after NAC to improve their prognosis by discussing that the efficacy of additional chemotherapy plus trastuzumab is superior to that of anti-HER2 therapy alone and not inferior to T-DM1.Additional chemotherapy plus trastuzumab-based HER2-targeted therapy can be used as an alternative regimen to T-DM1 when T-DM1 is unavailable.However,further clinical research on the selection of chemotherapeutic agents is warranted.
文摘Overexpression of human epidermal growth factor receptor-2(HER2) in metastatic breast cancer(MBC) is associated with poor prognosis.This single-arm open-label trial(EGF109491;NCT00508274) was designed to confirm the efficacy and safety of lapatinib in combination with capecitabine in 52 heavily pretreated Chinese patients with HER2-positive MBC.The primary endpoint was clinical benefit rate(CBR).Secondary endpoints included progression-free survival(PFS),time to response(TTR),duration of response(DoR),central nervous system(CNS) as first site of relapse,and safety.The results showed that there were 23 patients with partial responses and 7 patients with stable disease,resulting in a CBR of 57.7%.The median PFS was 6.34 months(95% confidence interval,4.93-9.82 months).The median TTR and DoR were 4.07 months(range,0.03-14.78 months) and 6.93 months(range,1.45-9.72 months),respectively.Thirteen(25.0%) patients had new lesions as disease progression.Among them,2(3.8%) patients had CNS disease reported as the first relapse.The most common toxicities were palmar-plantar erythrodysesthesia(59.6%),diarrhea(48.1%),rash(48.1%),hyperbilirubinemia(34.6%),and fatigue(30.8%).Exploratory analyses of oncogenic mutations of PIK3CA suggested that of 38 patients providing a tumor sample,baseline PIK3CA mutation status was not associated with CBR(P = 0.639) or PFS(P = 0.989).These data confirm that the lapatinib plus capecitabine combination is an effective and well-tolerated treatment option for Chinese women with heavily pretreated MBC,irrespective of PIK3CA status.
基金supported by grants from the National Natural Science Foundation of China (No.81302330,No.30973436 and No.81071629)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (No.2014BAI09B08)the 973 project 2013CB911004 and the 985-Ⅲ project
文摘Background： We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab. Methods： Women （n=372） with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paelitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core- biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy. Results： Eighteen percent （67/372） of patients achieved a pathologic complete response （pCR） in their breast. HER2-positive tumors had a significant higher pCR rate than HER2-negative tumors （33.0% versus 13.5%, P〈0.001） in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio （OR）, 2.26; 95% confidence interval （CI）, 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not （pCR, 27.2% versus 14.6%, P=0.005）. Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2- negative tumors in both anthracycline response group （40.5% versus 20.0%, P=0.025） and anthracycline non-response group （28.3% versus 11.3 %, P=0.002）. Conclusions： Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy.
