A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

Docetaxel plus S-1 versus docetaxel plus capecitabine as first-line treatment for advanced breast cancer patients:a prospective randomized phase II study

Background:This study was conducted to evaluate the efficacy and safety of docetaxel/S-1(TS)compared with docetaxel/capecitabine(TX)as a first-line treatment for advanced breast cancer.Methods:Patients with advanced metastatic breast cancer were randomly divided into the TS group(n=54)and the TX group(n=57)for first-line chemotherapy from August 2015 to April 2019(ClinicalTrials.org registration no.NCT02947061).Following the completion of combination therapy,patients without progression received S-1 or capecitabine maintenance treatment.The primary end point was progression-free survival(PFS).Results:Among 111 enrolled patients,the median PFS did not differ significantly between the TS group and the TX group(TS vs.TX,9.0 vs.7.4 months,P=0.365,95%confidence interval[CI]:0.50-1.11,hazard ratio[HR]:0.75).There was also no statistically significant difference in median overall survival(OS)between the two groups(TS vs.TX,40.2 vs.41.3 months,P=0.976).In addition,visceral metastasis and metastasis sites,such as the liver or lung,did not lead to a significant effect on PFS and OS.The two regimens showed no significant difference in adverse events,except hand-foot syndrome,which predominated in the TX group(38.6%vs.7.4%,P=0.001),and diarrhea(24.1%vs.3.6%,P=0.003)and elevation of aspartate aminotransferase(AST)/alanine aminotransferase(ALT)levels(14.8%vs.3.5%,P=0.049),which were more frequent in the TS group.Conclusions:The TS and TX regimens demonstrated similar efficacy and safety for the first-line treatment of advanced breast cancer.The TS regimen had fewer cases of severe hand-foot syndrome than the TX regimen,representing an effective alternative option to the TX regimen.Further studies are warranted to define the efficacy and safety of this strategy in real-world settings.

Comparison of Letrozole and Aminoglutethimide in Treatment of 113 Cases of Postmenopausal Women with Advanced Breast Cancer

Objective: To compare the efficacy and tolerability of letrozole with aminoglutethimide (AG) in postmenopausal women with advanced breast cancer. Methods: The multicenter, randomized controlled clinical trial was conducted in 113 patients. They randomly received letrozole 2.5 mg once daily (letrozole group) or AG 250 mg 4 times daily (AG group) with hydrocortisone. Results: The OR in letrozole group was 23.73% (2 cases of CR and 12 cases of PR, ITT OR was 21.88%), which was higher than in AG group (the OR 11.11%, 1 CASE of CR and 5 cases of PR, ITT 10.17%), but there was no statistically significant difference (P>0.05). Adverse events (AE) and the treatment related AE (RAE) in letrozole group (n=59) was 18.54% and 13.56% respectively, significantly lower than those (42.11% and 33.33% respectively) in AG group (n=57, P=0.002). Conclusion: The OR of letrozole in the treatment of postmenopausal advanced breast cancer positive or unknown for hormonal receptor is 23.73%, showing no significant difference to that of AG. The AE of letrozole are significantly less than AG.

Efficacy and safety of trastuzumab combined with chemotherapy for first-line treatment and beyond progression of HER2-overexpressing advanced breast cancer

Objective： To observe the efficacy and safety of trastuzumab combined with chemotherapy in patients with human epidermal growth factor receptor 2 （HER2）-overexpressing advanced breast cancer. Methods： A total of 90 patients with HER2-overexpressing advanced breast cancer were enrolled in this study. All patients were diagnosed with ductal invasive breast cancer by pathological analysis, and were aged between 31-73 years with a median of 51 years. HER2-positivity was defined as 3（＋） staining in immunochemistry or amplification of fluorescence in situ hybridization （FISH, ratio ≥2.0）. Trastuzumab was administered in combination with chemotherapy as first-line treatment and beyond progression as a second- line, third-line, and above treatment in 90, 34, 14, and 6 patients, respectively. The chemotherapy regimen was given according to normal clinical practice. The response rate was evaluated every two cycles, and the primary endpoints were progression-free survival （PFS） and overall survival （OS）. Survival curves were estimated by using Kaplan-Meier graphs and were compared by using log-rank test statistics. Multivariate analysis was done using Cox＇s proportional hazards regression model, and the level of significance was P〈0.05. Results： All 90 patients received at least one dose of trastuzumab, and efficacy could be evaluated in 85 patients. The median follow-up was 50 months. In total, 72 （80.00%） patients had visceral metastasis, and 43 （47.78%） patients had progressed after one or more extensive chemotherapy regimens for metastatic diseases. The median PFS for first-line trastuzumab was 10 months （range, 2-59 months）, and the median OS after metastasis or initially local advanced disease was 22 months （range, 2-1 16 months）. Conclusions： Trastuzumab combined with chemotherapy was active and well-tolerated as a first-line treatment and even beyond progression in HER2-overexpressing advanced breast cancer as a second-line or third-line treatment. However, its efficacy is certainly less beyond this point.

Exploratory clinical study of chidamide,an oral subtype-selective histone deacetylase inhibitor,in combination with exemestane in hormone receptor-positive advanced breast cancer

Objective: The recurrence or progression under endocrine therapy in hormone receptor-positive(HR+)advanced breast cancer(ABC) remained a critical clinical challenge.Chidamide is an oral subtype-selective histone deacetylase(HDAC) inhibitor with multiple functions in tumor growth inhibition and microenvironment modulation via epigenetic reprogramming.The purpose of this study was to evaluate the safety,pharmacokinetics(PK),and preliminary efficacy of chidamide in combination with exemestane in HR+ ABC patients.Methods: Eligible patients were postmenopausal women with HR+ ABC recurrent or progressed to at least one endocrine therapy.Blood samples were obtained in the run-in period and the first day of combination treatment for PK analysis.In combination treatment,patients were given exemestane 25mg daily and chidamide 30mg twice a week(BIW) until progression of disease or intolerable toxicities.A treatment cycle was defined as 4 weeks.Safety,PK parameters,and preliminary efficacy were evaluated.Results: A total of 20 patients were enrolled between July and December,2015.The median number of treatments cycle was 5.2(20.8 weeks) with 2 patients still on treatment at the data cut-off date of October,2017.The treatment-related adverse events(AE) ≥ grade 3 in more than 2 patients were neutropenia(35%),thrombocytopenia(30%),and leucopenia(20%).The plasma exposure of exemestane was consistent in the presence or absence of chidamide.A slight increase in chidamide exposure was noted in the presence of exemestane,probably due to the inter-and intra-patient variations.The best response in 16 evaluable patients was assessed by Response Evaluation Criteria in Solid Tumors(RECIST),including 4 patients with partial response,10 patients with stable disease.The median progression-free survival(PFS) was 7.6 months.Conclusions: The combination of chidamide with exemestane was generally well tolerated with promising preliminary efficacy in HR+ ABC patients.The overall results from this study encourage further pivotal trial in this patient population.

Symptom burden in advanced breast cancer patients and its association between death anxiety and psychological distress

Objective:Recent research has documented psychological distress in advanced breast cancer(ABC)patients,but few studies have examined how death anxiety is affected by the symptom burden.Therefore,this study aims to explore the association among symptom burden,death anxiety and psychological distress(depression and anxiety)in ABC patients.Methods:This cross-sectional study used the Death and Dying Anxiety Scale(DADDS),9-item Patient Health Questionnaire(PHQ-9),General Anxiety Disorder-7(GAD-7)and MD Anderson Symptom Inventory(MDASI)to assess death anxiety,depression,anxiety,and symptom burden,respectively.Bias-corrected bootstrapping methods were used to estimate indirect effects and 95%confidence intervals.Results:Two hundred ABC patients completed the questionnaires.All of the respondents were females,with a mean age of 50±10 years.Initial correlation analyses revealed significant associations of death anxiety with depression(r=0.57,P<0.001),anxiety(r=0.60,P<0.001)and symptom burden(r=0.43,P<0.001).Moreover,depression(r=0.53,P<0.001)and anxiety(r=0.45,P<0.001)were significantly correlated with symptom burden.An analysis using Hayes’PROCESS macro revealed the partial effecting role of death anxiety in the relationship between depression and symptom burden,and between anxiety and symptom burden(contributions to the total effect of 0.247 and 0.469,respectively).Conclusions:This study provides insight into the relationship between death anxiety and symptom burden.The results suggest that interventions addressing death anxiety may be more effective for alleviating the depression and anxiety experienced by ABC patients with a symptom burden.

Clinical observation of capecitabine monotherapy in elderly patients with advanced breast cancer

Objective The aim of the study was to evaluate the safety and efficacy of capecitabine mono-chemotherapy in elderly patients with advanced breast cancer. Methods The data from 36 cases of capecitabine monotherapy in elderly patients with advanced breast cancer were retrospectively analyzed. Oral administration of capecitabine 2000 mg/m^2 twice daily （D1-14） for 21 days constituted a cycle. The effect of the disease and main adverse reactions were evaluated every 2 cycles. Results The data from 36 elderly patients were studied. The median number of chemotherapy cycles was 4. The total effective rate was 30.6% （11/36） and the disease control rate was 72.2% （26/36）. The number of patients with clinical comptete remission was 2, clinical partial response was 9, stable disease was 15, and progressive disease was 10. Where treatment was effective, the median time to progression was 6 months and the median overall survival was 9.5 months. The main adverse events were gastrointestinal reactions, bone marrow suppression, and oral mucositis; most of the reactions were grade 1 to 2. Grade 3 to 4 adverse reactions included granulocytopenia in 2 patients （12.5%） and hand-foot syndrome in 1 patient （6.7%）. Conclusion Capecitabine monotherapy was effective in controlling disease progression, and adverse reactions were tolerated by elderly patients with advanced breast cancer.

Gemcitabine Based Combination Regimens for Treatment of Refractory Advanced Breast Cancer

Objective： Anthracycline and taxane are the standard agents in combined chemotherapy of advanced breast cancer. However, when these agents based chemotherapy is failure, the selection of salvage regimen is still of problem. Gemcitabine, an active agent in both lung cancer and pancreas cancer, is demonstrated effective in breast caner. But there have been relatively less data of gemcitabine in anthracycline and/or taxane-resistant breast cancer. Therefore we employe this study to explore the efficacy and safety of gemcitabine based combination regimen in this population. Methods： From May 2002 to March 2006, 28 patients with measurable lesion of advanced metastatic breast cancer who were resistant to prior anthracycline and taxane based chemotherapy were enrolled. Patients were treated with gemcitabine based combination chemotherapy with a median cycles of 3 （range 2-6）. Results： The overall response rate was 28.6% （8/28）, with 1 CR （Complete response 3.5%） and 7 PRs （Partial response 25%）. Stable disease was seen in 8 patients （28.6%） while disease progressed in 12 patiens （42.8%）. The median time to progression was 4.5 m （range, 2-23 m）. The main toxicity included bone marrow depression, alopecia, mucositis and peripheral neurotoxicity. The grade 3 to 4 clinical adverse effect was leukopenia in 5 cases （17.9%） and thrombocytopenia in 8 cases （30%）. Conclusion： Gemcitabine based combination regimens is feasible in anthracycline and taxane-resistant advanced breast cancer. The clinical response and TTP is acceptable with limited toxicity pattern.

Comparison of vinorelbine plus cisplatin with vinorelbine plus capecitabine in patients with anthracyclines- and taxanes-refractory advanced breast cancer

Objective: The aim of our study was to compare the efficacy and toxicities of vinorelbine plus cisplatin(NP) regimen with that of vinorelbine plus capecitabine(NX) regimen in the treatment of anthracycline- and taxane-refractory advanced breast cancer. Methods: Forty-six patients with anthracycline- and taxane-refractory advanced breast cancer were equally randomized into a NP group(n = 23) and a NX group(n = 23). Response rates and toxicities were evaluated after 2 cycles of chemotherapy. Results: The overall response rate were 48.0% in both groups. There were no significant differences in disease control rates(78.0% vs. 83%) or 1-year survival rates(54.6% vs. 55.9%). The main adverse events were bone marrow depression and gastrointestinal reaction, and no significant difference was found in toxicities between the groups. Conclusion: For anthracycline- and taxane-refractory advanced breast cancer, NP and NX regimens exerted similar curative effects with acceptable toxicity.

Evaluation of dynamic contrast-enhanced MRI in monitoring early response of locally advanced breast cancer to neoadjuvant chemotherapy

Objective： The aim of our study was to assess the value of dynamic contrast-enhanced magnetic resonance imaging （DMRI） in predicting early response to neoadjuvant chemotherapy （NAC） in patients with locally advanced breast cancer （LABC） and to assess the accuracy of DMRI in evaluating residual disease after NAC. Methods： DMRI were per- formed in 43 women with LABC （44 lesions, all were invasive ductal carcinoma） before, after the first and final cycle of NAC. Tumour volume, early enhanced ratio （El）, maximum enhanced ratio （Emax）, and maximum enhanced time （Tmax）, dynamic signal intensity-time curve were obtained during treatment. Residual tumour volumes obtained using DMRI were compared with pathological findings to assess the accuracy of DMRI. Results： After 1st cycle of NAC, the mean volume of responders decreased insignificantly, P 〉 0.05, but after NAC, mean volume of residual tumor decreased significantly （P 〈 0.01）. Morphol- ogy change： 29 cases showed a concentric shrinkage pattern while 7 cases showed a dendritic shrinkage pattern. Significant differences were found in El, Emax and Tmax between responders and non-responders （P 〈 0.05）. After 1st cycle of NAC, El, Emax and Tmax of responders changed significantly （P 〈 0.001）; while there is no significant change in non-responders （P 〉 0.05）. After NAC, dynamic signal intensity-time types were changed in responders, and tended to be significantly flat- tening, while no significant change was found in non-responders. The residual tumour volume correlation coefficient between DMRI and pathology measurements was very high （r = 0.866, P = 0.000）. Conclusion： DMRI is useful to evaluate the early response to NAC in LABC. The presence and volume of residual disease in LABC patients treated with NAC could be ac- curately evaluated by DMRI.

Evaluation of the effect of neoadjuvant chemotherapy on tumor and axillary lymph nodes in locally advanced breast cancer: a study of 50 patients

Objective： The purpose of the study was to correlate between effect of pre-neoadjuvant chemotherapy （NACT） and post-NACT clinical, sonographic and pathologic features of the tumor and axillary lymph nodes （ALNs） and to raise the possibility of applying the concept of sentinel lymph node biopsy （SLNB） in patients with initially positive ALNs before NACT. Methods： A prospective study of 50 female patients with locally advanced breast cancer （LABC） with clinically palpable.and cytologically （under ultrasonographic guidance） positive ALNs. All patients received NACT and then referred for ultrasono- graphic assessment of the axilla regarding any detectable sonographic criteria of metastatic deposits in ALNs as well as the tumor size in relation to its prechemotherapy size, All patients were then subjected either to modified radical mastectomy or breast conserving surgery. The clinical, sonographic and pathological response of the tumor and the ALNs were documented, classified and correlated with each other. Results： Patients＇ mean age was 47.7±9.1 years. The mean clinical tumor size was 6.7 ± 1.4 cm; stage IliA that was presented in 32 patients （64%） and IIIB was presented in 18 patients （36%）. Chemotherapy was given for a median of 4 cycles, there was reduction of the mean clinical tumor size from 6.7 ± 1.4 cm to 4.3 ± 2.7 cm （P 〈 0.001）. Clinical response was complete in 5 （10%） tumors, complete pathological tumor response （post-neoadjuvant） was detected in 6 （16%） of patients. Complete clinical nodal response （post-neoadjuvant） in 23 （46%） axillae, on sonographic assessment of the axilla, response was complete in 17 （34%） axillae. Complete pathological nodal response occurred in 16 （32%） axillae. Out of 17 axillae that showed complete sonographic response 11 axillae showed complete pathological nodal response （P 〈 0.001）. Conclusion： Formal axillary lymph node dissection can be avoided and replaced by SLNB post NACT in patients with LABC with metastatic ALNs if there were complete clinical and sonographic criteria of nodal response as well as complete pathological tumor response.

A narrative review on palbociclib for hormone receptor-positive and human epidermal growth factor receptor-2 negative advanced breast cancer

As a specific cyclin-dependent kinase 4/6 inhibitor,palbociclibimproved the prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer.Emerging data showed that palbociclib shed a new therapeutic regimen forbreast cancers and playsan essentialmilestone in the development of anti-tumor drugs,especially for advanced breast cancer.In this minireview,we aimed to summarize the mechanism,clinical application,and side effectsof palbociclib.

Entinostat,a classⅠselective histone deacetylase inhibitor,plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer:A multicenter,randomized,double-blind,placebo-controlled,phase 3 trial

Entinostat plus exemestane in hormone receptor-positive(HR+)advanced breast cancer(ABC)previously showed encouraging outcomes.This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR+ABC that relapsed/progressed after≥1 endocrine therapy.Patients were randomized(2:1)to oral exemestane 25 mg/day plus entinostat(n=235)or placebo(n=119)5 mg/week in 28-day cycles.The primary endpoint was the independent radiographic committee(IRC)-assessed progression-free survival(PFS).The median age was 52(range,28—75)years and 222(62.7%)patients were postmenopausal.CDK4/6 inhibitors and fulvestrant were previously used in 23(6.5%)and 92(26.0%)patients,respectively.The baseline characteristics were comparable between the entinostat and placebo groups.The median PFS was 6.32(95%CI,5.30—9.11)and 3.72(95%CI,1.91—5.49)months in the entinostat and placebo groups(HR,0.76;95%CI,0.58—0.98;P=0.046),respectively.Grade≥3 adverse events(AEs)occurred in 154(65.5%)patients in the entinostat group versus 23(19.3%)in the placebo group,and the most common grade≥3 treatment-related AEs were neutropenia[103(43.8%)],thrombocytopenia[20(8.5%)],and leucopenia[15(6.4%)].Entinostat plus exemestane significantly improved PFS compared with exemestane,with generally manageable toxicities in HR+ABC(ClinicalTrials.gov#NCT03538171).

Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing

Objective:To compare the efficacy of platinum-and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer(TNBC)and analyze the relationship between their efficacy and BRCA gene status.Methods:Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology,Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy.A total of 114 patients had BRCA1/2 gene tested by next generation sequencing(NGS)using peripheral blood,and we analyzed the correlation between their efficacy and BRCA1/2 gene status.Results:Non-platinum-based chemotherapy(NPCT)was administered to 129 and platinum-based chemotherapy(PBCT)to 91 study patients.The clinical benefit rate(CBR)and median progression-free survival(PFS)were not statistically different between NPCT and PBCT groups.The median overall survival(OS)was 30.0 and 22.5 months for PBCT and NPCT group,respectively[P=0.090,hazard ratios(HR)=0.703].BRCA status was assessed in 114 patients,14 of whom had deleterious germline BRCA1/2(g BRCA)mutations(seven in each group).In PBCT group,the CBR was 85.7%and 35.1%for patients with and without deleterious g BRCA mutations,respectively(P=0.039).The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious g BRCA mutations,respectively(P=0.001,P=0.161,respectively).Patients in PBCT group had significantly greater rates of grade 3-4 anemia(5.5%vs.0%)and thrombocytopenia(8.8%vs.0%),whereas palmar-plantar erythrodysesthesia(12.4%vs.0%)and peripheral neuropathy(8.6%vs.1.1%)occurred more frequently in NPCT group.Conclusions:Platinum-based regimens are more effective in patients with deleterious g BRCA mutations,but no difference in patients without BRCA gene mutations,so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect.And we recommend that patients with advanced TNBC should have BRCA gene test.

Advances in endocrine and targeted therapy for hormone-receptorpositive,human epidermal growth factor receptor 2-negative advanced breast cancer

Nearly 70%of breast cancer(BC)is hormone-receptor(HR)-positive,human epidermal growth factor receptor 2(HER2)-negative,and endocrine therapy is the mainstay of treatment for this subtype.However,intrinsic or acquired endocrine resistance can occur during the endocrine treatment.Based on insights of endocrine resistance mechanisms,a number of targeted therapies have been and continue to be developed.With regard to HR-positive,HER2-negative advanced BC,aromatase inhibitor(AI)is superior to tamoxifen,and fulvestrant is a better option for patients previously exposed to endocrine therapy.Targeted drugs,such as cyclindependent kinases(CDK)4/6 inhibitors,mammalian target of rapamycin(mTOR)inhibitors,phosphoinositide-3-kinase(PI3K)inhibitors,and histone deacetylase(HDAC)inhibitors,play a significant role in the present and show a promising future.With the application of CDK4/6 inhibitors becoming common,mechanisms of acquired resistance to them should also be taken into consideration.

Overcoming resistance to endocrine therapy in hormone receptorpositive human epidermal growth factor receptor 2-negative(HR^(+)/HER2^(-))advanced breast cancer:a meta-analysis and systemic review of randomized clinical trials

New targeted therapies have been developed to overcome resistance to endocrine therapy(ET)and improve the outcome of HR^(+)/HER2^(-)advanced breast cancer(ABC).We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR^(+)/HER2^(-)ABC.PUBMED and EMBASE databases were searched for eligible trials.Hazard ratios(HRs)for progression-free survival(PFS),odds ratios(ORs)for objective response rate(ORR),clinical benefit rate(CBR),and toxicity were meta-analyzed.Twenty-six studies with data on 10347 patients were included and pooled.The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS(pooled HR=0.547,P<0.001),overall survival(pooled HR=0.755,P<0.001),and tumor response rates(ORR,pooled OR=1.478,P<0.001;CBR,pooled OR=1.201,P<0.001)with manageable toxicities(pooled OR=3.280,P<0.001).The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients.Moderate improvement in PFS(pooled HR=0.686,P<0.001)yet pronounced toxicities(pooled OR=2.154,P<0.001)were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant.Future studies are warranted to optimize the population and the dosing sequence of these available options.

Metronomic chemotherapy of cyclophosphamide plus methotrexate for advanced breast cancer:Real-world data analyses and experience of one center

Background:Real-world data of the CM regimen[cyclophosphamide(CTX)plus methotrexate(MTX)]in metronomic pattern for advanced breast cancer is limited to small-sample or retrospective studies.This study was aimed to determine the effectiveness and safety of CM regimen in treating advanced breast cancer and to identify which patients are most likely to benefit from metronomic CM regimen.Methods:Patients with advanced breast cancer who received the metronomic CM regimen at least once between January 2009 and February 2019 in Sun Yat-sen University Cancer Center were included.Clinicopathological characteristics were collected.Overall survival(OS)and progression-free survival(PFS)were assessed using Kaplan-Meier estimates.Characteristics between patients with PFS<6 months and≥6 months were compared using the Chi-square test.Univariate and multivariate Cox regression model was used to estimate the prognostic factors for PFS and OS.Results:A total of 186 patients were included.The median age and follow-up were 49 years and 13.3 months,respectively.Over 50%of the patients were estrogen receptor/progesterone receptor-positive,and 60.8%had been heavily treated(≥3 lines).The objective response rate was 3.8%,the disease control rate at 12 weeks was 41.4%,and the clinical benefit rate at 24 weeks was 31.2%(58/186).The median PFS was 4.0 months[95%confidence interval(CI):3.6-4.7 months],the median duration of clinical benefit was 9.5 months(95%CI:8.2-10.8 months),and the median OS was 26.8 months(95%CI:20.9-37.7 months).Multivariate analysis for PFS revealed the CM regimen as maintenance therapy and no liver metastasis as favorable prognostic factors.Furthermore,patients without liver metastasis were more likely to have a PFS over 6 months than those with liver involvement(P=0.022).Liver,lymph node,and brain metastases were unfavorable prognostic factors for OS.The CM regimen was well-tolerated without newly reported adverse events.Conclusions:The CM regimen was effective in selected patients.In clinical practice,it would be better used as maintenance therapy and in patients without liver metastasis.Further follow-up investigation should be performed to examine its effect when used in combination with other treatments and determine predictive biomarkers.

The safety and efficacy of palbociclib in older patients with advanced breast cancer in a real-world setting

Aims:Palbociclib has been approved in combination with endocrine therapy(ET)for hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2-)advanced breast cancer(ABC),regardless of age.Even though ABC is one of the most prevalent cancers in older patients,very few patients≥65 years old were included in pivotal trials.Therefore,the current study evaluated the safety and efficacy of palbociclib in“real-world”routine treatment of unselected older patients with HR+/HER2-ABC.Methods:Data were collected on patients>70 years old who were treated with palbociclib plus ET for HR+/HER2-ABC in our institution.We analyzed safety data(CTCAE v4.0 criteria)and outcomes,such as progression-free survival(PFS)and overall survival(OS),as well as any associations between main geriatric characteristics and our results.Furthermore,we assessed safety at a national level by analyzing all palbociclib-related adverse events(AEs)reported in the French Pharmacovigilance Database(FPVD)during the same period.Results:From February 2016 to July 2019,52 patients were identified with a median age of 80.9 years,of whom 88%presented an AE.The most common grade 3-4 AE was neutropenia(64%).Median PFS and OS were nine months and not reached,respectively.The FPVD reports 227 cases of palbociclib-related AEs,with older and younger patients sharing similar characteristics.Conclusion:Palbociclib is well tolerated in older patients with efficacy comparable to that in younger patients.However,the addition of palbociclib to ET should be evaluated individually in this older and frailer subgroup.

Bilateral oophorectomy combined with exemestane treating advanced refractory breast cancer

Objective： Taking tamoxifen orally is the main endocrine therapy of the premenopausal breast cancer with positive hormone receptor, but numerous patients developed to be advanced refractory breast cancer because of drug resistance. Our study investigated a role of the combination of bilateral oophorectomy and exemestane in the management of advanced refractory breast cancer. Methods： The bilateral oophorectomy was carried out in 17 patients. One week after the operation, exemestane was taken orally （25 mg/d）. The median time to progression （TTP）, the median survival time and the survival rate were calculated using Kaplan-Meier methods. Results： Seventeen patients age ranged from 26 to 44 years （median, 36 years） were treated with an overall response rate of 64.70%, TTP was 8 months and the median survival time was 31 months. The survival rate of 1-year, 3 years and 5 years was 88.24%, 64.71%, 29.41%, respectively. There have no grade Ⅲ/Ⅳ side effects appeared. Conclusion： Bilateral oophorectomy combined with exemestane is safe and effective for advanced refractory premenopausal breast cancer with positive hormone receptor and it is well-torerated.

Multicenter phaseⅡstudy of apatinib single or combination therapy in HER2-negative breast cancer involving chest wall metastasis

Objective:Breast cancer(BC)with chest wall metastasis(CWM)usually shows rich neovascularization.This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2(HER2)-negative advanced BC involving CWM.Methods:This trial involved four centers in China and was conducted from September 2016 to March 2020.Patients received apatinib 500 mg/d[either alone or with endocrine therapy if hormone receptor-positive(HR+)]until disease progression or unacceptable toxicity.Progression-free survival(PFS)was the primary endpoint.Results:We evaluated 26 patients for efficacy.The median PFS(mPFS)and median overall survival(mOS)were4.9[range:2.0-28.5;95%confidence interval(95%CI):2.1-8.3]months and 18(range:3-55;95%CI:12.9-23.1)months,respectively.The objective response rate(ORR)was 42.3%(11/26),and the disease-control rate was76.9%(20/26).In the subgroup analysis,HR+patients compared with HR-negative patients had significantly improved mPFS of 7.0(95%CI:2.2-11.8)months vs.2.3(95%CI:1.2-3.4)months,respectively(P=0.001);and mPFS in patients without or with chest wall radiotherapy was 6.4(95%CI:1.6-19.5)months vs.3.0(95%CI:1.3-4.6)months,respectively(P=0.041).In the multivariate analysis,HR+status was the only independent predictive factor for favorable PFS(P=0.014).Conclusions:Apatinib was highly effective for BC patients with CWM,especially when combined with endocrine therapy.PFS improved significantly in patients with HR+status who did not receive chest wall radiotherapy.However,adverse events were serious and should be carefully monitored from the beginning of apatinib treatment.