Safety,tolerability,and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer:An open-label,dose-escalation,phase I study

Background:The introductions of anti-human epidermal growth factor receptor-2(HER2)agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer.BAT8001 is a novel antibodydrug conjugate targeting human epidermal growth factor receptor-2(HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine.This dose-escalation,phase I study was designed to assess the safety,tolerability,pharmacokinetics,and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.Methods:This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer(having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1)using a 3+3 design of escalating BAT8001 doses.Patients received BAT8001 intravenously in a 21-day cycle,with dose escalation in 5 cohorts:1.2,2.4,3.6,4.8,and 6.0 mg/kg.The primary objective was to evaluate the safety and tolerability of BAT8001.Preliminary activity of BAT8001 was also assessed as a secondary objective.Results:Between March 2017 to May 2018,29 HER2-positive breast cancer patients were enrolled.The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase.The maximum tolerated dose was determined to be 3.6 mg/kg.Grade 3 or greater adverse events(AEs)occurred in 14(48.3%)of 29 patients,including thrombocytopenia in 12(41.4%)patients,aspartate aminotransferase increased in 4(13.8%)patients,γ-glutamyl transferase increased in 2(6.9%)patients,alanine aminotransferase increased in 2(6.9%)patients,diarrhea in 2(6.9%)patients.Objective response was observed in 12(41.4%,95%confidence interval[CI]=23.5%-61.1%)and disease control(including patients achieving objective response and stable disease)was observed in 24(82.8%,95%CI=64.2%-94.2%)patients.Conclusions:BAT8001 demonstrated favorable safety profiles,with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer.BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

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.

CPSF4 promotes triple negative breast cancer metastasis by upregulating MDM4

Dear Editor,Breast cancer(BrC)is the most common cancer in women.Triple negative BrC(TNBC)is the subtype with highly aggressive clinical behaviors and heterogeneity.Metastasis is the leading cause of TNBC-related deaths,but its mechanism is not well-understood.Apart from PIK3CA,TP53,and PTEN,few recurrent mutations have been identified in TNBC so far,suggesting that TNBC phenotype could be driven by nongenetic alterations such as aberrant expression of oncogenes.