Publications by authors named "Binghe Xu"

218 Publications

Profile, treatment patterns, and influencing factors of anthracycline use in breast cancer patients in China: A nation-wide multicenter study.

Cancer Med 2021 Sep 2. Epub 2021 Sep 2.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Anthracycline-based chemotherapy (ABC) is one of the standard therapies against breast cancer. However, few guidelines are currently available to optimize the use of ABC. Therefore, the present analysis aimed at determining the profile and treatment patterns of ABC and the association of clinicopathological characteristics with ABC selection.

Methods: We retrospectively analyzed the data of a nation-wide multicenter epidemiological study, which collected the medical records of breast cancer patients receiving chemotherapy in different settings from seven geographic regions in China (NCT03047889).

Results: In total, 3393 patients were included, with 2917 treated with ABC. Among them, 553 (89.8%), 2165 (81.7%), and 814 (25.7%) were subjected to ABC as neoadjuvant, adjuvant, and advanced chemotherapy, respectively. The most frequently used regimens were anthracycline-taxane-based combinations for neo- and adjuvant chemotherapy, along with taxanes and oral fluorouracils for the palliative stages. In the overall cohort, patients aged < 40 or 40-65 (p < 0.001), in premenopause (p < 0.001), without comorbidities (p = 0.016), with invasive ductal carcinoma (p= 0.001), high lymph node involvement (p < 0.001), in the pTNM stage II, III, or IV versus stage I (p < 0.001), subjected to mastectomy (p < 0.001) or subjected to sentinel lymph node biopsy combined with axillary lymph node dissection (p = 0.044), or with a decreased disease-free survival (p < 0.001) were more likely to be recommended to ABC.

Conclusion: Taken together, ABC remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy. ABC was mainly used as a combination therapy, and the correlation between influencing factors and ABC choice varied during different settings, indicating the preference and different perspectives of medication considered by medical oncologists regarding the use ABC in China.
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http://dx.doi.org/10.1002/cam4.4215DOI Listing
September 2021

Effectiveness of Adding Everolimus to the First-line Treatment of Advanced Breast Cancer in Premenopausal Women Who Experienced Disease Progression While Receiving Selective Estrogen Receptor Modulators: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Aug 26:e213428. Epub 2021 Aug 26.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Importance: The effectiveness of the mammalian target of rapamycin (mTOR) inhibitor everolimus in premenopausal women with hormone receptor (HR)-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving selective estrogen receptor modulators (SERMs) is unknown.

Objective: To compare the effectiveness of everolimus plus letrozole vs letrozole alone in premenopausal women with HR-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs.

Design, Setting, And Participants: The Everolimus Trial for Advanced Premenopausal Breast Cancer (MIRACLE) was a multicenter, open-label phase 2 randomized clinical trial of everolimus plus letrozole vs letrozole alone as first-line treatment conducted from December 8, 2014, to September 26, 2018. Participants included premenopausal women with HR-positive, ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Analysis was performed on an intent-to-treat basis from January 5, 2015, to December 30, 2019.

Exposures: Patients were randomly assigned in a 1:1 ratio to receive everolimus (10 mg orally once daily) plus letrozole (2.5 mg orally once daily) (n = 101) or letrozole alone (2.5 mg orally once daily) (n = 98). Both groups received goserelin, 3.6 mg, subcutaneously on day 1 of each 28-day cycle. Patients in the letrozole group were permitted to cross over to receive everolimus with letrozole if disease progression occurred.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS), defined as the time from randomization to confirmed disease progression or death due to any cause.

Results: A total of 199 women (mean [SD] age, 44.3 [6.3] years) were randomized. Patients receiving everolimus plus letrozole achieved a significantly longer median PFS compared with those receiving letrozole alone (19.4 months [95% CI, 16.3-22.0 months] vs 12.9 months [95% CI, 7.6-15.7 months]; hazard ratio, 0.64 [95% CI, 0.46-0.89]; P = .008). A total of 56 of the 98 patients in the letrozole group (57.1%) were crossed over to also receive everolimus. The median PFS after crossover was 5.5 months (95% CI, 3.8-8.2 months).

Conclusions And Relevance: In this randomized clinical trial, PFS was significantly longer among premenopausal patients with HR-positive/ERBB2-negative advanced breast cancer who received everolimus plus letrozole than among those who received letrozole alone. The results revealed that everolimus was effective even among patients receiving treatment with the same endocrine agent after disease progression.

Trial Registration: ClinicalTrials.gov Identifier: NCT02313051.
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http://dx.doi.org/10.1001/jamaoncol.2021.3428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391779PMC
August 2021

Assessment of racial differences in the incidence of thrombocytopenia induced by trastuzumab emtansine: a systematic review and meta-analysis.

Ann Transl Med 2021 Jul;9(14):1139

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Trastuzumab emtansine (T-DM1) has been proved to have value and efficacy in the treatment of advanced metastatic cancer, including in the adjuvant setting. However, there is increasing concern about T-DM1-induced thrombocytopenia (TCP), which shows racial differences in incidence. This meta-analysis aimed to evaluate differences in the incidence of T-DM1-related TCP between Asian and non-Asian patients by combining accessible information from all single-agent T-DM1 clinical trials published to date.

Methods: We conducted systematic searches of the PubMed, Embase, and the Cochrane Library databases to identify relevant clinical studies of T-DM1 that reported on safety, including the incidence of TCP, which were published between January 1980 and March 2020. Two reviewers were responsible for the screening and extraction of data. The pooled-effect estimate calculated with a fixed-effects or random-effects model was represented as incidence with 95% confidence intervals (CIs).

Results: A total of 29 studies involving 6,188 patients were included. The incidence of all-grade TCP in Asian patients and non-Asian patients was 0.39 (95% CI: 0.11-0.67) and 0.29 (95% CI: 0.23-0.35), respectively. The incidence of TCP of grade 3 or higher in Asians was 0.20 (95% CI: 0.10-0.29), compared with 0.02 (95% CI: 0.01-0.03) in non-Asians. Gastrointestinal cancer type and a T-DM1 treatment dose of 2.4 mg/kg Q3W were related to grade 3 or higher TCP events.

Discussion: Asian patients have a higher risk of developing TCP after receiving T-DM1 than non-Asian patients. Clinicians should be aware of the importance of careful observation of platelet count in patients receiving T-DM1 therapy.
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http://dx.doi.org/10.21037/atm-21-2763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350666PMC
July 2021

The molecular tumor burden index as a response evaluation criterion in breast cancer.

Signal Transduct Target Ther 2021 Jul 7;6(1):251. Epub 2021 Jul 7.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Circulating tumor DNA (ctDNA) is a potential biomarker of prognosis and therapeutic response. We conducted this study to explore the role of the molecular tumor burden index (mTBI) in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study. We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study (NCT01917279). Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples. The pretreatment mTBI value was correlated with tumor burden (P = 0.025). Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI, and the median overall survival was 40.9 months and 68.4 months, respectively (P = 0.011). Patients with mTBI decrease to less than 0.02% at the first tumor evaluation had longer progression-free survival and overall survival (P < 0.001 and P = 0.007, respectively). The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans (88.5% and 87.5%, respectively). The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort (P < 0.001 and P = 0.036, respectively), as well as in the cohort in which computed tomography scans were defined as representing stable disease (P = 0.027 and P = 0.015, respectively). The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.
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http://dx.doi.org/10.1038/s41392-021-00662-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260637PMC
July 2021

Phase I Study and Pilot Efficacy Analysis of Entinostat, a Novel Histone Deacetylase Inhibitor, in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer.

Target Oncol 2021 Jul 1. Epub 2021 Jul 1.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China.

Background: Previous clinical trials have demonstrated that entinostat in combination with exemestane had good tolerability and significant clinical efficacy in patients with advanced hormone receptor positive (HR+) and HER2 negative (HER2-) metastatic breast cancer (MBC) in the USA. However, no clinical trials have been conducted in Chinese populations.

Objective: To investigate the safety, pharmacokinetics, and pilot efficacy of entinostat with or without exemestane in Chinese postmenopausal patients with locally advanced or metastatic HR+ /HER2- MBC.

Patients And Methods: Nineteen patients received entinostat for 4 weeks (dose-limiting toxicity (DLT) observation stage) at 3, 5, or 7 mg/week, with a "3+3" dose-escalation design and in combination with exemestane thereafter (extended treatment stage: entinostat, 3 or 5 mg/week; exemestane, 25 mg/day). An additional 21 patients were enrolled to assess the entinostat (5 mg) plus exemestane (25 mg) pharmacokinetic profile and potential efficacy.

Results: The peak entinostat serum concentration and area under the curve increased dose proportionally, without significant interaction between entinostat and exemestane. Entinostat was well tolerated at all doses. The most common grade 3/4 adverse effects (AEs) included neutropenia (31.6%) and thrombocytopenia (15.8%). In the DLT observation stage, grade 3/4 AEs accounted for 16.7% in the 5 mg group with one suspicious DLT (G3 ventricular tachycardia) and 33.3% in the 7 mg group. In the extended treatment stage, 2/16 patients achieved partial response and three patients experienced stable disease (> 12 weeks). The median progression-free survival was 9.41 months for the additional 21 patients, who experienced grade 3/4 AEs of neutropenia (38%), thrombocytopenia (9.5%), anemia (9.5%), and fatigue (9.5%).

Conclusion: Entinostat with exemestane showed reasonable safety, tolerability, and encouraging efficacy in Chinese patients with HR+/HER2- MBC. These results support further evaluation in a randomized, double-blind Phase III study with a weekly 5 mg entinostat dose in a Chinese population.

Trial Registration: NCT02833155.
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http://dx.doi.org/10.1007/s11523-021-00823-4DOI Listing
July 2021

Epithelial-Mesenchymal-Transition-Like Circulating Tumor Cell-Associated White Blood Cell Clusters as a Prognostic Biomarker in HR-Positive/HER2-Negative Metastatic Breast Cancer.

Front Oncol 2021 2;11:602222. Epub 2021 Jun 2.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Although positive Circulating tumor cells (CTCs) status has been validated as a prognostic marker in breast cancer, the interaction between immune cells and CTCs during the progress of Epithelial-mesenchymal-transition (EMT), and the clinical implications of CTC-associated white blood cell clusters (CTC-WBC clusters) for metastatic breast cancer are largely uncharacterized.

Methods: We optimized a filter-based method combined with an RNA hybridization technique according to the epithelial- and mesenchymal-markers to analyze EMT in CTC-WBC clusters. Serial peripheral blood samples from 135 patients with Hormone receptor (HR)-positive/HER2-negative metastatic breast cancer receiving first-line chemotherapy with docetaxel plus capecitabine were prospectively collected until disease progression from Nov 2013 to March 2019. Follow-up data collection was conducted until July 2020.

Results: A total of 452 blood samples at all time-points were collected and analyzed. Median age of the cohort was 51.0 years (range, 27 to 73 years), and most of them (76.3%) had visceral metastases. Median progression-free survival (PFS) was 10.6 months (95% CI, 8.8 to 12.3 months). The presence of EMT-like CTC-WBC clusters was more frequently evident among patients with simultaneous bone and lymph node metastases (87.5% 36.2%, =0.006), whereas no associations were observed between CTC-WBC clusters and other clinicopathologic characteristics before chemotherapy. The patients with EMT-like CTC-WBC clusters tended to show a significantly increased number of total CTC count (median,19.0 5.0, <0.001). The patients with at least one detectable EMT-like CTC-WBC cluster at baseline were characterized by significantly worse PFS, when compared to the patients with no EMT-like CTC-WBC clusters detected (7.0 10.7 months, =0.023), and those with five or more epithelial-based CTCs detected per 5mL of peripheral blood (7.0 12.7 months, =0.014). However, the total CTC-WBC clusters were not correlated with patients' survival in the cohort (8.4 10.6 months, =0.561).

Conclusions: Our data provide evidence that the emergence of CTC-WBC clusters underwent EMT before treatment is associated with significantly poorer PFS in HR-positive/HER2-negative metastatic breast cancer patients receiving docetaxel plus capecitabine, which may be used as a parameter to predict the clinical outcomes and a potential target for individualized therapy.
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http://dx.doi.org/10.3389/fonc.2021.602222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208036PMC
June 2021

Tumor Microenvironment Subtypes and Immune-Related Signatures for the Prognosis of Breast Cancer.

Biomed Res Int 2021 1;2021:6650107. Epub 2021 Jun 1.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.

Objective: To better understand the immune-related heterogeneity of tumor microenvironment (TME) and establish a prognostic model for breast cancer in clinical practice.

Methods: For the 2620 breast cancer cases obtained from The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium, the CIBERSORT algorithm was performed to identify the immunological pattern, which underwent consensus clustering to curate TME subtypes, and biological profiles were explored by enrichment analysis. Random forest analysis, least absolute shrinkage, and selection operator analysis, in addition to uni- and multivariate COX regression analyses, were successively employed to precisely select the significant genes with prediction values for the introduction of the prognostic model.

Results: Three TME subtypes with distinct molecular and clinical features were identified by an unsupervised clustering approach, of which the molecular heterogeneity could be the result of cell cycle dysfunction and the variation of cytotoxic T lymphocyte activity. A total of 15 significant genes were proposed to construct the prognostic immune-related score system, and a predictive model was established in combination with clinicopathological characteristics for the survival of breast cancer patients. For immunological signatures, proactivity of CD8 T lymphocytes and hyperangiogenesis could be attributed to heterogeneous survival profiles.

Conclusions: We developed and validated a prognostic model based on immune-related signatures for breast cancer. This promising model is justified for validation and optimized in future clinical practice.
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http://dx.doi.org/10.1155/2021/6650107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189770PMC
June 2021

Cutaneous adverse events associated with immune checkpoint blockade: A systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 Jul 2;163:103376. Epub 2021 Jun 2.

Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. Electronic address:

Dermatological toxicity is the most common immune-related adverse events (irAEs) following immune checkpoint inhibitors (ICIs). A better understanding of this side effect enables early recognition, diagnosis and management in clinical practice. We did a systematic review and meta-analysis of literature published on ClinicalTrials.gov, Pubmed, Embase, and Cochrane Library to assess the differences in cutaneous irAEs among ICIs, the effect from dosage and combined treatment on the incidence, and the predictive values for prognosis. A total of 46 eligible RCTs involving 28,569 patients were included. This study indicates that cutaneous irAEs are dose-independent and agent-specific immune reactions with the highest risk observed in CTLA-4 blockade and might not a surrogate prognostic indicator.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103376DOI Listing
July 2021

Risk Factors and Survival of Patients With Liver Metastases at Initial Metastatic Breast Cancer Diagnosis in Han Population.

Front Oncol 2021 11;11:670723. Epub 2021 May 11.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

The risk factors for morbidity and mortality in patients with breast cancer liver metastases (BCLM) upon initial metastatic breast cancer (MBC) diagnosis have not been adequately identified in Han population. Data of 3,161 female patients who were initially diagnosed with MBC from December 1991 to September 2019 and treated in the China National Cancer Center were extracted and a total of 2,263 MBC patients were included in our study, among which 550 patients had liver metastases. Multivariable logistic regression was performed to identify risk factors for the presence of liver metastases at initial MBC diagnosis. Univariable and multivariable Cox proportional hazards regression analyses were conducted to determine prognostic factors for the survival of BCLM patients. Patients with hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive (35.0% of the entire population) subtype had the highest incidence of liver metastases. stage IV breast cancer, HR-/HER2+ and HR+/HER2+ subtypes were associated with higher odds of liver metastases and patients with lung metastases had lower risk of liver metastases at initial MBC diagnosis. The median overall survival of BCLM patients was 31.4 months and BCLM patients with HR+/HER2- subtype had the longest survival of 38.2 months. Older age, worse performance status, later stage of initial breast cancer, triple-negative subtype and lung metastases were significantly associated with a poorer prognosis in BCLM patients. Our study offers insights into the incidence and prognosis of BCLM patients at initial MBC diagnosis in Han population.
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http://dx.doi.org/10.3389/fonc.2021.670723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147724PMC
May 2021

The emerging role of RNA N6-methyladenosine methylation in breast cancer.

Biomark Res 2021 May 27;9(1):39. Epub 2021 May 27.

Department of Medical Oncology, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Beijing, 100021, China.

N6-methyladenosine (m6A) modification is the most prevalent internal mRNA modification and is involved in many biological processes in eukaryotes. Accumulating evidence has demonstrated that m6A may play either a promoting or suppressing role in breast cancer, including in tumorigenesis, metastasis and angiogenesis. In this review, we summarize the latest research progress on the biological function and prognostic value of m6A modification in breast cancer, as well as potential related therapeutic strategies.
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http://dx.doi.org/10.1186/s40364-021-00295-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161983PMC
May 2021

Phase II study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA.

Cancer Biol Med 2021 May 26. Epub 2021 May 26.

Unit of Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma 00176, Italy.

Objective: Apatinib is an oral TKI targeting VEGFR-2. Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated mBC. Oral vinorelbine also holds promise as a treatment of choice in patients with mBC. This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated mBC. In addition, we detected gene variants in ctDNA to explore the therapeutic implications.

Methods: This study enrolled patients with HER2-negative mBC who were pretreated with anthracycline/taxanes. Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m on days 1, 8, and 15 of every cycle (3 weeks). The primary endpoint was PFS. The secondary endpoints were ORR, CBR, OS, and safety. Patients eligible for ctDNA detection were evaluated before and during treatment.

Results: Forty patients were enrolled. The median PFS was 5.2 months (95% CI, 3.4-7.0 months), and the median OS was 17.4 months (95% CI, 8.0-27.0 months). The ORR was 17.1% (6/35), and the CBR was 45.7% (16/35). The most common AEs included gastrointestinal reaction, myelosuppression, and hypertension. In 20 patients, ctDNA was detected at baseline and during treatment. A significant difference was found in PFS for undetected detected baseline ctDNA (13.9 months 3.6 months, = 0.018).

Conclusions: All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative mBC, with acceptable and manageable toxicity profiles. Patients with no gene variant detected and lower variant allele frequencies in ctDNA at baseline showed longer PFS.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330536PMC
May 2021

Expression and clinical prognostic value of m6A RNA methylation modification in breast cancer.

Biomark Res 2021 Apr 29;9(1):28. Epub 2021 Apr 29.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Beijing, 100021, China.

Background: N6-methyladenosine(m6A) methylation modification affects the tumorigenesis, progression, and metastasis of breast cancer (BC). However, the expression characteristics and prognostic value of m6A modification in BC are still unclear. We aimed to evaluate the relationship between m6A modification and clinicopathological characteristics, and to explore the underlying mechanisms.

Methods: Three public cohorts and our clinical cohort were included: 1091 BC samples and 113 normal samples from the TCGA database, 1985 BC samples from the METABRIC database, 1764 BC samples from the KM Plotter website, and 134 BC samples of our clinical cohort. We collected date from these cohorts and analyzed the genetic expression, gene-gene interactions, gene mutations, copy number variations (CNVs), and clinicopathological and prognostic features of 28 m6A RNA regulators in BC.

Results: This study demonstrated that some m6A regulators were significantly differenially expressed in BCs and their adjacent tissues, and also different in various molecular types. All 28 studied m6A regulators exhibited interactions. KIAA1429 had the highest mutation frequency. CNVs of m6A regulators were observed in BC patients. The expression of the m6A regulators was differentially associated with survival of BC. Higher CBLL1 expression was associated with a better prognosis in BC than lower CBLL1 expression. Functional analysis showed that CBLL1 was related to the ESR1-related pathway, apoptosis-related pathway, cell cycle pathway and immune-related pathway in BC.

Conclusions: m6A RNA modification modulated gene expression and thereby affected clinicopathological features and survival outcomes in BC. CBLL1 may be a promising prognostic biomarker for BC patients.
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http://dx.doi.org/10.1186/s40364-021-00285-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082898PMC
April 2021

Safety and efficacy study of oral metronomic vinorelbine combined with trastuzumab (mNH) in HER2-positive metastatic breast cancer: a phase II trial.

Breast Cancer Res Treat 2021 Jul 25;188(2):441-447. Epub 2021 Apr 25.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.

Purpose: We conducted a single-arm prospective phase II trial to evaluate the efficacy and safety of oral metronomic vinorelbine combined with trastuzumab (mNH) in human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer (MBC) patients.

Methods: HER2-positive MBC patients received oral vinorelbine 40 mg thrice a week and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoints were objective response rate (ORR), clinical benefit rate (CBR; CR + PR + SD for ≥ 24 weeks). The secondary endpoints were progression-free survival (PFS), tolerability, and overall survival (OS).

Results: Twenty patients with HER2-positive MBC were enrolled, with a median of 1 prior chemotherapy regimens for MBC. Median age was 61.5 years (95% Confidence Interval (CI) 48.6-63.1). Visceral involvements presented in 14 patients (70.0%). ORR was 20.0%, and CBR was 75% with 4 PR (20.0%) and 11 SD (55.0%). The median PFS (mPFS) and median OS (mOS) were 7.4 months (95% CI 3.2-11.5) and 45.8 months (95%CI: not reached), respectively. The mPFS was 17.7 months (95%CI not reached) and 5.8 months (95%CI 5.6-5.9) in mNH as first-line and ≥ second-line therapy (log rank p = 0.03), respectively. The most common grade 1 adverse events (AEs) included nausea (15%), leukopenia (15%), ALT/AST elevation (15%), diarrhea (10%), and peripheral neuropathy (10%). Grade 2 adverse events included leukopenia (5%) and neutropenia (10%). No grade 3/4 AEs were observed.

Conclusions: Oral metronomic vinorelbine combined with trastuzumab is a well-tolerated and effective anti-tumor regimen for HER2-positive MBC.
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http://dx.doi.org/10.1007/s10549-021-06216-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070982PMC
July 2021

A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer.

Biomark Res 2021 Apr 12;9(1):24. Epub 2021 Apr 12.

Jiangsu Hengrui Medicine Co. Ltd, Shanghai, China.

Background: Dalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC).

Methods: In this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25-175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8-10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics.

Results: Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50-175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8-77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4-97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1-not reached).

Conclusions: Dalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.

Trial Registration: ClinicalTrials.gov identifier: NCT02684266 . Registered Feb 17, 2016.
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http://dx.doi.org/10.1186/s40364-021-00271-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042970PMC
April 2021

Pharmacokinetics, safety, activity, and biomarker analysis of palbociclib plus letrozole as first-line treatment for ER+/HER2- advanced breast cancer in Chinese women.

Cancer Chemother Pharmacol 2021 07 9;88(1):131-141. Epub 2021 Apr 9.

Pfizer Inc, San Diego, CA, USA.

Purpose: This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China.

Methods: Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments.

Results: By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUC was 1217 and 2501 ng∙h/mL, and t was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed.

Conclusions: Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile.

Clinical Trial Registration: NCT02499146.
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http://dx.doi.org/10.1007/s00280-021-04263-9DOI Listing
July 2021

Efficacy, Safety, and Immunogenicity of HLX02 Compared with Reference Trastuzumab in Patients with Recurrent or Metastatic HER2-Positive Breast Cancer: A Randomized Phase III Equivalence Trial.

BioDrugs 2021 May 7;35(3):337-350. Epub 2021 Apr 7.

Shanghai Henlius Biotech, Inc., Shanghai, China.

Background: HLX02 is an approved biosimilar of trastuzumab.

Objective: This study aimed to evaluated the efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer.

Patients And Methods: This randomized, double-blind, phase III study was conducted at 89 centers in China, the Philippines, Poland, and Ukraine. Eligible patients were randomized (1:1) to receive HLX02 or European Union (EU)-sourced trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel intravenously. The primary endpoint was overall response rate up to week 24 (ORR). Equivalence was declared if the 95% confidence interval (CI) of difference was within ± 13.5%. Safety and immunogenicity were evaluated in patients who received at least one dose of study medication.

Results: Between 11 November 2016 and 10 July 2019, a total of 649 patients were enrolled. The ORR was 71.3 and 71.4% in the HLX02 (n = 324) and EU-trastuzumab (n = 325) groups, with a difference of - 0.1% (95% CI - 7 to 6.9), which fell entirely in the predefined equivalence margins. No statistically significant differences were observed in all secondary efficacy analyses. Safety profiles and immunogenicity were comparable in HLX02 and EU-trastuzumab groups. In total, 98.8% of patients in each group experienced at least one treatment-emergent adverse event (TEAE), 23.8 and 24.9% experienced serious TEAEs, and 0.6% in each group had antidrug antibodies.

Conclusions: Among patients with HER2-positive recurrent or metastatic breast cancer, HLX02 demonstrated equivalent efficacy and similar safety and immunogenicity to reference trastuzumab.

Clinical Trial Registration: Chinadrugtrials.org CTR20160526 (12 September 2016), ClinicalTrials.gov NCT03084237 (20 March 2017), EudraCT 2016-000206-10 (27 April 2017).
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http://dx.doi.org/10.1007/s40259-021-00475-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084805PMC
May 2021

Randomized and dose-escalation trials of recombinant human serum albumin /granulocyte colony-stimulating factor in patients with breast cancer receiving anthracycline-containing chemotherapy.

BMC Cancer 2021 Mar 31;21(1):341. Epub 2021 Mar 31.

Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.

Background: To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents.

Methods: The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 μg, 2100 μg, and 2400 μg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 μg and rhG-CSF 5 μg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 μg, 1500 μg, and continuous rhG-CSF 5 μg/kg.

Results: Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 μg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 μg to 2400 μg, while the double delivery of HSA/G-CSF 2400 μg failed to meet the noninferiority in comparison with rhG-CSF.

Conclusion: The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 μg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial.

Trial Registration: ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).
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http://dx.doi.org/10.1186/s12885-021-08093-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010964PMC
March 2021

Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D).

Eur J Cancer 2021 May 23;148:287-296. Epub 2021 Mar 23.

Institute Jules Bordet and l' Université Libre de Bruxelles (U.L.B), Brussels, Belgium.

Aim: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial.

Patients And Methods: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac).

Results: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups.

Conclusion: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer.

Trial Registration: clinicaltrials.gov Identifier NCT00490139.
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http://dx.doi.org/10.1016/j.ejca.2021.01.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103014PMC
May 2021

Sex-Based Heterogeneity in the Clinicopathological Characteristics and Prognosis of Breast Cancer: A Population-Based Analysis.

Front Oncol 2021 24;11:642450. Epub 2021 Feb 24.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Purpose: To better understand the differences in clinicopathological features and prognosis between male breast cancer (MBC) and female breast cancer (FBC).

Material And Methods: Data on patients diagnosed with breast cancer from January 1, 2010, to December 31, 2016, were obtained from the Surveillance, Epidemiology, and End Results database. Selected patients were classified into MBC and FBC, of which population demographics and clinicopathological features at baseline were successively extracted for analysis. Comparative analysis was performed to explore the differences in baseline characteristics, followed by propensity-score matching to calibrate the objective distinctions for adjusted analysis. Survival analysis was carried out to investigate divergences presented in prognosis from the two cohorts, and risk factors for prognosis were successively identified using univariate and multivariate COX regression analyses.

Results: A total of 407341 individuals were eligible, including 3111 MBC (0.7%) and 404230 FBC (99.3%) patients. Comparatively, patients with MBC tended to be older at diagnosis, with a higher confirmation of ductal carcinoma, a higher histological grade, a higher TNM stage, a higher proportion of luminal-like subtype, a higher rate of lung metastasis, a lower incidence of liver involvement, and a lower rate of surgical, radiation, and chemotherapeutic delivery. The overall prognosis of MBC was significantly worse than that of FBC, with a decreasing divergence both in median overall survival (65.5 months vs. 72.7 months, <0.0001) and median breast cancer-specific survival (75.4 months vs. 77.8 months, <0.0001). However, these discrepancies were not consistent among patients from different subgroups stratified by molecular subtype, age at diagnosis, or disease stage.

Conclusion: In this study, sex-based heterogeneity in clinicopathological characteristics and prognostic profiles was observed in the overall population of patients with breast cancer and was significantly variable among different subgroups. A male-specific design with reasonable endpoints for a clinical trial protocol will be warranted in the future.
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http://dx.doi.org/10.3389/fonc.2021.642450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945032PMC
February 2021

Anlotinib has good efficacy and low toxicity: a phase II study of anlotinib in pre-treated HER-2 negative metastatic breast cancer.

Cancer Biol Med 2021 Mar 12. Epub 2021 Mar 12.

Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Objective: Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis. This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer.

Methods: Patients with HER2-negative breast cancer, who were pre-treated with anthracycline or taxanes in a neoadjuvant, adjuvant, or metastatic setting, and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled. Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred. Simultaneously, 5-10 mL of venous blood was collected to perform circulating tumor DNA (ctDNA) testing every 2 treatment cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival, safety, and biomarkers.

Results: Twenty-six eligible patients were enrolled, with a median age of 56 (30-75) years. The median follow-up time was 10.5 months. The ORR was 15.4%, the DCR was 80.8%, and the median PFS was 5.22 months (95% confidence interval 2.86-6.24). Fourteen (53.8%) patients survived for more than 10 months. The changes in the detectable ctDNA variant allele frequency were consistent with the tumor response. The most common treatment-related adverse events were hypertension (57.7%), thyroidstimulating hormone elevation (34.6%), and hand-foot syndrome (23.1%).

Conclusions: Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated, metastatic HER2-negative breast cancer. The dynamic changes in the ctDNA variant allele fraction may be predictive of the tumor response.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330540PMC
March 2021

DNA damage response as a prognostic indicator in metastatic breast cancer via mutational analysis.

Ann Transl Med 2021 Feb;9(3):220

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: High tumor heterogeneity contributes to breast cancer recurrence and metastasis. However, the lack of indicators to serve as precise and reliable means of predicting breast cancer prognosis has yet to be addressed. This study aims to reveal the prognostic relevance of mutations in metastatic breast cancer (MBC) by large-scale circulating tumor DNA (ctDNA) analysis in China.

Methods: We performed ctDNA panel-captured sequencing of 958 blood samples from MBC patients including 494 hormone receptor (HR)-positive cases, 130 human epidermal growth factor receptor 2-positive cases, and 177 triple-negative breast cancer (TNBC) cases. The somatic mutations and potential targets were assessed. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method.

Results: In 801 of the 958 MBC blood samples, 663 mutated genes and 5,829 nonsynonymous alterations were identified. Mutated genes of the highest frequency were tumor protein p53 (, 54%), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (, 41%), estrogen receptor 1 (, 12%), myeloid/lymphoid or mixed-lineage leukemia protein 3 (, 11%), DNA (cytosine-5)-methyltransferase 3A (, 10%), erb-b2 receptor tyrosine kinase 2 (, 10%), GATA binding protein 3 (, 8%), FAT atypical cadherin 1 (, 7%), phosphatase and tensin homolog (, 6%), and mitogen-activated protein kinase kinase kinase 1 (, 6%). Enriched mutations and driver genes in MBC varied across stages and in multiple subtypes. Moreover, , , or coexisting / mutations in MBC were remarkably related with shorter PFS. Mutated DNA damage response (DDR) genes were significantly associated with tumor mutation burden and mutant-allele tumor heterogeneity score, as well as with worse clinical outcome.

Conclusions: Our findings indicate that the mutations of , , , and in particular, DDR genes, in MBC might be relevant indicators of unfavorable prognosis in MBC.
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http://dx.doi.org/10.21037/atm-20-2137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940884PMC
February 2021

A Phase II, Single-Arm Study of Apatinib and Oral Etoposide in Heavily Pre-Treated Metastatic Breast Cancer.

Front Oncol 2020 15;10:565384. Epub 2021 Feb 15.

Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Introduction: We performed this clinical trial to evaluate the efficacy and safety of apatinib and oral etoposide in patients with HER2-negative locally advanced or metastatic breast cancer (MBC).

Methods: Patients with HER2-negative MBC previously treated with anthracycline and taxanes and failed ≥1 prior chemotherapy regimens were recruited. The starting dose of apatinib was 500 and 425 mg in patients with ECOG scores of 0-1 and 2, respectively. The etoposide capsules were given at 50 mg/m on days 1 to 10 for 21 days. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety.

Results: Thirty-one eligible patients were enrolled. The median follow-up time was 11 months. The median PFS for all patients was 6.9 months [95% confidence interval (CI) 6.0-7.9], and 6.9 months (95% CI 5.3-8.6) and 6.6 months (95% CI 1.4-11.7) for patients with apatinib 425 and 500mg once daily, respectively. The ORR was 35.5% (11/31). The DCR was 87.1% (27/31). The median OS was 20.4 months (95% CI 11.4-29.3). The median PFS of patients who had hypertension and proteinuria was longer than that for those without hypertension and proteinuria. The most common grade 3/4 treatment-related AEs were hypertension (12/31, 38.7%), fatigue (3/31, 9.7%), thrombocytopenia (3/31, 9.7%).

Conclusion: Apatinib combined with etoposide capsules is effective and tolerable in heavily pretreated, metastatic HER2-negative breast cancer patients. A lower apatinib dose provide equivalent efficacy and reduced toxicity.

Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT03535961.
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http://dx.doi.org/10.3389/fonc.2020.565384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917213PMC
February 2021

Clinical Utility of Eribulin Mesylate in the Treatment of Breast Cancer: A Chinese Perspective.

Authors:
Peng Yuan Binghe Xu

Breast Cancer (Dove Med Press) 2021 24;13:135-150. Epub 2021 Feb 24.

National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.

Eribulin mesylate, a synthetic derivative of the anti-mitotic agent halichondrin B, has a unique tubulin-based mechanism of action that is distinct from other anti-microtubule agents including taxanes and vinca alkaloids. Consistent with this unique activity, eribulin has shown clinical efficacy in patients with metastatic breast cancer (MBC) that progressed following prior taxane and anthracycline therapy. The evidence presented in this review indicates that eribulin represents a treatment option for patients with HER2-negative metastatic breast cancer. Improved survival outcomes and better tolerability compared with vinorelbine supported the first approval of eribulin in China in 2019; eribulin was approved for women with locally advanced/metastatic HER2-negative breast cancer after treatment failure with at least two chemotherapy regimens, including an anthracycline and a taxane. Eribulin has also shown promising efficacy in patients with HER2-positive advanced breast cancer when used in combination with trastuzumab or pertuzumab, and subgroup analyses from the Phase III clinical trials support the continued evaluation of eribulin in patients with triple-negative disease. The unique non-mitotic effects of eribulin, including vascular remodeling, coupled with its clinical efficacy and safety profile, may permit the broader use of this agent in patients with MBC.
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http://dx.doi.org/10.2147/BCTT.S231298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917473PMC
February 2021

Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: A Nation-Wide Multicenter Epidemiological Study in China.

Front Oncol 2020 11;10:599604. Epub 2021 Feb 11.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Clinical guidelines generally recommend endocrine therapy (ET) as first-line treatment of hormone receptor-positive advanced breast cancer (HR+ ABC) whereas chemotherapy (CT) should be considered in the presence of life-threatening disease or limited clinical benefit after three sequential ET regimens. However, it is unclear if real-world clinical practice is in accordance with the current guidelines. This study was to present the real-world treatment patterns and ET regimens among HR+ ABC patients in China.

Methods: Using data from the Nation-wide Multicenter Retrospective Clinical Epidemiology Study of Female Advanced Breast Cancer in China (ClinicalTrials.gov identifier: NCT03047889), we investigated the clinicopathological characteristics, clinical profiles, and treatment patterns of HR+ ABC patients from January 2012 to December 2014.

Results: A total of 2,342 patients with HR+ ABC were included in this study. Our findings revealed that, in comparisons with those receiving initial CT (n = 1445), patients initiated ET (n =402) were significantly older, later recurrent after adjuvant treatment, with a lower rate of visceral involvement and a decreasing quantity of metastatic sites. A total of 1,308 patients received palliative ET while only 18.9% patients (n = 247) reached three lines of ET. Among patients completing more than one line of ET, the median treatment duration was 8 months for the first line, 6 months for the second line, and 3 months for the third line for patients receiving ET. In the advanced setting, the choices of palliative ET regimens were diverse, yet aromatase inhibitor (AI) monotherapy was still the overall mainstay of ET; in contrast, patients were less accessible to everolimus plus AI regimen in this population.

Conclusions: Less than one quarter of patients initiated palliative ET for HR+ ABC in routine clinical practice. Patients who received multi-lines of ET experienced successive shorter durations following each line of therapy. This real-life data provides a solid overview of ET for HR+ ABC from China, indicating unmet need for treatment options that improve the effectiveness of endocrine therapy.
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http://dx.doi.org/10.3389/fonc.2020.599604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905089PMC
February 2021

Pertuzumab and trastuzumab as adjuvant treatment for HER2-positive early breast cancer: outcomes in Chinese patients in the APHINITY study.

Jpn J Clin Oncol 2021 Mar;51(3):345-353

The University of Hong Kong, Hong Kong.

Background: The addition of pertuzumab to trastuzumab plus standard chemotherapy as adjuvant therapy following surgery significantly improved invasive disease-free survival (IDFS) in patients with HER2-positive early breast cancer in the multinational randomized APHINITY trial (NCT01358877, BIG 4-11/BO25126/TOC4939G). We analyzed clinical outcomes in the subgroup of patients recruited at Chinese sites.

Methods: Patients were randomized to standard adjuvant chemotherapy plus 1 year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis.

Results: Chinese patients had similar demographic characteristics to the global population, but a higher proportion had nodal involvement. Although this subgroup analysis was not powered to detect statistical significance, a numerical improvement in IDFS was observed with the addition of pertuzumab to trastuzumab in Chinese patients (hazard ratio, 0.69; 95% confidence interval: 0.39-1.19; 3-year IDFS event-free estimates 92.5% [pertuzumab] and 91.7% [placebo]), which was consistent with the primary analysis of the global population. Further subgroup analyses showed numerical improvements in the Chinese node-positive, hormone receptor-negative and -positive subgroups, although confidence intervals were wide due to the low number of events. The incidence of diarrhea was higher in the pertuzumab arm, and no primary cardiac events occurred in Chinese patients in either arm.

Conclusions: Pertuzumab, used in combination with trastuzumab and chemotherapy in APHINITY, is effective as an adjuvant treatment regimen for Chinese patients with HER2-positive early breast cancer in a setting with curative intent. The safety profile in Chinese patients was consistent with that of the global population.
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http://dx.doi.org/10.1093/jjco/hyaa216DOI Listing
March 2021

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 03 11;22(3):351-360. Epub 2021 Feb 11.

Shandong Tumor Hospital, Jinan, China.

Background: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab.

Methods: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805.

Findings: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related.

Interpretation: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy.

Funding: Jiangsu Hengrui Medicine and National Key R&D Program of China.

Translations: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(20)30702-6DOI Listing
March 2021

Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.

Ann Transl Med 2021 Jan;9(2):109

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.

Methods: TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.

Results: A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.

Conclusions: For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
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http://dx.doi.org/10.21037/atm-20-4590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867954PMC
January 2021

Primary Trastuzumab Resistance After (Neo)adjuvant Trastuzumab-containing Treatment for Patients With HER2-positive Breast Cancer in Real-world Practice.

Clin Breast Cancer 2021 06 16;21(3):191-198. Epub 2020 Dec 16.

Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address:

Background: It is difficult to define patients with primary trastuzumab resistance (PTR) after (neo)adjuvant trastuzumab with minimal data and understanding of the actual prevalence, prognosis, and potential treatment strategies in the real-world setting.

Patients And Methods: The medical records of 1096 patients with human epidermal growth factor receptor 2-positive early-stage breast cancer who had received (neo)adjuvant trastuzumab-containing treatment from 2010 to 2016 in the Cancer Hospital and Chinese Academy of Medical Sciences were reviewed. PTR was defined as recurrence during adjuvant trastuzumab or within 12 months from their last (neo)adjuvant trastuzumab dosage. The cutoff date for data collection was September 1, 2018, with a median follow-up time of 46 months.

Results: A total of 126 recurrences were observed, and 75 (6.8%; 75/1096) of them were categorized as PTR; the remaining were non-PTR. The prognosis of patients in the PTR group was much inferior to those in the non-PTR group (27 months vs. not reached; P < .01). As expected, patients with PTR did possess a much lower response rate to first-line trastuzumab-containing therapy (27.3% vs. 61.9%; P = .02). Subgroup analyses indicated that patients in the PTR group seemed to get little survival benefit from the reuse of trastuzumab compared with those without trastuzumab (26 months vs. 28 months; P = .80). However, in the non-PTR group, re-treatment with trastuzumab in the metastatic setting prolonged the survival of patients compared to those without trastuzumab (not reached vs. 34 months; P = .04).

Conclusion: This study verified the rationality of present definition of PTR after (neo)adjuvant trastuzumab. Patients with PTR did have a poor prognosis. Further research and clinical trials are required to establish the best treatment patterns for these patients.
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http://dx.doi.org/10.1016/j.clbc.2020.09.003DOI Listing
June 2021

HER2-targeted regimens after prior trastuzumab for patients with HER2-positive unresectable, locally advanced or metastatic breast cancer: a network meta-analysis of randomized controlled trials.

Ann Transl Med 2020 Dec;8(24):1634

Department of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Several human epidermal growth factor receptor 2 (HER2)-targeted regimens (anti-HER2 target agent combined chemotherapy) have been introduced for the treatment of HER2-positive locally advanced or metastatic breast cancer progressed after trastuzumab. We therefore conducted a network meta-analysis to compare and rank HER2-targeted regimens in this population after trastuzumab therapy.

Methods: The electronic databases of PubMed, EmBase, Cochrane Central Register of Controlled Trials, and the websites of http://clinicaltrials.gov/ (US NIH) were systematically searched for published and unpublished randomized controlled trials (RCTs) from their inception to October, 2020. Nine treatment regimens were eligible to be included in this analysis. The primary outcomes were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), while the secondary outcomes were grade ≥3 adverse events.

Results: A total of 2,104 citations were identified and 12 RCTs comprising 3,769 patients were selected for final analysis. For HER2 positive unresectable, locally advanced or metastatic patients progressed after trastuzumab therapy pyrotinib plus capecitabine ranked the highest surface under the cumulative ranking area (SUCRA) in PFS, ORR and its SUCRA in OS was higher than Trastuzumab emtansine (T-DM1). T-DM1 plus atezolizumab, pyrotinib plus capecitabine, and pertuzumab plus trastuzumab plus capecitabine had comparable SUCRA in OS (76.1% 74.5% 71.2%). Six of included studies reported any grade ≥3 adverse events, the prevalence of any grade ≥3 adverse events in lapatinib plus capecitabine (353/683), T-DM1 (213/558), trastuzumab plus capecitabine (130/218), pertuzumab plus trastuzumab plus capecitabine (118/228), pyrotinib plus capecitabine (220/384), T-DM1 plus atezolizumab (43/132) and capecitabine (24/94) were 51.7%, 38.2%, 59.6%, 51.8%, 57.3%, 32.6% and 25.5%, respectively. Specific adverse event characteristics related to different HER2-targeted regimens need to be well known ahead and managed during the therapy.

Conclusions: The results indicated that for HER2 positive breast cancer with previous trastuzumab therapy pyrotinib plus capecitabine was probably more efficacious in PFS and ORR. T-DM1 plus atezolizumab, pyrotinib plus capecitabine and pertuzumab plus trastuzumab plus capecitabine have comparable effect on OS improvement and all of them were likely better than T-DM1. The risk of grade ≥3 adverse events for specific treatment regimens were also provided.
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http://dx.doi.org/10.21037/atm-20-5149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812178PMC
December 2020

Correction to: Discrepancies in Genetic Testing Procedures of BRCA1/2 Mutations: A National Survey Across China.

Mol Diagn Ther 2021 Mar 21;25(2):267-268. Epub 2021 Jan 21.

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1007/s40291-021-00512-yDOI Listing
March 2021
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