Publications by authors named "Xiuwen Guan"

42 Publications

Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer.

Cancer Cell 2021 Oct 5. Epub 2021 Oct 5.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address:

In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13 T cells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13 T cells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13 T cells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.
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http://dx.doi.org/10.1016/j.ccell.2021.09.010DOI Listing
October 2021

Chemotherapeutic drug-induced immunogenic cell death for nanomedicine-based cancer chemo-immunotherapy.

Nanoscale 2021 Oct 13. Epub 2021 Oct 13.

College of Pharmacy, Weifang Medical University, Weifang 261053, China.

Chemotherapy has been a conventional paradigm for cancer treatment, and multifarious chemotherapeutic drugs have been widely employed for decades with significant performances in suppressing tumors. Moreover, some of the antitumor chemotherapeutic agents, such as doxorubicin (DOX), oxaliplatin (OXA), cyclophosphamide (CPA) and paclitaxel (PTX), can also tackle tumors through the induction of immunogenic cell death (ICD) in tumor cells to trigger specific antitumor immune responses of the body and improve chemotherapy efficacy. In recent years, chemo-immunotherapy has attracted increasing attention as one of the most promising combination therapies to struggle with malignant tumors. Many effective antitumor therapies have benefited from the successful induction of ICD in tumors, which could incur the release of endogenous danger signals and tumor-associated antigens (TAAs), further stimulating antigen-presenting cells (APCs) and ultimately initiating efficient antitumor immunity. In this review, several well-characterized damage-associated molecular patterns (DAMPs) were introduced and the progress of ICD induced by representative chemotherapeutic drugs for nanomedicine-based chemo-immunotherapy was highlighted. In addition, the combination strategies involving ICD cooperated with other therapies were discussed. Finally, we shared some perspectives in chemotherapeutic drug-induced ICD for future chemo-immunotherapy. It was hoped that this review would provide worthwhile presentations and enlightenments for cancer chemo-immunotherapy.
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http://dx.doi.org/10.1039/d1nr05512gDOI Listing
October 2021

Sequentially pH-Responsive Drug-Delivery Nanosystem for Tumor Immunogenic Cell Death and Cooperating with Immune Checkpoint Blockade for Efficient Cancer Chemoimmunotherapy.

ACS Appl Mater Interfaces 2021 Sep 10;13(37):43963-43974. Epub 2021 Sep 10.

College of Pharmacy, Weifang Medical University, Weifang 261053, China.

Chemoimmunotherapy has anchored a new blueprint for cancer management. As a burgeoning approach, immunotherapy has shifted the paradigm of traditional chemotherapy and opened up new prospects for cancer treatment. Here, a sequentially pH-responsive doxorubicin (DOX) delivery nanosystem is designed for simultaneous chemotherapy and tumor immunogenic cell death (ICD). DOX is modified into pH-sensitive -aconityl-doxorubicin (CAD) for being easily adsorbed by polycationic polyethylenimine (PEI), and the PEI/CAD complexes are in situ-shielded by aldehyde-modified polyethylene glycol (PEG). The PEG/PEI/CAD nanoparticles (NPs) can keep stable in neutral physiological pH during systemic circulation but will detach PEG shielding once in slightly acidic tumor extracellular pH. The exposed positive PEI/CAD complexes are endocytosed effortlessly, and CAD is then converted back to DOX by endosomal-acidity-triggered -aconityl cleavage. The released DOX further elicits ICD, and the moribund tumor cells will release antigens and damage-associated molecular patterns to recruit dendritic cells and activate antitumor immunity. An excellent therapeutic effect is achieved when the immune checkpoint PD-1 antibody (aPD-1) is utilized to cooperate with the PEG/PEI/CAD NPs for blocking tumor immune escape and maintaining antitumor activity of the ICD-instigated T cells. The sequentially pH-responsive DOX delivery nanosystem cooperating with immune checkpoint blockade will provide a potential strategy for cancer chemoimmunotherapy.
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http://dx.doi.org/10.1021/acsami.1c10643DOI Listing
September 2021

CpG-Based Nanovaccines for Cancer Immunotherapy.

Int J Nanomedicine 2021 5;16:5281-5299. Epub 2021 Aug 5.

College of Pharmacy, Weifang Medical University, Weifang, 261053, People's Republic of China.

Cancer has been a serious health hazard to the people all over the world with its high incidence and horrible mortality. In recent years, tumor vaccines in immunotherapy have become a hotspot in cancer therapy due to their many practical advantages and good therapeutic potentials. Among the various vaccines, nanovaccine utilized nanoparticles (NPs) as the carrier and/or adjuvant has presented significant therapeutic effect in cancer treatment. For tumor nanovaccines, unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) is a commonly used adjuvant. It has been reported that CpG ODN was the most effective immune stimulant among the currently known adjuvants. It could be recognized by toll-like receptor 9 (TLR9) to activate humoral and cellular immunity for preventing or treating cancer. In this review, the topic of CpG-based nanovaccines for cancer immunotherapy will be focused. The types and properties of different CpG will be introduced in detail first, and then some representative tumor nanovaccines will be reviewed according to the diverse loading modes of CpG, such as electrostatic adsorption, covalent bonding, hydrophilic and hydrophobic interaction, and DNA self-assembly, for summarizing the current progress of CpG-based tumor nanovaccines. Finally, the challenges and future perspectives will be discussed. It is hoped that this review will provide valuable references for the development of nanovaccines in cancer immunotherapy.
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http://dx.doi.org/10.2147/IJN.S317626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352601PMC
August 2021

Selective thermotherapy of tumor by self-regulating photothermal conversion system.

J Colloid Interface Sci 2022 Jan 30;605:752-765. Epub 2021 Jul 30.

College of Pharmacy, Weifang Medical University, Weifang 261053, China; Collaborative Innovation Center for Target Drug Delivery System, Weifang Medical University, Weifang 261053, China; Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang Medical University, Weifang 261053, China. Electronic address:

One major challenge of photothermal therapy (PTT) is achieving thermal ablation of the tumor without damaging the normal cells and tissues. Here, we designed a self-regulating photothermal conversion system for selective thermotherapy based on self-assembling gold nanoparticles (S-AuNPs) and investigated the selectivity effect using a novel home-made in vitro selective photothermal transformation model and an in vivo skin damaging assessment model. In the in vitro selective photothermal transformation model, laser irradiation selectively increased the temperature of the internal microenvironment (pH 5.5) and resulted in an obvious temperature difference (ΔT ≥ 5 °C) with that of the external environment (pH 7.4). More importantly, in the in vivo skin damaging assessment model, S-AuNPs achieved good tumor inhibition without damaging the normal skin tissue compared with the conventional photothermal material. This work provides not only a novel validation protocol for tumor thermotherapy to achieve the biosafety of specifically killing tumor cells and normal tissue but also an evaluation methodology for other precise therapy for cancers.
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http://dx.doi.org/10.1016/j.jcis.2021.07.134DOI Listing
January 2022

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

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

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

Fabrication and Characterization of Chitosan/Poly(Lactic-Co-glycolic Acid) Core-Shell Nanoparticles by Coaxial Electrospray Technology for Dual Delivery of Natamycin and Clotrimazole.

Front Bioeng Biotechnol 2021 5;9:635485. Epub 2021 Mar 5.

College of Pharmacy, Weifang Medical University, Weifang, China.

Natamycin (NAT) is the drug of choice for the treatment of fungal keratitis (FK). However, its inherent shortcomings, such as poor solubility, high dosing frequency, and long treatment cycle, need to be urgently addressed by designing a new delivery to widen its clinical utility. Growing research has confirmed that clotrimazole (CLZ) plays a significant role in fungal growth inhibition. Hence, coaxial electrospray (CO-ES) technology is used herein to prepare nano-systems with an average hydrodynamic particle size of 309-406 nm for the co-delivery of NAT and CLZ in chitosan (CTS) and poly(lactic-co-glycolic acid) (PLGA). The resulting NAT/[email protected]/PLGA formulations were characterized by a transmission electron microscope (TEM) and release test. The results show that the formulations had obvious core-shell structures, uniform particle distribution, and also can sustain the release of drugs over 36 h. Furthermore, hemolysis, corneal irritation test, local allergenic test, and antifungal activity analyses are performed to evaluate the safety and efficiency of the formulations. Thus, good biosafety along with a significant anti-candidiasis effect are found in the NAT/[email protected]/PLGA nanoparticles (NPs). Taken together, the results suggest that this design may provide a promising drug delivery system and a new option for the treatment of FK.
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http://dx.doi.org/10.3389/fbioe.2021.635485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973235PMC
March 2021

Tumor acidic microenvironment-induced drug release of RGD peptide nanoparticles for cellular uptake and cancer therapy.

Colloids Surf B Biointerfaces 2021 Jun 4;202:111673. Epub 2021 Mar 4.

School of Bioscience and Technology, Weifang Medical University, Weifang, 261053, PR China. Electronic address:

Spatial accuracy is crucial in drug delivery, especially to increase the efficacy and reduce the side effects of antitumor drugs. In this study, we developed a simple and broadly applicable strategy in which a target peptide ligand was introduced to construct a pH-responsive drug-loading system to achieve targeted delivery and drug release in lesions. In addition to reaching the tumor tissue through passive targeting modalities such as the enhanced permeability and retention (EPR) effect, active targeting nanoparticles used RGD motifs coupled to nanocarriers to specifically bind certain integrins, such as ανβ3, which is expressed on the surface of tumor cells, to achieve active tumor cell targeting. Self-assembling peptides have significant advantages in their structural design. The amphiphilic peptide LKR could form a spherical and self-assembled nanoparticle, which encapsulated the fat-soluble antitumor drug doxorubicin (Dox) in neutral medium. The Dox-encapsulating peptide nanoparticles swelled and burst, rapidly releasing Dox in an acidic microenvironment. Flow cytometry and fluorescence detection showed that the self-assembled LKR nanoparticles enhanced the drug accumulation in tumor cells compared with normal mammalian cells. The Dox-encapsulating peptide nanoparticles exhibited desirable antitumor effects in vivo. In summary, the acidic microenvironment of tumors was used to induce drug release from a targeted peptide drug-loading system to enhance cellular uptake and therapeutic effects in situ, providing a promising therapeutic approach for the treatment of major diseases such as hepatoma.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111673DOI Listing
June 2021

Incidence, risk factors and survival of patients with brain metastases at initial metastatic breast cancer diagnosis in China.

Breast 2021 Feb 4;55:30-36. Epub 2020 Dec 4.

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. Address: NO.17 Panjiayuannanli, Chaoyang District, Beijing, 100021, China. Electronic address:

Purpose: To characterize the incidence, risk factors and survival of patients with brain metastases at initial diagnosis of metastatic breast cancer (MBC) in China.

Methods: The China National Cancer Center database was used to identify 2087 MBC patients diagnosed between 2003 and 2015. Clinicopathological features, treatment and survival information were extracted. Multivariable logistic and Cox regression were performed to determine factors predictive of brain metastases at MBC diagnosis and survival, respectively.

Results: Brain metastases occurred in ninety patients (4.3%) at MBC diagnosis, and in 27 patients (2.5%), 42 patients (7.2%) and 21 patients (5.2%) with hormone receptor positive, human epidermal growth factor receptor 2 negative (HR + HER2-), HER2-positive and triple negative breast cancer (TNBC), respectively. HER2-positive subtype (OR = 2.38; 95% CI 1.40-4.04; p < 0.0001), TNBC subtype (OR = 1.89; 95% CI 1.02-3.51; p = 0.005), and metastases to all three sites of bone, liver and lungs (OR = 3.23; 95% CI 1.52-6.87; p = 0.002) were shown to increase the risk of BM at MBC diagnosis. Median survival after BM was 23.7 months. First-line tyrosine kinase inhibitors (TKI) improved survival compared to trastuzumab-based regimen (44.9 vs 35.4 months, p = 0.09). Factors that independently decreased BM death risk were ECOG<2, brain metastases only and multidisciplinary treatment.

Conclusion: HER2-positive and TNBC subtypes have a higher incidence of BM at initial MBC diagnosis. Brain screening might be considered in patients with HER2-positive disease at MBC diagnosis, and further prospective randomized study is warranted.
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http://dx.doi.org/10.1016/j.breast.2020.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736978PMC
February 2021

Development and Validation of a New Clinical Prediction Model of Catheter-Related Thrombosis Based on Vascular Ultrasound Diagnosis in Cancer Patients.

Front Cardiovasc Med 2020 26;7:571227. Epub 2020 Oct 26.

Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Central venous catheters are convenient for drug delivery and improved comfort for cancer patients, but they also cause serious complications. The most common complication is catheter-related thrombosis (CRT). This study aimed to evaluate the incidence and risk factors for CRT in cancer patients and develop an effective prediction model for CRT in cancer patients. The development of our prediction model was based on a retrospective cohort ( = 3,131) from the National Cancer Center. Our prediction model was confirmed in a prospective cohort from the National Cancer Center ( = 685) and a retrospective cohort from the Hunan Cancer Hospital ( = 61). The predictive accuracy and discriminative ability were determined by receiver operating characteristic (ROC) curves and calibration plots. Multivariate analysis demonstrated that sex, cancer type, catheter type, position of the catheter tip, chemotherapy status, and antiplatelet/anticoagulation status at baseline were independent risk factors for CRT. The area under the ROC curve of our prediction model was 0.741 (CI: 0.715-0.766) in the primary cohort and 0.754 (CI: 0.704-0.803) and 0.658 (CI: 0.470-0.845) in validation cohorts 1 and 2, respectively. The model also showed good calibration and clinical impact in the primary and validation cohorts. Our model is a novel prediction tool for CRT risk that accurately assigns cancer patients into high- and low-risk groups. Our model will be valuable for clinicians when making decisions regarding thromboprophylaxis.
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http://dx.doi.org/10.3389/fcvm.2020.571227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649194PMC
October 2020

Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer.

NPJ Breast Cancer 2020 30;6:59. Epub 2020 Oct 30.

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, 100021 China.

Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. However, little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. We analysed the HER2 mutation features of 1184 patients with invasive breast cancer. In addition, a single-arm, prospective, phase-II study (NCT03412383) of pyrotinib was conducted in patient with metastatic HER2 amplification-negative, mutation-positive breast cancer. Peripheral blood was collected from each patient and circulating tumour DNA (ctDNA) sequencing was performed using a 1021 gene panel. HER2 mutations were detected in 8.9% (105/1184) of patients. The HER2 amplification-positive patients had a higher mutation frequency than the HER2 amplification-negative patients (19.5% vs. 4.8%,  < 0.001). A multivariate Cox regression analysis indicated that patients with HER2 mutations had a shorter progression-free survival (PFS) than HER2 wild-type patients (median PFS 4.7 months vs. 11.0 months, hazard ratio 2.65, 95% confidence interval 1.25-5.65,  = 0.011). Ten HER2 amplification-negative, mutation-positive patients who received pyrotinib monotherapy were ultimately included in the efficacy analysis. The median PFS was 4.9 months. The objective response rate (complete response + partial response) was 40.0% and the clinical benefit rate (complete response + partial response + stable disease over 24 weeks) was 60%. In conclusion, a HER2 gene mutation analysis is potentially useful to identify biomarkers of trastuzumab resistance in HER2 amplification-positive patients. Patients with HER2-mutated, non-amplified metastatic breast cancers may benefit from pyrotinib.
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http://dx.doi.org/10.1038/s41523-020-00201-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603305PMC
October 2020

Development and validation of a nomogram for predicting survival of advanced breast cancer patients in China.

Breast 2020 Oct 12;53:172-180. Epub 2020 Aug 12.

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, 100021, PR China. Electronic address:

Background: There is a lack of prognostic models predicting the overall survival (OS) of advanced breast cancer (ABC) patients in China.

Methods: Data from the China National Cancer Center database that recorded 4039 patients diagnosed with breast cancer between 1987 and 2019 were extracted and a total of 2263 ABC participants were enrolled in this study, which were further randomized 3:1 and divided into training (n = 1706) and validation (n = 557) groups. The nomogram was built based on independent predictors identified by univariate and multivariate cox regression analyses. The discriminatory and predictive capacities of the nomogram were assessed by Harrell's concordance index (C-index) and calibration plots.

Results: Univariate and multivariate analyses found that age, Eastern Cooperative Oncology Group (ECOG) score, T-stage, N-stage, tumor subtype, the presence of distant lymph node (DLN)/liver/brain metastasis, local therapy, efficacy of first-line therapy and metastatic-free interval (MFI) were significantly related to OS (all P < 0.05). These variables were incorporated into a nomogram to predict the 2-year and 3-year OS of ABC patients. The C-indexes of the nomogram were 0.700 (95% confidence interval [CI]: 0.683-0.717) for the training set and 0.686 (95% CI: 0.652-0.719) for the validation set. The calibration curves revealed satisfactory consistency between actual survival and nomogram prediction in both the internal and external validations. The nomogram was capable of stratifying patients into different risk cohorts.

Conclusions: We constructed and validated a nomogram that might serve as an efficient tool to provide prognostic prediction for ABC patients and guide the physicians to make personalized treatment decisions.
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http://dx.doi.org/10.1016/j.breast.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451432PMC
October 2020

Genome-wide chromosomal instability by cell-free DNA sequencing predicts survival in patients with metastatic breast cancer.

Breast 2020 Oct 25;53:111-118. Epub 2020 Jul 25.

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: Genome-wide chromosomal instability, instead of specific somatic mutations or copy-number alterations in selected genes, is a significant property of cancer and may suggest a new strategy for treatment. Here we utilized cell-free DNA (cfDNA) sequencing to display the whole picture of chromosomal instability in patients with metastatic breast cancer (MBC), and evaluate its predictive value for patient survival.

Methods: The clinical data of 65 patients who had frozen plasma and planned to change the therapeutic regimen were retrospectively enrolled. Low-coverage whole-genome sequencing of cfDNA was performed to generate the chromosomal instability represented by chromosomal instability (CIN) score.

Results: Tumors with diverse status of hormone receptor and HER2 represented diverse chromosomal instability across the whole genome. According to the receiver operating characteristic curve and the statistical distribution, CIN score exceed 3881 was defined as "High". 32 (53.3%) patients with high CIN score had similar clinicopathologic characteristics compared with low CIN score patients. The median overall survival of patients with high CIN score was 21.2 months (95% CI 14.1-28.3), which was significantly inferior to those with low CIN score (not reached, P = 0.006). Regardless of various treatment regimens, the median progression free survival in patients with high CIN score was 7.3 months, which was significantly worse than those in the low CIN score population (11.0 months, P = 0.034). Multivariate analysis revealed that CIN score was an independent prognostic factor, with hazard ratio of 3.563 (P = 0.005).

Conclusions: To our knowledge, this is the first study illustrating the prognostic value of chromosomal instability derived from cfDNA in MBC.
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http://dx.doi.org/10.1016/j.breast.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503795PMC
October 2020

Gut Microbiota Profiling in Patients With HER2-Negative Metastatic Breast Cancer Receiving Metronomic Chemotherapy of Capecitabine Compared to Those Under Conventional Dosage.

Front Oncol 2020 7;10:902. Epub 2020 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.

Low-dose metronomic chemotherapy can achieve disease control with reduced toxicity compared to conventional chemotherapy in maximum tolerated dose. Characterizing the gut microbiota of cancer patients under different dosage regimens may describe a new role of gut microbiota associated with drug efficacy. Therefore, we evaluated the composition and the function of gut microbiome associated with metronomic capecitabine compared to conventional dosage. The fecal samples of HER2-negative metastatic breast cancer patients treated with capecitabine as maintenance chemotherapy were collected and analyzed by 16S ribosome RNA gene sequencing. A total of 15 patients treated with metronomic capecitabine were compared to 16 patients under a conventional dose. The unweighted-unifrac index of the metronomic group was statistically significantly lower than that of the routine group ( = 0.025). Besides that, the Bray-Curtis distance-based redundancy analysis illustrated that the microbial genera between the two groups can be separated partly. Nine Kyoto Encyclopedia of Genes and Genomes (KEGG) modules were enriched in the metronomic group, while no KEGG modules were significantly enriched in the routine group. Moreover, univariate and multivariate analyses suggested that the median progression-free survival (PFS) was significantly shorter in patients with the gut microbial composition of (9.2 vs. 32.7 months, = 0.004), while the patients with had a significantly prolonged PFS than those without (32.7 vs. 12.9 months, = 0.013). The proof-of-principle study suggested that the gut microbiota of patients receiving metronomic chemotherapy was different in terms of diversity, composition, and function from those under conventional chemotherapy, and the presence of specific bacterial species may act as microbial markers associated with drug resistance monitoring and prognostic evaluation.
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http://dx.doi.org/10.3389/fonc.2020.00902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358584PMC
July 2020

Safety and efficacy of sirolimus combined with endocrine therapy in patients with advanced hormone receptor-positive breast cancer and the exploration of biomarkers.

Breast 2020 Aug 16;52:17-22. Epub 2020 Apr 16.

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, 100021, China. Electronic address:

Background: We performed a retrospective study on the efficacy and safety of sirolimus (an mTOR inhibitor) in hormone receptor (HR)-positive advanced breast cancer and searched for biomarkers to predict its efficacy.

Methods: All patients with HR-positive metastatic breast cancer treated with sirolimus plus endocrine therapy between December 2017 and July 2018 at the Cancer Hospital, Chinese Academy of Medical Sciences were consecutively and retrospectively reviewed. Mutations in circulating tumour DNA (ctDNA) were assayed for 1021 tumour-related genes via gene panel target capture-based next-generation sequencing.

Results: Thirty-six patients with metastatic breast cancer treated with sirolimus plus endocrine therapy were included. The progression-free survival (PFS) rates between the sirolimus group and everolimus group were similar, and the median PFS was 4.9 months and 5.5 months, respectively (hazard ratio 1.56, 95% CI 0.86-2.81, P = 0.142). The objective response rate in the 36 patients was 19.4%, and the clinical benefit rate was 41.7%. Lipid metabolism disorder was the most common adverse event (69.4%), and 13.9% of patients had stomatitis. Most (94.4%) adverse events were grade 1-2. Twenty patients (55.6%) underwent ctDNA analysis before receiving sirolimus therapy. For patients who received less than 3 lines of chemotherapy, those with PI3K/Akt/mTOR pathway alterations had a better response to sirolimus than those without alterations, with a median PFS of 7.0 months vs 4.3 months (hazard ratio = 0.01, 95% CI 0.00-0.34, P = 0.010).

Conclusions: Sirolimus is a potentially effective treatment option for patients with HR-positive advanced breast cancer.
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http://dx.doi.org/10.1016/j.breast.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375615PMC
August 2020

Longitudinal HER2 amplification tracked in circulating tumor DNA for therapeutic effect monitoring and prognostic evaluation in patients with breast cancer.

Breast 2020 Feb 20;49:261-266. Epub 2019 Dec 20.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; 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, 100021, China. Electronic address:

Background: Human epidermal growth factor receptor 2(HER2) status is a crucial predictive factor for prognostic assessment and targeted therapy selection, which may be influenced by intratumor heterogeneity and molecular divergence between the primary site and different metastases. Therefore, we performed a prospective study to confirm the concordance of HER2 amplification in circulating tumor DNA(ctDNA) with primary tumor tissue and verified its clinical implications.

Methods: A total of 105 breast cancer patients were enrolled, and dynamic monitoring of HER2 copy numbers in ctDNA was conducted in 31 participants during the treatment. Totally 186 plasma samples were prospectively obtained and blinded to test HER2 copy numbers in ctDNA based on low-coverage whole genome sequencing(WGS) by next-generation sequencing(NGS).

Results: Comparing HER2 copy numbers in ctDNA collected before the initiation of next line of anticancer treatment with primary tumor tissue, the concordant rate of HER2 amplification was 86.5%(χ = 52.901, p < 0.001), with a positive and negative predictive value of 94.9% and 80.7%, respectively. Histopathologically positive, high-level amplification of HER2 copy numbers in the baseline was significantly correlated with best objective response during the anticancer therapy(p = 0.010). Moreover, HER2 copy numbers fluctuated with HER2-targeted therapeutic response, and the patients with a constantly positive level after 6 weeks of treatment appeared to suffer from significantly reduced progression free survival(p < 0.001).

Conclusions: HER2 amplification in ctDNA, with a concordance rate of over 80% with primary tumors, may be a predictive index for prognostic evaluation and therapeutic response monitoring in a noninvasive, repeatable and practical method for breast cancer patients.
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http://dx.doi.org/10.1016/j.breast.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375665PMC
February 2020

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer.

Cancer Commun (Lond) 2019 10 11;39(1):57. Epub 2019 Oct 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, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, P. R. China.

Background: Breast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers.

Methods: We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR), and the ribonucleotide reductase M1 gene (RRM1) in 342 MBC patients treated with capecitabine-based chemotherapy. The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson's χ test, and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis. The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci (eQTL) browser online tools.

Results: We found 4 positive sites for HFS in the TYMS and MTHFR genes: TYMS rs2606241 (P = 0.022), TYMS rs2853741 (P = 0.019), MTHFR rs3737964 (P = 0.029), and MTHFR rs4846048 (P = 0.030). Logistic regression analyses showed that the genotype AG of MTHFR rs3737964 [odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.31-0.97, P = 0.038] and MTHFR rs4846048 (OR = 0.54, 95% CI 0.30-0.98, P = 0.042) were protective factors of HFS, whereas the genotype CT of TYMS rs2853741 (OR = 2.25, 95% CI 1.31-3.87, P = 0.012) increased the risk of HFS. The association between the genotype GT of TYMS rs2606241 (OR = 1.27, 95% CI 0.73-2.23, P = 0.012) and HFS was uncertain. Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis.

Conclusions: We have identified four potentially useful pharmacogenetic markers, TYMS rs2606241, TYMS rs2853741, MTHFR rs3737964, and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.
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http://dx.doi.org/10.1186/s40880-019-0399-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787984PMC
October 2019

Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer.

Int J Cancer 2020 03 4;146(5):1359-1368. Epub 2019 Jul 4.

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.

Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.
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http://dx.doi.org/10.1002/ijc.32536DOI Listing
March 2020

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial.

Clin Cancer Res 2019 09 28;25(17):5212-5220. Epub 2019 May 28.

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: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC).

Patients And Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers.

Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naïve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, = 0.006).

Conclusions: In a population largely naïve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4173DOI Listing
September 2019

Everolimus in hormone receptor-positive metastatic breast cancer: PIK3CA mutation H1047R was a potential efficacy biomarker in a retrospective study.

BMC Cancer 2019 May 14;19(1):442. Epub 2019 May 14.

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: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), has been shown to increase the efficacy of endocrine therapies in hormone receptor (HR)-positive metastatic breast cancer. However, because breast cancer is a highly heterogeneous disease, the responses of different patients to everolimus may vary. Therefore, we performed this study to better select patients who will benefit most from or be resistant to everolimus.

Methods: Patients with HR-positive breast cancer who were treated with everolimus at the Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to March 2017 were enrolled in the present study. Mutations in ctDNA were assayed in 1021 tumor-related genes via gene panel target capture-based next-generation sequencing.

Results: In total, 120 patients with metastatic breast cancer who were treated with everolimus were enrolled in the present study. The median progression-free survival (PFS) of all patients was 5.1 months (95% confidence interval [CI] 3.9-6.3 months). No difference in survival was observed between patients who received endocrine drugs used in previous treatment regimens and patients who did not receive these drugs (median PFS 5.2 and 5.1 months, respectively, p > 0.05). Additionally, we did not find any difference in outcomes between patients who had primary resistance to previously used endocrine drugs and patients who had nonprimary resistance to previous treatments (p > 0.05). Multivariate analysis showed that < 3 metastatic sites, < 2 lines of previous endocrine therapy, < 2 lines of previous chemotherapy, and treatment with everolimus combined with fulvestrant were associated with improved survival (p < 0.05). Sixteen patients underwent ctDNA analysis before everolimus treatment. The frequency of PIK3CA gene mutations was 62.5%, and H1047R was the most frequently detected mutation. Patients with the PIK3CA/H1047R mutation had longer PFS than patients with wild-type or other mutant forms of PIK3CA, and the median PFS in these two groups of patients was 8.8 and 4.1 months, respectively (p < 0.05).

Conclusions: Our data suggest that patients who receive more lines of chemotherapy or endocrine therapy are less likely to benefit from everolimus. For everolimus combination therapy, we can even select endocrine drugs that gave rise to primary resistance in previous treatments. Additionally, the PIK3CA/H1047R mutation may be a potential biomarker of sensitivity to everolimus.
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http://dx.doi.org/10.1186/s12885-019-5668-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515626PMC
May 2019

The prognostic and therapeutic implications of circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers in the first-line chemotherapy of HER2-negative metastatic breast cancer.

Cancer Commun (Lond) 2019 01 3;39(1). Epub 2019 Jan 3.

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, P. R. China.

Background: Epithelial-mesenchymal transition (EMT) is implicated in the metastatic process and presents a challenge to epithelial cell adhesion molecule-based detection of circulating tumor cells (CTCs), which have been demonstrated to be a prognostic indicator in metastatic breast cancer. Although evidence has indicated that heterogeneity of CTCs based on EMT markers is associated with disease progression, no standard recommendations have been established for clinical practice. This study aimed to evaluate the prognostic significance of dynamic CTC detection based on EMT for metastatic breast cancer patients.

Methods: We enrolled 108 human epidermal growth factor receptor 2-negative metastatic breast cancer patients from the prospective phase III CAMELLIA study and applied the CanPatrol CTC enrichment technique to identify CTC phenotypes (including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs) in peripheral blood samples. Receiver operating characteristic curve analyses of total CTC count and the proportion of mesenchymal CTCs for predicting the 1-year progression-free survival (PFS) rate were conducted to determine the optimal cut-off values, and Kaplan-Meier analysis and Cox proportional hazards regression analysis were performed to investigate the prognostic value of the cut-off values of both total CTC count and the proportion of mesenchymal CTCs in combination.

Results: For predicting the 1-year PFS rate, the optimal cut-off value of total CTC count was 9.5 (Area under the curve [AUC] = 0.538, 95% confidence interval [CI] = 0.418-0.657), and that of the proportion of mesenchymal CTCs was 10.7% (AUC = 0.581, 95% CI = 0.463-0.699). We used the two cut-off values in combination to forecast PFS in which the total CTC count was equaled to or exceeded 10/5 mL with the proportion of mesenchymal CTCs surpassed 10.7%. Patients who met the combined criteria had significantly shorter median PFS than did those who did not meet the criteria (6.2 vs. 9.9 months, P =0.010). A nomogram was constructed based on the criteria and significant clinicopathological characteristics with a C-index of 0.613 (P = 0.010).

Conclusions: The criteria, which combine the total CTC count and the proportion of mesenchymal CTCs, may be used to monitor therapeutic resistance and predict prognosis in patients with metastatic breast cancer. Trial registration ClinicalTrials.gov. NCT01917279. Registered on 19 July 2013, https://clinicaltrials.gov/ct2/show/NCT01917279?term=NCT01917279&rank=1 .
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http://dx.doi.org/10.1186/s40880-018-0346-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319003PMC
January 2019

The association between early-onset cardiac events caused by neoadjuvant or adjuvant chemotherapy in triple-negative breast cancer patients and some novel autophagy-related polymorphisms in their genomic DNA: a real-world study.

Cancer Commun (Lond) 2018 12 4;38(1):71. Epub 2018 Dec 4.

Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, P. R. China.

Background: An increasing number of cancer patients die of cardiovascular diseases. The cardiotoxicity of chemotherapy is particularly important in triple-negative breast cancer (TNBC) with limited therapeutic options. Cardiac autophagy is an important mechanism of cardiotoxicity. This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC, screen the susceptible population, and determine the relationship between cardiotoxicity and autophagy-related polymorphisms.

Methods: From a total of 2450 stage I-III TNBC patients, 147 met the inclusion criteria and finally recruited. Electrocardiography (ECG) was performed before most chemotherapy cycles, and echocardiography (UCG) was performed according to clinical needs. All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease, Fuwai Hospital. According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database, we selected 25 single nucleotide polymorphisms (SNPs) related to autophagy and genotyped the 147 TNBC patients. Paired-sample T tests, Chi squared tests, and logistic regression models were employed for the analysis.

Results: Only 46 (31.3%) patients had normal ECG records after every chemotherapy cycle. Among the 16 patients who underwent UCG, 2 (12.5%) had a reversible decrease of left ventricular ejection fraction. The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities. With the continuation of chemotherapy, heart rate gradually increased. Anthracyclines were associated with QRS duration abnormalities (P = 0.043). After genotyping for 25 autophagy-related SNPs, we found that the G allele of autophagy-related 13 (ATG13) rs10838611 was significantly associated with ECG abnormalities (odds ratio = 2.258, 95% confidence interval = 1.318-3.869; P = 0.003).

Conclusion: ECG abnormalities caused by chemotherapy are common in the real world. Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity, thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.
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http://dx.doi.org/10.1186/s40880-018-0343-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280434PMC
December 2018

Efficient PD-L1 gene silence promoted by hyaluronidase for cancer immunotherapy.

J Control Release 2019 01 23;293:104-112. Epub 2018 Nov 23.

Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.

The immune checkpoint blockade of programmed death ligand-1 (PD-L1) or programmed death-1 (PD-1) has been a promising strategy to restore T cell mediated tumor suppression. In this study, a plasmid DNA which expressed small hairpin RNA of PD-L1 (shPD-L1) was loaded in the ultrasensitive pH triggered charge/size dual-rebound P[(GP)D] nanoparticles (NPs) to silence the PD-L1 gene for reducing the PD-L1/PD-1 interactions between tumors and T cells. To increase the penetration of the shPD-L1 loaded P[(GP)D] NPs ([email protected]) in tumors, hyaluronidase (HAase) was utilized to degrade the overexpressed hyaluronicacid (HA) in the extracellular matrix (ECM) of the tumor tissues. The HAase-enhanced tumor accumulation and penetration of the P[(GP)D] NPs were carefully explored. Further in vivo antitumor therapy was carried out in the malignant melanoma mouse tumor model, and a significant tumor inhibition effect was achieved by the combination treatment of HAase and [email protected] Our results verified that the HAase could effectively degrade the HA in tumors and increase the penetration of the [email protected] for achieving more efficient PD-L1 gene silence and finally realizing potent tumor suppression. This combination treatment strategy has great potentials to be adopted for other nanomedicines, and it will have broad applications for cancer therapy in the future.
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http://dx.doi.org/10.1016/j.jconrel.2018.11.022DOI Listing
January 2019

Highly enhanced cancer immunotherapy by combining nanovaccine with hyaluronidase.

Biomaterials 2018 07 21;171:198-206. Epub 2018 Apr 21.

Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.

Tumor vaccine has been one of the research hotspots for cancer immunotherapy in recent years. By introducing tumor antigens into the body, the patient's own immune system will be specifically activated to induce effective immune responses for controlling or eliminating the malignant tumor cells. In this study, a simple nanovaccine was developed to induce antigen-specific anti-tumor immune responses. Polycationic polyethylenimine (PEI) was utilized to co-deliver the antigen ovalbumin (OVA) and the adjuvant unmethylated cytosine-phosphate-guanine (CpG) by electrostatic binding. The positively charged PEI could be beneficial to augment the PEI/CpG/OVA nanovaccine uptake in dendritic cells (DCs) and facilitate the endosomal escape of the nanovaccine for antigen delivering into the cytoplasm. The nanovaccine showed significant stimulation on DCs' maturation in vitro, and it was further applied for in vivo anti-tumor immunotherapy. To enhance the tumor infiltration of the nanovaccine-generated tumor-specific T cells, hyaluronidase (HAase) was employed to increase the permeability of the tumor tissues by breaking down the hyaluronan (HA) in the extracellular matrix (ECM) of tumors. Highly enhanced in vivo anti-tumor therapeutic efficiency was achieved by combining the PEI/CpG/OVA nanovaccine with HAase, which was attributed to the increased quantity of OVA-specific T cells in tumor tissues. The combination of nanovaccine with HAase has offered a simple and efficient strategy for inducing powerful anti-tumor effect in cancer immunotherapy.
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http://dx.doi.org/10.1016/j.biomaterials.2018.04.039DOI Listing
July 2018

pH-Responsive Natural Polymeric Gene Delivery Shielding System Based on Dynamic Covalent Chemistry.

ACS Biomater Sci Eng 2018 Jan 22;4(1):193-199. Epub 2017 Dec 22.

Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Renmin Street 5625, Changchun 130022, China.

A novel pH-responsive system based on aldehyde-bearing dextran derivatives (ODEX or FDEX) was designed to use as gene carrier shielding. Through pH sensitive Schiff base bonds between amino groups of PEI (in PEI/DNA polyplex) and aldehyde groups of dextran derivatives, PEI/DNA polyplex could be shielded and further condensed to obtain an effectively decreasing ζ-potential with smaller size. Schiff base bonds were pH-responsive, which were relatively stable in neutral environment but were deformed in slightly acidic and acidic environments. Through use of this characteristic, the PEI/DNA polyplex was effectively shielded during circulation in the body, and upon arrival at the tumor, the slightly acid pH triggered the breaking of Schiff base bonds to expose the positive PEI/DNA polyplex, which further interacted with tumor cell membranes, achieving efficient gene expression. Use of such characteristics could effectively address the high transfection efficiency versus stability dilemma of gene carriers. FDEX/PEI/DNA nanoparticles not only mediate higher cellular uptake and transfection efficiency in vitro but also effectively accumulate in tumors with gene expression in vivo higher than that of the ODEX analogues. As a result, this pH-responsive system is a promising strategy for cancer therapy.
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http://dx.doi.org/10.1021/acsbiomaterials.7b00869DOI Listing
January 2018

Plasma cell-free DNA and survival in non-small-cell lung cancer: A meta-analysis.

Mol Clin Oncol 2017 Aug 28;7(2):167-172. Epub 2017 Jun 28.

Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.

In recent years, plasma cell-free DNA (cfDNA) has been attracting increasing attention as a potential tumor marker, as this method is easily applied and minimally invasive. A series of studies have confirmed the association between the level of cfDNA and overall survival (OS) in non-small-cell lung cancer (NSCLC), but the findings remain inconclusive. We herein conducted a meta-analysis of published articles evaluating the correlation between the level of cfDNA and OS. A total of 9 studies enrolling 1,170 patients were included. For the overall population, a high level of cfDNA was found to be significantly correlated with worse OS [hazard ratio (HR) = 1.57, 95% confidence interval (CI): 1.18-2.10] in NSCLC. The subgroup analysis suggested that a high cfDNA level was associated with worse outcome in stage III-IV patients (HR=1.53, 95% CI: 1.07-2.19). However, the level of cfDNA and OS were not found to be significantly associated in the subgroup of patients with tumor stage I-II. The present meta-analysis revealed that a high level of cfDNA may be correlated with poor OS in NSCLC.
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http://dx.doi.org/10.3892/mco.2017.1301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532691PMC
August 2017

Landscape of somatic mutations in different subtypes of advanced breast cancer with circulating tumor DNA analysis.

Sci Rep 2017 07 20;7(1):5995. Epub 2017 Jul 20.

Department of Medical Oncology, National Cancer Center/Cancer hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

It is particularly important to provide precise therapies and understand tumor heterogeneity based on the molecular typing of mutational landscape. However, the landscape of somatic mutations in different subtypes of advanced breast cancer (ABC) is largely unknown. We applied target-region capture deep sequencing to determine the frequency and spectrum of common cancer-related gene mutations in circulating tumor DNA (ctDNA) among different ABC subtypes and analyze their association with clinical features. In this retrospective study of 100 female advanced breast cancer patients, 96 (96.0%) had somatic genomic alterations in ctDNA, including copy number variants and point mutations. The results revealed that different subtypes of ABC have distinct features in terms of genetic alterations. Multivariate regression analyses revealed that the number of somatic mutations increased with the line of endocrine therapy and the fractions of trunk mutations was positive associated with the line of target therapy.
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http://dx.doi.org/10.1038/s41598-017-06327-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519668PMC
July 2017

The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis.

Breast Cancer Res Treat 2017 Jul 21;164(1):1-11. Epub 2017 Apr 21.

Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Purpose: Breast cancer is the most common cancer in females and the leading cause of death worldwide. The effects of statins on breast cancer prognosis have long been controversial; thus, it is important to investigate the relationship between statin type, exposure time, and breast cancer prognosis. This study sought to explore the effect of statins, as well as the different effects of statin solubility and variable follow-up times, on breast cancer prognosis.

Methods: We searched the MEDLINE (via PubMed), EMBASE (via OvidSP), Cochrane Library, and ISI Web of Knowledge databases using combinations of the terms "breast neoplasms[MeSH]," "statins" or "lipid-lowering drug," "prognosis" or "survival," or "mortality" or "outcome" with no limit on the publication date. We searched the databases between inception and October 15, 2016. Reference lists of the included studies and relevant reviews were also manually screened. The initial search identified 71 publications, and 7 of these studies, which included a total of 197,048 women, met the selection criteria. Two authors independently screened each study for inclusion and extracted the data. The data were analyzed using Stata/SE 11.0.

Results: Overall statin use was associated with lower cancer-specific mortality and all-cause mortality, although the benefit appeared to be constrained by statin type and follow-up time. Lipophilic statins were associated with decreased breast cancer-specific and all-cause mortality; however, hydrophilic statins were weakly protective against only all-cause mortality and not breast cancer-specific mortality. Of note, one group with more than 4 years of follow-up did not show a significant correlation between statin use and cancer-specific mortality or all-cause mortality, whereas groups with less than 4 years of follow-up still showed the protective effect of statins against cancer-specific mortality and all-cause mortality.

Conclusions: Although statins can reduce breast cancer patient mortality, the benefit appears to be constrained by statin type and follow-up time. Lipophilic statins showed a strong protective function in breast cancer patients, whereas hydrophilic statins only slightly improved all-cause mortality. Finally, the protective effect of statins could only be observed in groups with less than 4 years of follow-up. These findings are meaningful in clinical practice, although some conclusions contradict conventional wisdom and will thus require further exploration.
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http://dx.doi.org/10.1007/s10549-017-4246-0DOI Listing
July 2017
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