Publications by authors named "Shusen Wang"

125 Publications

Distribution Characteristics and Prognostic Value of Immune Infiltration in Oligometastatic Breast Cancer.

Front Oncol 2021 11;11:747012. Epub 2021 Nov 11.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: To assess the distribution characteristics and the prognostic value of immune infiltration in female oligometastatic breast cancer patients.

Methods: We retrospectively analyzed the clinicopathological data of oligometastatic breast cancer (OMBC) patients diagnosed between June 2000 and January 2020. Immune markers were quantified by immunohistochemistry on FFPE tissues in paired normal breast tissues, primary breast cancers and oligometastatic lesions. Survival analyses were performed using the Kaplan-Meier curves and Cox-proportional hazards model.

Results: A total of 95 female OMBC patients visited Sun Yat-sen University Cancer Center between June 2000 and January 2020, and 33 of them had matched normal breast tissues, primary cancers and oligometastatic lesions and were reviewed in immune infiltration analysis. CD8 of primary tumors had a higher expression than that in matched normal tissues. The expressions of CD8 and FOXP3 were higher in the primary sites than that in the oligometastatic lesions. CD3, CD4 and CD8 were significantly lower in the intratumoral regions than that in the peritumoral regions both in primary and oligometastatic lesions. Notably, the high percentage of CD3 in the intratumoral oligometastatic lesions predicted the longer PFS and OS, and higher CD4 in the same lesions also predicted a better OS. There was obviously positive correlation between CD4/CD3 and Ki-67 in primary cancers and negative correlation between CD4/CD3 and ER in oligometastatic sites.

Conclusion: We explored immune distribution and evolution in time and space in OMBC to provide new understandings for biological behaviors of this disease and further divided patients in different prognosis.
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http://dx.doi.org/10.3389/fonc.2021.747012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632540PMC
November 2021

BRAF V600E Mutation in Triple-Negative Breast Cancer: A Case Report and Literature Review.

Oncol Res Treat 2021 Nov 24:1-7. Epub 2021 Nov 24.

Department of Oncology, Sun Yat-Sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: The B-Raf proto-oncogene (BRAFV600E) gene mutation has been identified in a variety of malignancies, but no evidence of the efficacy of vemurafenib treatment in BRAFV600E mutant breast cancer (BC) has been reported.

Case Presentation: We reported a 60-year-old woman with confirmed triple-negative BC with BRAFV600E mutation. Progression-free survival (PFS) for first-line chemotherapy was 7 months. The patient received vemurafenib and albumin-bound paclitaxel as second-line therapy, exhibiting regression of some pulmonary metastatic lesions with concomitant progression of other lesions, and achieved 4.4 months of PFS. Genetic testing of the progressed pulmonary lesion revealed the BRAFV600E mutation, and acquired new mutations and AR amplification. The patient ultimately died of multiple organ failure and achieved 12 months of overall survival.

Conclusions: The BRAFV600E mutation may be a potential prognostic factor and therapeutic target for BC.
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http://dx.doi.org/10.1159/000520453DOI Listing
November 2021

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Metastatic Breast Cancer with Hormone Receptor-positive and HER2-positive (SYSUCC-002).

Clin Cancer Res 2021 Nov 22. Epub 2021 Nov 22.

Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center

Purpose: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first line management of hormone receptor (HR)-positive and HER2- positive metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is non-inferior to trastuzumab plus chemotherapy.

Experimental Design: We conducted an open-label, non-inferiority, phase-3, randomized, controlled trial (NCT01950182) at nine hospitals in China. Patients with HR+HER2+ MBC were enrolled. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a non-inferiority upper margin of 1.35 for the hazard ratio. The intention-to-treat population was used in primary and safety analyses.

Results: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n=196) or trastuzumab plus chemotherapy (CT group, n=196). After a median follow-up of 30.2 months (IQR 15.0-44.7), the median PFS was 19.2 months (95%CI 16.7-21.7) in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio 0.88, 95%CI 0.71-1.09; p <0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group.

Conclusions: Trastuzumab plus endocrine therapy was non-inferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-3435DOI Listing
November 2021

Climate impact from agricultural management practices in the Canadian Prairies: Carbon equivalence due to albedo change.

J Environ Manage 2022 Jan 20;302(Pt A):113938. Epub 2021 Oct 20.

Ottawa Research and Development Centre, Agriculture and Agri-Food Canada, Ottawa, Ontario, K1A0C6, Canada.

It is generally accepted that land use and land management practices impact climate change through sequestration of carbon in soils, but modulation of surface energy budget can also be important. Using Landsat data to characterize cropland albedos in Canada's three prairie soil zones, this study estimates the atmospheric carbon equivalent drawdown of albedo radiative forcing for three management practices: 1) moving from conventional tillage to no-till, 2) eliminating summer fallow in crop rotations, and 3) growing crops with higher albedos. In a 50-year time horizon, conversion from conventional tillage to no-till results in a total equivalent atmospheric CO (CO-eq) drawdown of 1.0-1.5 kg m, and conversion from summer fallow to crops results in CO-eq drawdown of 1.1-2.4 kg m. Conversion of summer fallow to crops results in different magnitudes of CO-eq drawdown depending on specific crops. Lentils, peas, and canola have relatively higher albedo than that of spring wheat and flax; hence, a larger magnitude of CO-eq drawdown results when they replace summer fallow in the rotation. For the management changes from 1990 to 2019 for the whole Canadian Prairies, albedo changes induced a CO-eq drawdown of about 179.3 ± 20.9 Tg due to increased area of no-till, and 101.6 ± 9.5 Tg due to reduced area under fallow. The study shows that the magnitudes of CO-eq drawdown due to albedo change are comparable to that due to soil carbon sequestration. Therefore, it is important to account for cropland albedo changes in assessing the potential of agricultural management practices to mitigate climate change.
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http://dx.doi.org/10.1016/j.jenvman.2021.113938DOI Listing
January 2022

Identification of a risk prediction model for clinical prognosis in HER2 positive breast cancer patients.

Genomics 2021 Oct 16;113(6):4088-4097. Epub 2021 Oct 16.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address:

Background New biomarkers are needed to identify different clinical outcomes for HER2+ breast cancer (BC). Methods Differential genes of HER2+ BC were screened based on TCGA database. We used WGCNA to identify the genes related to the survival. Genetic Algorithm was used to structure risk prediction model. The prognostic model was validated in GSE data. Results We constructed a risk prediction model of 6 genes to identify prognosis of HER2+ BC, including CLEC9A, PLD4, PIM1, PTK2B, AKNAD1 and C15orf27. Kaplan-Meier curve showed that the model effectively distinguished the survival of HER2+ BC patients. The multivariate Cox regression suggested that the risk model was an independent predictor for HER2+ BC. Analysis related to immune showed that significant differences in immune infiltration between high- and low-risk groups classified by the prognostic model. Conclusions Our study identified a risk prediction model of 6 genes that could distinguish the prognosis of HER2+ BC.
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http://dx.doi.org/10.1016/j.ygeno.2021.10.010DOI Listing
October 2021

Miller-Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy.

Front Oncol 2021 24;11:735670. Epub 2021 Sep 24.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Introduction: HR+/HER2- breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2- non-pCR populations, it is essential to accurate identification new prognostic markers.

Materials And Methods: The study retrospectively analyzed 105 stage II-III patients who were diagnosed with HR+/HER2- BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller-Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.

Results: Among the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) ( = 0.004, = 0.021, and = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1-2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4-5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10-0.80; = 0.018]. DFS was longer in the good response (MP grades 3-4) group than in the poor response (MP grades 1-2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05-0.47; = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS ( = 0.048). Due to the short median follow-up time of 34.5 months (5.9-75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.

Conclusion: The study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.
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http://dx.doi.org/10.3389/fonc.2021.735670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498026PMC
September 2021

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

Cancer Med 2021 Oct 2;10(19):6744-6761. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495288PMC
October 2021

Cyclin G2 reverses immunosuppressive tumor microenvironment and potentiates PD-1 blockade in glioma.

J Exp Clin Cancer Res 2021 Aug 27;40(1):273. Epub 2021 Aug 27.

The Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Liaoning Province, Shenyang, People's Republic of China.

Background: Expression of aberrant cyclin G2 is a key factor contributing to cancer biological processes, including glioma. However, the potential underlying mechanisms of cyclin G2 in the glioma tumor immune microenvironment remain unclear.

Methods: Co-immunoprecipitation (co-IP), in situ proximity ligation assay (PLA), and in vitro kinase assay were conducted to reveal the underlying mechanism by which cyclin G2 regulates Y10 phosphorylation of LDHA. Further, the biological roles of cyclin G2 in cell proliferation, migration, invasion capacity, apoptosis, glycolysis, and immunomodulation were assessed through in vitro and in vivo functional experiments. Expressions of cyclin G2 and Foxp3 in glioma specimens was determined by immunohistochemistry.

Results: In this study, we found that cyclin G2 impeded the interaction between LDHA and FGFR1, thereby decreasing Y10 phosphorylation of LDHA through FGFR1 catalysis. Cyclin G2 inhibited proliferation, migration, invasion capacity, and glycolysis and promoted apoptosis glioma cells via suppressing Y10 phosphorylation of LDHA. Moreover, we further verified that cyclin G2 reversed the immunosuppressive to antitumor immune microenvironment through inhibiting lactate production by glioma cells. Besides, cyclin G2 potentiated PD-1 blockade and exerted strong antitumor immunity in the glioma-bearing mice model.

Conclusions: Cyclin G2 acts as a potent tumor suppressor in glioma and enhances responses to immunotherapy. Our findings may be helpful in selecting glioma patients for immunotherapy trials in the future.
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http://dx.doi.org/10.1186/s13046-021-02078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400712PMC
August 2021

Long non-coding RNAs HERH-1 and HERH-4 facilitate cyclin A2 expression and accelerate cell cycle progression in advanced hepatocellular carcinoma.

BMC Cancer 2021 Aug 26;21(1):957. Epub 2021 Aug 26.

National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China.

Background: The advanced hepatocellular carcinoma (HCC), such as the recurrent tumor after liver transplantation (LT), is an obstacle of HCC treatment. The aim of this study was to discover the underlying mechanism of HCC progression caused by non-coding RNAs (ncRNAs).

Methods: To this end, we investigated the selected patient cohort of matching primary and recurrent HCC after receiving LT. The recurrent tumors after LT were regarded as clinical models of the advanced HCC. Microarrays were used to profile lncRNA and mRNA expression in HCC recurrent and primary tissue samples. The mRNA profile characteristics were analyzed by bioinformatics. Two cell lines, HepG2 and QGY-7703, were used as HCC cell models. The protein-coding potential, length, and subcellular location of the interested lncRNAs were examined by bioinformatics, Northern blot, fluorescent in situ hybridization (FISH), and quantitative RT-PCR (qRT-PCR) assays. HCC cell proliferation was detected by CCK-8, doubling time and proliferation marker gene quantitation assays. DNA replication during the cell cycle was measured by EdU/PI staining and flow cytometry analyses. Promoter activity was measured using a luciferase reporter assay. Interactions between DNA, RNA, and protein were examined by immunoprecipitation and pull-down assays. The miRNA-target regulation was validated by a fluorescent reporter assay.

Results: Both lncRNA and mRNA profiles exhibited characteristic alterations in the recurrent tumor cells compared with the primary HCC. The mRNA profile in the HCC recurrent tissues, which served as model of advanced HCC, showed an aberrant cell cycle regulation. Two lncRNAs, the highly expressed lncRNA in recurrent HCC (HERH)-1 and HERH-4, were upregulated in the advanced HCC cells. HERH-1/4 enhanced proliferation and promoted DNA replication and G1-S transition during the cell cycle in HCC cells. HERH-1 interacted with the transcription factor CREB1. CREB1 enhanced cyclin A2 (CCNA2) transcription, depending on HERH-1-CREB1 interaction. HERH-4 acted as an miR-29b/c sponge to facilitate CCNA2 protein translation through a competing endogenous RNA (ceRNA) pathway.

Conclusions: The oncogenic lncRNA HERH-1/4 promoted CCNA2 expression at the transcriptional and post-transcriptional levels and accelerated cell cycle progression in HCC cells. The HERH-1-CREB1-CCNA2 and HERH-4-miR-29b/c-CCNA2 axes served as molecular stimuli for HCC advance.
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http://dx.doi.org/10.1186/s12885-021-08714-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390207PMC
August 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 Oct 21;7(10):e213428. Epub 2021 Oct 21.

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
October 2021

Red- and Far-Red-Emitting Zinc Probes with Minimal Phototoxicity for Multiplexed Recording of Orchestrated Insulin Secretion.

Angew Chem Int Ed Engl 2021 12 15;60(49):25846-25855. Epub 2021 Sep 15.

College of Future Technology, Institute of Molecular Medicine, National Biomedical Imaging Center, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China.

Zinc biology, featuring intertwining signaling networks and critical importance to human health, witnesses exciting opportunities in the big data era of physiology. Here, we report a class of red- and far-red-emitting Zn probes with K values ranging from 190 nM to 74 μM, which are particularly suitable for real-time monitoring the high concentration of Zn co-released with insulin during vesicular secretory events. Compared to the prototypical rhodamine-based Zn probes, the new class exploits morpholino auxochromes which eliminates phototoxicity during long-term live recording of isolated islets. A Si-rhodamine-based Zn probe with high turn-on ratio (>100), whose synthesis was enabled by a new route featuring late-stage N-alkylation, allowed simultaneous recording of Ca influx, mitochondrial signal, and insulin secretion in isolated mouse islets. The time-lapse multicolor fluorescence movies and their analysis, enabled by red-shifted Zn and other orthogonal physiological probes, highlight the potential impact of biocompatible fluorophores on the fields of islet endocrinology and system biology.
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http://dx.doi.org/10.1002/anie.202109510DOI Listing
December 2021

Establishment of Prognostic Nomograms for Predicting the Survival of HR-Positive, HER2-Negative Metastatic Breast Cancer Patients Treated with Everolimus.

Drug Des Devel Ther 2021 10;15:3463-3473. Epub 2021 Aug 10.

Departments of Medical Oncology, Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.

Background: There are no clinically available prognostic models for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer treated with everolimus. We aimed to develop a tool to predict the progression-free survival (PFS) and overall survival (OS) of these patients and to identify optimal candidates who would benefit from everolimus-based treatment in this heterogeneous patient population.

Methods: The clinical data of patients with HR+, HER2- metastatic breast cancer receiving everolimus between May 2012 and January 2018 at Sun Yat-sen University Cancer Center were retrospectively retrieved. Based on potential prognostic factors derived from multivariate Cox analysis, we established predictive nomogram models for PFS and OS and evaluated their predictive values by means of the concordance index (C-index). Calibration curves were used to estimate the consistency between the actual observations and the nomogram-predicted probabilities.

Results: A total of 116 patients with HR+, HER2- metastatic breast cancer were enrolled in this study. Three independent prognostic factors, including the line of everolimus in the metastatic setting, everolimus clinical benefit rate and number of liver metastatic lesions, were identified from the multivariate Cox analysis. Prognostic models for individual survival prediction were established and graphically presented as nomograms. The C-index was 0.738 (95% confidence interval [CI]: 0.710-0.767) for the PFS nomogram and 0.752 (95% CI: 0.717-0.788) for the OS nomogram, which showed favourable discrimination. The calibration curves for the probabilities of 6-, 9-, and 12-month PFS and 1-, 2-, and 3-year OS suggested satisfactory consistency between the actual observations and the predicted probabilities.

Conclusion: We constructed convenient nomogram models for patients with HR+, HER2- metastatic breast cancer to individually predict their potential benefits from everolimus in the metastatic setting. The models showed good performance in terms of accuracy, discrimination capacity and clinical application value.
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http://dx.doi.org/10.2147/DDDT.S314723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364432PMC
August 2021

Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in the Chinese population.

Ann Med 2021 12;53(1):1358-1369

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.

Background: Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients.

Methods: Formalin-fixed paraffin-embedded (FFPE) tumour tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumour mutational burden (TMB).

Results: In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging six alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%) and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least one CRGA, and 87% of patients had at least one actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion for the first time, which has not been reported in breast cancer before.

Conclusions: The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.
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http://dx.doi.org/10.1080/07853890.2021.1966086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381897PMC
December 2021

Defective insulin maturation in patients with type 2 diabetes.

Eur J Endocrinol 2021 Sep 1;185(4):565-576. Epub 2021 Sep 1.

Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.

Objective: Progressive beta-cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown.

Methods: We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon, were detected by immunofluorescence.

Results: We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI+/INS-) cells were evident in T2D, and this increase was strongly correlated with levels of hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed a higher degree of co-localization with the golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI+/INS- cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI+/INS-. The decreased NKX6.1+/PI+/INS+ was strongly correlated with levels of HbA1c in T2D. Almost all PI+/INS- cells showed absence of NKX6.1. Moreover, the percentages of PI+/INS- cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining.

Conclusion: Our data demonstrate defective insulin maturation in patients with T2D.
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http://dx.doi.org/10.1530/EJE-21-0144DOI Listing
September 2021

CPSF4 promotes triple negative breast cancer metastasis by upregulating MDM4.

Signal Transduct Target Ther 2021 May 19;6(1):184. Epub 2021 May 19.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

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http://dx.doi.org/10.1038/s41392-021-00565-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131696PMC
May 2021

Trastuzumab emtansine (T-DM1) versus trastuzumab in Chinese patients with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy for HER2-positive breast cancer in the phase 3 KATHERINE study.

Breast Cancer Res Treat 2021 Jun 15;187(3):759-768. Epub 2021 Apr 15.

Fudan University Shanghai Cancer Center, No. 270, Dongan Road, Shanghai, 200032, China.

Purpose: In the KATHERINE study (NCT01772472), patients with HER2-positive early breast cancer (EBC) and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy who were treated with adjuvant trastuzumab emtansine (T-DM1) had a 50% reduction in the risk of an invasive disease-free survival (IDFS) event compared to patients treated with adjuvant trastuzumab. In metastatic disease, T-DM1 has resulted in higher rates of thrombocytopenia in Asian versus non-Asian patients. Here, we report safety and efficacy in Chinese patients from KATHERINE.

Methods: Patients with HER2-positive EBC and residual invasive disease after taxane- and trastuzumab-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was time to an IDFS event.

Results: Among Chinese patients (T-DM1 n = 51, trastuzumab n = 50), T-DM1 treatment resulted in a 43% reduction in risk of an IDFS event compared to trastuzumab (HR = 0.57; 95% CI 0.25-1.31), with similar results for secondary endpoints. As in the global population, Chinese patients receiving T-DM1 versus trastuzumab had more grade ≥ 3 adverse events (AEs; 39.2% versus 4.1%) and AEs leading to treatment discontinuation (27.5% versus 0%). The most common grade ≥ 3 AE with T-DM1 was thrombocytopenia (21.6%), a frequency higher than the frequency in the global population (5.7%). Grade ≥ 3 hemorrhage was reported in 1 patient (T-DM1 arm).

Conclusions: In the KATHERINE study, T-DM1 demonstrated increased efficacy compared to trastuzumab in Chinese patients. Consistent with previous data in Asian patients, T-DM1 was associated with more grade ≥ 3 AEs, and AEs leading to discontinuation, which was driven by an increase in thrombocytopenia.
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http://dx.doi.org/10.1007/s10549-021-06166-yDOI Listing
June 2021

The complete mitochondrial genome of (Orthoptera: Acridoidea: Gomphoceridae).

Mitochondrial DNA B Resour 2021 Apr 1;6(4):1310-1312. Epub 2021 Apr 1.

Institute of Life Science and Technology, Inner Mongolia Normal University, Hohhot, China.

The complete mitogenome was sequenced through Illumina HiSeq 2500 platform and the resulting data were analyzed in this paper. The mitochondrial genome of is a typical circular DNA molecule of 15,781 bp with 37 genes and 74.5% A + T content, which encoded 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and the control region. The mitochondrial genome and 27 mitochondrial genomes (downloaded from NCBI) were employed to construct phylogenetic tree, in which and were the outgroups. Phylogenetic reconstruction validated the taxonomic status of , which was placed in the monophyletic Gomphocerinae in Acrididae.
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http://dx.doi.org/10.1080/23802359.2021.1907803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018437PMC
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

High-dose tamoxifen in high-hormone-receptor-expressing advanced breast cancer patients: a phase II pilot study.

Ther Adv Med Oncol 2021 26;13:1758835921993436. Epub 2021 Feb 26.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510000, China.

Background: Tumor progression following endocrine therapy is considered to indicate resistance to endocrine drugs due to a variety of mechanisms. An insufficient dose of endocrine drugs is one of the causes for treatment failure in some patients with high hormone-receptor (HR)-expressing advanced breast cancer. This study aimed to explore the efficacy of high-dose tamoxifen (TAM) treatment in patients with advanced breast cancer with highly expressed HR.

Materials & Methods: This was a single-arm, phase II pilot study that enrolled patients with advanced breast cancer with high HR expression (estrogen receptor ⩾60% and/or progesterone receptor ⩾60%) following routine endocrine therapy. All enrolled patients received a high-dose of TAM (100 mg/day) until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Exploratory endpoints included the predictive value of α-F-β-fluoroestradiol quantitative positron emission tomography/computed tomography (F-FES PET/CT) for treatment efficacy.

Results: A total of 30 patients were enrolled between September 2017 and February 2019. The median PFS was 6 months [95% confidence interval (CI) 4.9-7.1] and the median OS was 15.6 months (95% CI 8.3-22.9). Five patients experienced a partial response (PR) and none experienced a complete response (CR), with an ORR of 16.7% and CBR of 33.3%. No severe adverse events were observed. Lesions with F-FES maximum standardized uptake value (SUVmax) ⩾4 had a significantly longer PFS [median 9.2 months, (95% CI 6.9-11.6)] compared with lesions with a F-FES SUVmax <4 [median 4.8 months, (95% CI 3.9-5.6);  = 0.022].

Conclusion: A high-dose of TAM is effective and safe for patients with advanced breast cancer with high HR expression. F-FES SUVmax values may predict the local clinical benefits of high-dose TAM .

Trial Registration: [ClinicalTrials.gov identifier: NCT0304565].
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http://dx.doi.org/10.1177/1758835921993436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934038PMC
February 2021

Increased frequency of β cells with abnormal NKX6.1 expression in type 2 diabetes but not in subjects with higher risk for type 2 diabetes.

BMC Endocr Disord 2021 Mar 12;21(1):47. Epub 2021 Mar 12.

NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, 300384, China.

Background: NKX6.1 is a transcription factor for insulin, as well as a marker for β cell maturity. Abnormal NKX6.1 expression in β cells, such as translocation from the nucleus to cytoplasm or lost expression, has been shown as a marker for β cell dedifferentiation.

Methods: We obtained pancreatic sections from organ donors and immunofluorescence staining with NKX6.1 and insulin was performed to characterize NKX6.1 expression in subjects with or without type 2 diabetes mellitus (T2DM).

Results: Our results showed that cells with insulin expression but no nucleic NKX6.1 expression (NKX6.1Ins), and cells with cytoplasmic NKX6.1 expression but no insulin expression (NKX6.1Ins) were significantly increased in T2DM subjects and positively correlated with glycated hemoglobin (HbA1c), indicating the elevated β cell dedifferentiation with NKX6.1 inactivation in T2DM. To investigate whether β cell dedifferentiation has initiated in subjects with higher risks for T2DM, we next analyzed the association between β-cell dedifferentiation level in ND subjects with different ages, body mass index, and HbA1c. The results showed the absolute number and percentage of dedifferentiated β cells with NKX6.1 inactivation did not significantly change in subjects with advanced aging, obesity, or modest hyperglycemia, indicating that the β cell dedifferentiation might mainly occur after T2DM was diagnosed.

Conclusion: Our results suggested that NKX6.1 expression in β cells was changed in type 2 diabetic subjects, evidenced by significantly increased NKX6.1Ins and NKX6.1Ins cells. This abnormality did not occur more frequently in subjects with a higher risk for T2DM, suggesting that β cell dedifferentiation might be secondary to the pathological changes in T2DM.
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http://dx.doi.org/10.1186/s12902-021-00708-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955633PMC
March 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

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

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

Cancer Commun (Lond) 2021 02 2;41(2):171-182. Epub 2021 Feb 2.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.

Background: The introductions of anti- human epidermal growth factor receptor-2 (HER2) agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer. BAT8001 is a novel antibody-drug conjugate targeting human epidermal growth factor receptor-2 (HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.

Methods: This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21-day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective.

Results: Between March 2017 to May 2018, 29 HER2-positive breast cancer patients were enrolled. The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ-glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%-61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%-94.2%) patients.

Conclusions: BAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.
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http://dx.doi.org/10.1002/cac2.12135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896747PMC
February 2021

Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.

J Clin Invest 2021 01;131(2)

Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes.
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http://dx.doi.org/10.1172/JCI142240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810482PMC
January 2021

Expression of miRNA-29 in Pancreatic β Cells Promotes Inflammation and Diabetes via TRAF3.

Cell Rep 2021 01;34(1):108576

Key Laboratory of Human Functional Genomics of Jiangsu Province, Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China. Electronic address:

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.
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http://dx.doi.org/10.1016/j.celrep.2020.108576DOI Listing
January 2021

Identification and characterization of critical genes associated with tamoxifen resistance in breast cancer.

PeerJ 2020 4;8:e10468. Epub 2020 Dec 4.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Tamoxifen resistance in breast cancer is an unsolved problem in clinical practice. The aim of this study was to determine the potential mechanisms of tamoxifen resistance through bioinformatics analysis.

Methods: Gene expression profiles of tamoxifen-resistant MCF-7/TR and MCF-7 cells were acquired from the Gene Expression Omnibus dataset GSE26459, and differentially expressed genes (DEGs) were detected with R software. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was generated, and we analyzed hub genes in the network with the Search Tool for the Retrieval of Interacting Genes database. Finally, we used siRNAs to silence the target genes and conducted the MTS assay.

Results: We identified 865 DEGs, 399 of which were upregulated. GO analysis indicated that most genes are related to telomere organization, extracellular exosomes, and binding-related items for protein heterodimerization. PPI network construction revealed that the top 10 hub genes-, and -might be associated with tamoxifen resistance. Consistently, RT-qPCR analysis indicated that the expression of these 10 genes was increased in MCF-7/TR cells comparing with MCF-7 cells. Four hub genes ( and ) were related to overall survival in patients who accepted tamoxifen. In addition, knockdown of HSPH1 by siRNA may lead to reduced growth of MCF-7/TR cell with a trend close to significance ( = 0.07), indicating that upregulation of HSPH1 may play a role in tamoxifen resistance.

Conclusion: This study revealed a number of critical hub genes that might serve as therapeutic targets in breast cancer resistant to tamoxifen and provided potential directions for uncovering the mechanisms of tamoxifen resistance.
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http://dx.doi.org/10.7717/peerj.10468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720728PMC
December 2020

Spatial variations and long-term trends of potential evaporation in Canada.

Sci Rep 2020 12 16;10(1):22089. Epub 2020 Dec 16.

Canada Centre for Remote Sensing, Natural Resources Canada, 560 Rochester Street, Ottawa, ON, K1A 0E4, Canada.

Assessing the status and trend of potential evaporation (PE) is essential for investigating the climate change impact on the terrestrial water cycle. Despite recent advances, evaluating climate change impacts on PE using pan evaporation (E) data in cold regions is hindered by the unavailability of E measurements in cold seasons due to the freezing of water and sparse spatial distribution of sites. This study generated long-term PE datasets in Canada for 1979-2016 by integrating the dynamic evolutions of water-ice-snow processes into estimation in the Ecological Assimilation of Land and Climate Observations (EALCO) model. The datasets were compared with E before the spatial variations and trends were analyzed. Results show that EALCO PE and E measurements demonstrate similar seasonal variations and trends in warm seasons in most areas. Annual PE in Canada varied from 100 mm in the Northern Arctic to approximately 1000 mm in southern Canadian Prairies, southern Ontario, and East Coast, with about 600 mm for the entire landmass. Annual PE shows an increasing trend at a rate of 1.5-4 mm/year in the Northern Arctic, East, and West Canada. The increase is primarily associated with the elevated air temperature and downward longwave and shortwave radiation, with some regions contributed by augmented wind speed. The increase of annual PE is mainly attributed to the augmentation of PE in warm seasons.
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http://dx.doi.org/10.1038/s41598-020-78994-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744546PMC
December 2020

A Phase II Study of Fulvestrant 500 mg as Maintenance Therapy in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Patients with Advanced Breast Cancer After First-Line Chemotherapy.

Oncologist 2021 05 8;26(5):e742-e748. Epub 2020 Dec 8.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.

Lessons Learned: Fulvestrant 500 mg maintenance therapy showed a clinical benefit rate of 76% and median progression-free survival of 16.1 months in patients who achieved objective responses or disease control after first-line chemotherapy. Adverse events with fulvestrant maintenance therapy were consistent with the known safety profile of the drug.

Background: Evidence for maintenance hormonal therapy after chemotherapy for estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer is scarce. This study aimed to evaluate the efficacy of fulvestrant 500 mg maintenance therapy in patients after first-line chemotherapy.

Methods: We enrolled postmenopausal women with ER-positive/HER2-negative advanced breast cancer who attained tumor responses or disease control with four to eight cycles of chemotherapy as first-line treatment. Fulvestrant 500 mg was injected on days 1, 15, and 29 and every 28 (±3) days thereafter. The primary endpoint was the clinical benefit rate (CBR); the secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), and safety.

Results: We included 58 patients; the median follow-up duration was 32.6 months. The CBR since commencing fulvestrant maintenance therapy was 76% (95% confidence interval [CI], 63%-86%), and ORR was 14% (95% CI, 6%-25%); eight patients achieved partial response. The median PFS for fulvestrant maintenance therapy was 16.1 months (95% CI, 10.3-21.0 months). Thirty-nine patients (67%) reported at least one adverse event, of which most were grade 1/2, whereas three patients (5%) reported grade 3 adverse events.

Conclusion: Fulvestrant 500 mg is a feasible and promising hormonal maintenance strategy in patients with ER-positive/HER2-negative advanced breast cancer who have no disease progression after first-line chemotherapy.
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http://dx.doi.org/10.1002/onco.13614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100565PMC
May 2021

Effects of cellulose, hemicellulose, and lignin on the combustion behaviours of biomass under various oxygen concentrations.

Bioresour Technol 2021 Jan 7;320(Pt B):124375. Epub 2020 Nov 7.

Rose-Hulman Institute of Technology, Terre Haute 47803, IN, USA.

The combustion behaviours of three components, namely hemicellulose, cellulose, and lignin, and four types of biomass, namely rice straw, bamboo, peanut shell, and chestnut shell, were examined in a drop tube furnace set at 1273 K, in O/N atmospheres containing 21-100% O. Radiant energy analysis technology was employed to infer the temperatures of the samples. The results show that the ignition mechanisms of cellulose and hemicellulose change at 30% and 70% O, respectively, and the lignin particle ignites homogeneously at 20-30% O, heterogeneously at 50% O, and hetero-homogeneously at 70-100% O, respectively. The changes in the ignition mechanisms of biomass particles with lignin content > 10% and < 10% under a certain oxygen concentration depend considerably on the lignin and cellulose contents in the biomass particle, respectively. The expansion of biomass particles with lignin content > 10% and < 10% during combustion process are caused by lignin and hemicellulose, respectively.
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http://dx.doi.org/10.1016/j.biortech.2020.124375DOI Listing
January 2021
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