Publications by authors named "Hongyun Zhao"

150 Publications

FOXM1 variant contributes to gefitinib resistance via activating wnt/β-catenin signal pathway in non-small cell lung cancer patients.

Clin Cancer Res 2022 Jun 13. Epub 2022 Jun 13.

Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.

Purpose: Although gefitinib prolonged the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients, unpredictable resistance limited its clinical efficacy. Novel predictive biomarkers with explicit mechanisms are urgently needed.

Experimental Design: A total of 282 NSCLC patients with gefitinib treatment were randomly assigned in a 7:3 ratio to exploratory (n=192) and validation (n=90) cohorts. The candidate polymorphisms were selected with Haploview4.2 in Hapmap and genotyped by a MassARRAY system, and the feature variables were identified through Randomforest Survival analysis. Tans-well and clonogenic assays, base editing and cell-derived tumor xenograft model were performed to uncover the underlying mechanism.

Results: We found that the germline missense polymorphism rs3742076 (A>G, S628P), located in transactivation domain of FOXM1, was associated with PFS in exploratory (median PFS: GG vs. GA&AA, 9.20 vs. 13.37 months, P=0.00039, HR=2.399) and validation (median PFS: GG vs. GA&AA, 8.13 vs. 13.80 months, P=0.048, HR=2.628) cohorts. We elucidated that rs3742076_G conferred resistance to gefitinib by increasing protein stability of FOXM1 and facilitating an aggressive phenotype in vitro and in vivo through activating wnt/β-catenin signaling pathway. Meanwhile, FOXM1 level was highly associated with prognosis in EGFR-mutant NSCLC patients. Mechanistically, FOXM1 rs3742076_G upregulated wnt/β-catenin activity by directly binding to β-catenin in cytoplasm and promoting transcription of β-catenin in nucleus. Remarkably, inhibition of β-catenin markedly reversed rs3742076_G-induced gefitinib resistance and aggressive phenotypes.

Conclusion: These findings characterized rs3742076_G as a gain-of-function polymorphism in mediating gefitinib resistance and tumor aggressiveness, and highlighted the variant as a predictive biomarker in guiding gefitinib treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-22-0791DOI Listing
June 2022

Automated Multi-View Multi-Modal Assessment of COVID-19 Patients Using Reciprocal Attention and Biomedical Transform.

Front Public Health 2022 25;10:886958. Epub 2022 May 25.

Department of Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan, China.

Automated severity assessment of coronavirus disease 2019 (COVID-19) patients can help rationally allocate medical resources and improve patients' survival rates. The existing methods conduct severity assessment tasks mainly on a unitary modal and single view, which is appropriate to exclude potential interactive information. To tackle the problem, in this paper, we propose a multi-view multi-modal model to automatically assess the severity of COVID-19 patients based on deep learning. The proposed model receives multi-view ultrasound images and biomedical indices of patients and generates comprehensive features for assessment tasks. Also, we propose a reciprocal attention module to acquire the underlying interactions between multi-view ultrasound data. Moreover, we propose biomedical transform module to integrate biomedical data with ultrasound data to produce multi-modal features. The proposed model is trained and tested on compound datasets, and it yields 92.75% for accuracy and 80.95% for recall, which is the best performance compared to other state-of-the-art methods. Further ablation experiments and discussions conformably indicate the feasibility and advancement of the proposed model.
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http://dx.doi.org/10.3389/fpubh.2022.886958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174692PMC
June 2022

Predictive Value of High Preoperative Serum Total Protein and Elevated Hematocrit in Patients with Non-Small-Cell Lung Cancer after Radical Resection.

Nutr Cancer 2022 Jun 1:1-13. Epub 2022 Jun 1.

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

Background: The relationship between the dynamic alterations of nutritional indexes before and after surgery, and the prognosis of non-small-cell lung cancer (NSCLC) after radical surgery are unclear. This study enrolled 100 NSCLC patients in stages I-III who received radical surgery. The preoperative and postoperative 6-month levels of nine nutrition-related indicators were assessed in patients. Survival was analyzed using Kaplan-Meier curves as well as Cox regression models.

Results: Patients had better disease-free survival (DFS) with baseline total protein (TP) >76.66 g/L (75% vs. 50%,  = .027), baseline albumin (ALB) >37.7 g/L (60% vs. 26.7%,  = .002), baseline albumin to globulin ratio (AGR) >1.31 (63.5% vs. 40.5%,  = .006), or baseline globulin (GLOB) <31.42 g/L (39.4% vs. 62.7%,  = .037). Moreover, patients with increased hematocrit (HCT) (69.8% vs. 43.9%  = .013) and mean corpuscular volume (MCV) (73.2% vs. 42.4%,  = .014) at the postoperative 6-month examination had superior DFS. Cox proportional hazards regression analyses demonstrated that age >65 years, adenocarcinoma (pathological type), higher baseline TP, and post-surgery elevated HCT independently predicted favorable DFS.

Conclusion: Lower baseline TP and decreased postoperative HCT levels are independent predictors of prognosis in NSCLC following radical surgical procedures.
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http://dx.doi.org/10.1080/01635581.2022.2079683DOI Listing
June 2022

The Arabidopsis Mitochondrial Pseudouridine Synthase Homolog FCS1 Play Critical Roles in Plant Development.

Plant Cell Physiol 2022 May 13. Epub 2022 May 13.

State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Science, Henan University, Kaifeng 475001, China.

As the most abundant RNA modification, pseudouridylation has been shown to play critical roles in E. coli, yeast, and humans. However, its function in plants is still unclear. Here, we characterized FCS1, which encodes a pseudouridine synthase in Arabidopsis. fcs1 mutants exhibited severe defects in plant growth, such as delayed development and reduced fertility, and were significantly smaller than the wild type at different developmental stages. FCS1 protein is localized in the mitochondrion. The absence of FCS1 significantly reduces pseudouridylation of mitochondrial 26S rRNA at the U1692 site, which sits in the peptidyl transferase center (PTC). This affection of mitochondrial 26S rRNA may lead to the disruption of mitochondrial translation in the fcs1-1 mutant, causing high accumulation of transcripts but low production of proteins. Dysfunctional mitochondria with abnormal structures were also observed in the fcs1-1 mutant. Overall, our results suggest that FCS1-mediated pseudouridylation of mitochondrial 26S rRNA is required for mitochondrial translation, which is critical for maintaining mitochondrial function and plant development.
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http://dx.doi.org/10.1093/pcp/pcac060DOI Listing
May 2022

Distinct Functional Metagenomic Markers Predict the Responsiveness to Anti-PD-1 Therapy in Chinese Non-Small Cell Lung Cancer Patients.

Front Oncol 2022 21;12:837525. Epub 2022 Apr 21.

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

Background: Programmed death 1 (PD-1) and the ligand of PD-1 (PD-L1) are central targets for immune-checkpoint therapy (ICT) blocking immune evasion-related pathways elicited by tumor cells. A number of PD-1 inhibitors have been developed, but the efficacy of these inhibitors varies considerably and is typically below 50%. The efficacy of ICT has been shown to be dependent on the gut microbiota, and experiments using mouse models have even demonstrated that modulation of the gut microbiota may improve efficacy of ICT.

Methods: We followed a Han Chinese cohort of 85 advanced non-small cell lung cancer (NSCLC) patients, who received anti-PD-1 antibodies. Tumor biopsies were collected before treatment initiation for whole exon sequencing and variant detection. Fecal samples collected biweekly during the period of anti-PD-1 antibody administration were used for metagenomic sequencing. We established gut microbiome abundance profiles for identification of significant associations between specific microbial taxa, potential functionality, and treatment responses. A prediction model based on random forest was trained using selected markers discriminating between the different response groups.

Results: NSCLC patients treated with antibiotics exhibited the shortest survival time. Low level of tumor-mutation burden and high expression level of HLA-E significantly reduced progression-free survival. We identified metagenomic species and functional pathways that differed in abundance in relation to responses to ICT. Data on differential enrichment of taxa and predicted microbial functions in NSCLC patients responding or non-responding to ICT allowed the establishment of random forest algorithm-adopted models robustly predicting the probability of whether or not a given patient would benefit from ICT.

Conclusions: Overall, our results identified links between gut microbial composition and immunotherapy efficacy in Chinese NSCLC patients indicating the potential for such analyses to predict outcome prior to ICT.
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http://dx.doi.org/10.3389/fonc.2022.837525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069064PMC
April 2022

A CT-based radiomics model to predict subsequent brain metastasis in patients with ALK-rearranged non-small cell lung cancer undergoing crizotinib treatment.

Thorac Cancer 2022 Jun 18;13(11):1558-1569. Epub 2022 Apr 18.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)-based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies.

Methods: A total of 75 eligible patients were enrolled from Sun Yat-sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis-free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log-rank test was performed to describe the difference of BMFS risk.

Results: Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C-index], 0.762; 95% confidence interval [CI], 0.663-0.861) and validation cohort (C-index, 0.724; 95% CI, 0.601-0.847).

Conclusion: We have developed a CT-based radiomics model to predict subsequent BM in patients with non-brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.
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http://dx.doi.org/10.1111/1759-7714.14386DOI Listing
June 2022

Time to raise the bar: Transition rate of phase 1 programs on anticancer drugs.

Cancer Cell 2022 03 24;40(3):233-235. Epub 2022 Feb 24.

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

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http://dx.doi.org/10.1016/j.ccell.2022.01.007DOI Listing
March 2022

The MIEL1-ABI5/MYB30 regulatory module fine tunes abscisic acid signaling during seed germination.

J Integr Plant Biol 2022 Apr 5;64(4):930-941. Epub 2022 Apr 5.

State Key Laboratory of Crop Stress Adaptation and Improvement, Key Laboratory of Plant Stress Biology, School of Life Sciences, Henan University, Kaifeng, 475001, China.

The transcription factor ABSCISIC ACID INSENSITIVE5 (ABI5) plays a crucial role in abscisic acid (ABA) signaling during seed germination. However, how ABI5 is regulated during this process is poorly understood. Here, we report that the ubiquitin E3 ligase MIEL1 and its target transcription factor MYB30 modulate ABA responses in Arabidopsis thaliana during seed germination and seedling establishment via the precise regulation of ABI5. MIEL1 interacts with and ubiquitinates ABI5 to facilitate its degradation during germination. The transcription factor MYB30, whose turnover is mediated by MIEL1 during seed germination, also interacts with ABI5 to interfere with its transcriptional activity. MYB30 functions downstream of MIEL1 in the ABA response, and both are epistatic to ABI5 in ABA-mediated inhibition of seed germination and postgerminative growth. ABA treatment induces the degradation of MIEL1 and represses the interaction between MIEL1 and ABI5/MYB30, thus releasing both ABI5 and MYB30. Our results demonstrate that MIEL1 directly mediates the proteasomal degradation of ABI5 and inhibits its activity via the release of its target protein MYB30, thus ensuring precise ABA signaling during seed germination and seedling establishment.
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http://dx.doi.org/10.1111/jipb.13234DOI Listing
April 2022

Correction to: Lymphocyte activating gene 3 protein expression in nasopharyngeal carcinoma is correlated with programmed cell death-1 and programmed cell death ligand-1, tumor-infiltrating lymphocytes.

Cancer Cell Int 2022 Jan 29;22(1):46. Epub 2022 Jan 29.

Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.

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http://dx.doi.org/10.1186/s12935-022-02458-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8801109PMC
January 2022

Reducing number of target lesions for RECIST1.1 to predict survivals in patients with advanced non-small-cell lung cancer undergoing anti-PD1/PD-L1 monotherapy.

Lung Cancer 2021 Dec 31;165:10-17. Epub 2021 Dec 31.

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

Objectives: The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 provides conventional and standardized response assessment for multiple solid tumors. We investigated the smallest number of target lesions that can be measured without compromising response categorization and survival prediction in patients with advanced non-small-cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 monotherapy.

Material And Methods: 125 aNSCLC patients with at least two measurable lesions undergoing PD-1/PD-L1 inhibitor treatment were retrospectively studied. Tumor measurements allowing up to two lesions per organ and five lesions in total were reviewed. Inter-individual agreement and κ values for inter-method concordance on response status were evaluated based on up to five target lesions versus the largest one through four lesions. C-index was calculated to evaluate the prognostic accuracy of response categorization based on the selected number of target lesions for predicting overall survival (OS). Cox regression analysis was conducted for survival analysis.

Results: The highly consistent response assignment (99.2%) could be obtained when measuring the largest two lesions versus up to five lesions. Using the largest two through four lesions produced κ values of 0.986, 1.000 and 1.000 for response assessment, values significantly higher than those obtained when measuring the largest single lesion (κ = 0.850). C-index for overall survival (OS) was similar when assessing the largest one through five lesions, ranging from 0.646 to 0.654. Cox regression analyses showed that radiological response significantly predicted OS, irrespective of the number of target lesions selected.

Conclusions: Reducing the number of target lesions does not affect OS prediction in aNSCLC patients treated with anti-PD-1/PD-L1 therapy. Considering the high intra-individual and inter-method concordance, using the largest two lesions in total is proposed to assess response.
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http://dx.doi.org/10.1016/j.lungcan.2021.12.015DOI Listing
December 2021

Determinants of survival in advanced non-small cell lung cancer patients treated with anti-PD-1/PD-L1 therapy.

Ann Transl Med 2021 Nov;9(22):1639

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: The present study aimed to investigate the determinant factors of survival in patients with pretreated advanced stage non-small cell lung cancer (NSCLC) who received anti-PD-1/PD-L1 therapy.

Methods: In this observational retrospective study, the clinical profiles and laboratory parameters of patients with NSCLC treated with anti-PD-1/PD-L1 therapy were consecutively collected. Lung Immune Prognostic Index (LIPI) was calculated based on the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase level (LDH). Modified Glasgow Prognostic Score (mGPS) was calculated based on serum C reactive protein and albumin, and tumor mutation burden (TMB) was calculated using a targeted next-generation sequencing panel based on 422 cancer-relevant genes. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. The Cox regression model was used to identify the potential determinant factors of survival benefit. Trained oncologists at Sun Yat-sen University Cancer Center followed all of the participants through visits to doctors' offices or via telephone calls to determine their clinical status.

Results: Seventy-three patients were included in our study. With a median follow up time of 637 days, there was a significant difference in PFS between patients with high TMB compared to those with low TMB (3.7 2.1 months; P=0.004), while no significant difference was found in OS (14.0 16.4 months; P=0.972). Patients with a good LIPI score had a significantly longer OS compared to patients with a poor LIPI score (19.2 12.6 months; P=0.010). The median OS in patients with a good and a poor mGPS was 16.8 and 4.3 months, respectively (P=0.029). In multivariate analysis, TMB was found to be significantly associated with PFS (HR, 0.38; 95% CI: 0.21-0.69; P=0.002), while LIPI score was found to be significantly associated with OS (HR, 0.50; 95% CI: 0.28-0.89; P=0.012).

Conclusions: In the present study, LIPI score was a significant determinant of OS in patients with advanced NSCLC who received ICIs; however, TMB was only associated with PFS and not associated with OS.
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http://dx.doi.org/10.21037/atm-21-1702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667098PMC
November 2021

Emerging immunological strategies: recent advances and future directions.

Front Med 2021 Dec 6;15(6):805-828. Epub 2021 Dec 6.

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

Immunotherapy plays a compelling role in cancer treatment and has already made remarkable progress. However, many patients receiving immune checkpoint inhibitors fail to achieve clinical benefits, and the response rates vary among tumor types. New approaches that promote anti-tumor immunity have recently been developed, such as small molecules, bispecific antibodies, chimeric antigen receptor T cell products, and cancer vaccines. Small molecule drugs include agonists and inhibitors that can reach the intracellular or extracellular targets of immune cells participating in innate or adaptive immune pathways. Bispecific antibodies, which bind two different antigens or one antigen with two different epitopes, are of great interest. Chimeric antigen receptor T cell products and cancer vaccines have also been investigated. This review explores the recent progress and challenges of different forms of immunotherapy agents and provides an insight into future immunotherapeutic strategies.
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http://dx.doi.org/10.1007/s11684-021-0886-xDOI Listing
December 2021

Incidence and risk factors of second primary cancer after the initial primary human papillomavirus related neoplasms.

MedComm (2020) 2020 Dec 3;1(3):400-409. Epub 2020 Dec 3.

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.

Comprehensive studies in second primary cancer (SPC) after the initial primary human papillomavirus (HPV)-related cancer still remain warranted. We aimed to analyze the incidence and risk factors of SPC after HPV-related cancer. We identified 86 790 patients diagnosed with initial primary HPV-related cancer between 1973 and 2010 in the SEER database. Standardized incidence ratio (SIR) and cumulative incidence were calculated to assess the risk of SPC after HPV-related cancer. The SIR of SPC after HPV-related cancer was 1.60 (95% confidence interval [CI], 1.55-1.65) for male and 1.25 (95% CI, 1.22-1.28) for female. SIR of second primary HPV-related cancer (7.39 [95% CI, 6.26-8.68] male and 4.35 [95% CI, 4.04-4.67] female) was significantly higher than that of HPV-unrelated cancer (1.54 [95% CI, 1.49-1.60] male and 1.16 [95% CI, 1.13-1.19] female). The 5-year cumulative incidence of SPC was 7.22% (95% CI, 6.89-7.55%) for male and 3.72% (95% CI, 3.58-3.88%) for female. Risk factors for SPC included being married and having initial primary cancer (IPC) diagnosed at earlier stage for both genders, and IPC diagnosed at older age as well as surgery performed for female. Patients diagnosed with HPV-related cancer are more likely to develop another primary cancer, compared with the age-specific reference population.
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http://dx.doi.org/10.1002/mco2.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491207PMC
December 2020

Influence of Welding Speed on Microstructure and Mechanical Properties of 5251 Aluminum Alloy Joints Fabricated by Self-Reacting Friction Stir Welding.

Materials (Basel) 2021 Oct 18;14(20). Epub 2021 Oct 18.

State Key Laboratory of Advanced Welding and Joining, Harbin Institute of Technology, Harbin 150001, China.

In the present study, 8 mm-thick 5251 aluminum alloy was self-reacting friction stir welded (SRFSW) employing an optimized friction stir tool to analyze the effect of welding speed from 150 to 450 mm/min on the microstructure and mechanical properties at a constant rotation speed of 400 rpm. The results indicated that high-quality surface finish and defect-free joints were successfully obtained under suitable process parameters. The microhardness distribution profiles on the transverse section of joint exhibited a typical "W" pattern. The lowest hardness values located at the heat-affected zone (HAZ) and the width of the softened region decreased with increasing welding speed. The tensile strength significantly decreased due to the void defect, which showed mixed fracture characteristics induced by the decreasing welding speed. The average tensile strength and elongation achieved by the SRFSW process were 242.61 MPa and 8.3% with optimal welding conditions, and the fracture surface exhibited a typical toughness fracture mode.
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http://dx.doi.org/10.3390/ma14206178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537164PMC
October 2021

Utility of comprehensive genomic profiling in directing treatment and improving patient outcomes in advanced non-small cell lung cancer.

BMC Med 2021 10 1;19(1):223. Epub 2021 Oct 1.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China.

Background: With the identification of new targetable drivers and the recent emergence of novel targeted drugs, using comprehensive genomic profiling in lieu of the routine testing for classic drivers in the clinical care for advanced NSCLC has been increasingly advocated. However, the key assumption justifying this practice, that comprehensive genomic profiling could lead to effective anticancer therapies and improve patient outcomes, remains unproved.

Methods: Comprehensive genomic profiling was prospectively applied in 1564 advanced NSCLC patients to identify potentially actionable genomic alterations. Patients were assigned to genotype-matched targeted therapies or nonmatched therapies based on the profiling results. Its utility in directing treatments was determined by the proportion of patients receiving genotype-matched targeted therapies and the proportion of patients being enrolled into genotype-matched clinical trials. Its impacts on patient outcomes were assessed by comparing progression-free survival (PFS) and overall survival (OS) between patients who received a genotype-matched and nonmatched therapy.

Results: From October 2016 to October 2019, tumor genomic profiles were established in 1166 patients, leading to a matched targeted therapy in 37.7% (n = 440) and a genotype-matched trial enrollment in 20.9% of patients (n = 244). Potentially actionable alterations were detected in 781 patients (67.0%). For these patients, a genomic profiling-directed matched therapy significantly improved PFS (9.0 months vs 4.9 months, P < 0.001) and OS (3.9 years vs 2.5 years, P < 0.001) compared with a nonmatched therapy. Excluding patients with standard targeted therapies, genomic profiling led to a matched targeted therapy in 16.7% (n = 24) and a matched trial enrollment in 11.2% (n = 16) of patients. No PFS (4.7 months vs 4.6 months, P = 0.530) or OS (1.9 years vs 2.4 years, P = 0.238) benefit was observed with the use of genotype-matched targeted therapies in this population.

Conclusions: Comprehensive genomic profiling is of clinical utility in assisting treatment selection, facilitating clinical trial enrollment, and improving patient outcomes in advanced NSCLC. However, for patients carrying alterations without standard-of-care targeted drugs, the interpretation of genomic profiling results should be careful given the low likelihood of benefit from the investigational or off-label use of targeted therapies in this population in the current treatment landscape.

Trial Registration: ChiCTR1900027582 (retrospectively registered on 19 November 2019).
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http://dx.doi.org/10.1186/s12916-021-02089-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485523PMC
October 2021

Afatinib as a Potential Therapeutic Option for Patients With NSCLC With G724S.

JTO Clin Res Rep 2021 Jul 24;2(7):100193. Epub 2021 May 24.

Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

Introduction: G724S has been described to mediate resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs). In vitro experiments have provided compelling evidence that G724S retains sensitivity for afatinib. Nevertheless, limited data have reported the clinical efficacy of afatinib in patients with NSCLC harboring G724S mutation.

Methods: We identified 52 patients with NSCLC with G724S from an inhouse database and comprehensively profiled their concurrent mutation statuses. Treatments and clinical outcomes were also collected.

Results: Of 52 G724S-positive patients, 39 harbored concomitant exon 19 deletion (19del), and all 37 of the 39 patients who had available clinical data were detected with a G724S mutation after receiving EGFR TKIs. A rare variant of 19del E746_S752delinsV co-occurred with G724S the most frequently (n = 29), whereas 7 of 10 patients with concomitant exon 20 mutation were TKI treatment naive. S768I was the most common mutation in exon 20 (n = 7). One patient harbored a concomitant exon 21 mutation, and two lacked co-occurring mutations A total of 23 patients provided valid clinical outcome data, of whom eight were treated with afatinib after the emergence of G724S, whereas 15 received non-afatinib treatment (alternative EGFR TKI, chemotherapy, or best supportive care). The disease control rate in afatinib-treated patients (n = 8) reached 100% with a median progression-free survival of 4.5 months, significantly longer than that of non-afatinib-treated (n = 15, 1.7 mo, hazard ratio [HR] = 0.32,  = 0.037) and alternative EGFR TKI-treated (n = 11, 1.8 mo, HR = 0.28,  = 0.042) patients. In the subset who had progressed on osimertinib, afatinib also yielded a superior progression-free survival (6.2 mo) than non-afatinib therapies (1.0 mo, HR = 0.04,  = 0.005) and alternative EGFR TKIs (1.8 mo, HR = 0.06,  = 0.033). Analysis of acquired mutations at afatinib progression revealed re-emergence of T790M or amplification as the potential mechanism of afatinib resistance.

Conclusions: G724S emerges as a resistant mutation against EGFR TKI preferentially in the context of a rare variant of 19del, whereas it might mediate differential mechanisms in the context of exon 20 mutation. We also found that afatinib could be a potential therapeutic option for patients with NSCLC with G724S.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474270PMC
July 2021

iRGD Peptide-Mediated Liposomal Nanoparticles with Photoacoustic/Ultrasound Dual-Modality Imaging for Precision Theranostics Against Hepatocellular Carcinoma.

Int J Nanomedicine 2021 21;16:6455-6475. Epub 2021 Sep 21.

Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.

Purpose: Prepare a multifunctional ultrasound molecular probe, cell-penetrating peptide-modified 10-hydroxycamptothecin-loaded phase-transformation lipid nanoparticles (iRGD-ICG-10-HCPT-PFP-NPs), and to combine iRGD-ICG-10-HCPT-PFP -NPs with low-intensity focused ultrasound (LIFU) for precision theranostics against hepatocellular carcinoma (HCC).

Materials And Methods: The morphology of nanoparticles (NPs) and iRGD-ICG-10-HCPT-PFP-NPs was detected. In vitro, we examined targeting ability by flow cytometry and confocal laser scanning microscopy (CLSM), assessed penetration ability into hepatoma cells, and assessed killing ability. In vivo, we examined the targeting ability of the NPs with a photoacoustic (PA) imager and fluorometer (FL), while LIFU irradiation was used to trigger the release of chemotherapeutic drugs, which had a therapeutic effect on tumors.

Results: The particle size of iRGD-ICG-10-HCPT-PFP-NPs was 298.4 ± 10.42 nm. In vitro, iRGD-ICG-10-HCPT-PFP-NPs bound more to SK-Hep1 cells than ICG-10-HCPT-PFP-NPs. iRGD-ICG-10-HCPT-PFP-NPs could achieve PA/ultrasound imaging. The percentage of antiproliferative and apoptotic cells in the iRGD-ICG-10-HCPT-PFP-NPs+LIFU group was significantly higher. In vivo, iRGD-ICG-10-HCPT-PFP-NPs can target tumor sites and achieve PA/ultrasound imaging. The tumor volume in the iRGD-ICG-10-HCPT-PFP-NPs+LIFU group was significantly smaller, and the antiproliferative and proapoptotic effects were higher.

Conclusion: We successfully prepared a novel molecular probe that has good targeting, can perform ultrasound/PA dual-modality imaging, and can penetrate deep into tumors to achieve better therapeutic tumor effects, providing a new idea and method for theranostics of HCC.
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http://dx.doi.org/10.2147/IJN.S325891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464346PMC
November 2021

Response to "Limitations of the Hazard Ratio as a Summary Measure in Cancer Clinical Trials".

J Thorac Oncol 2021 10;16(10):e87-e88

Jiangsu Hengrui Pharmaceuticals Co. Ltd., Shanghai, People's Republic of China.

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http://dx.doi.org/10.1016/j.jtho.2021.08.001DOI Listing
October 2021

Lymphocyte activating gene 3 protein expression in nasopharyngeal carcinoma is correlated with programmed cell death-1 and programmed cell death ligand-1, tumor-infiltrating lymphocytes.

Cancer Cell Int 2021 Aug 28;21(1):458. Epub 2021 Aug 28.

Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.

Background: Immunotherapy has shown promising efficacy in patients with nasopharyngeal carcinoma (NPC). Lymphocyte activating 3 gene (LAG-3) represents a significant immune target, however, its relationship with NPC remains unclear. This study aimed to evaluate LAG-3 expression in NPC and its association with CD3+ tumor-infiltrating lymphocytes (TILs), Granzyme B (GZMB), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) expression.

Methods: A total of 182 patients with NPC from Sun Yat-sen University Cancer Center, China, were included in this retrospective study. LAG-3 expression in 15 NPC cell lines and LAG-3, CD3+ TILs, GZMB, PD-L1 and PD-1 in clinical samples were estimated using immunohistochemistry. The Chi-square test was used to estimate the association between LAG-3, other biomarkers, and clinical characteristics. Survival analysis was performed using the Kaplan-Meier method and the Cox regression model.

Results: LAG-3 was negatively expressed in all of the 15 NPC cell lines, whereas, 147 patients with NPC (80.8%) exhibited high LAG-3 expression on TILs from tumor tissues. Male patients and those who were EBV-positive presented higher LAG-3 expression. Correlation analyses showed that LAG-3 expression was related to PD-1 expression on TILs, as well as, PD-L1 expression on tumor cells (TCs) and TILs. Both the univariate and multivariate Cox models indicated that pathological type III (P = 0.036), higher LAG-3 on TILs (P < 0.001), higher PD-L1 on TCs (P = 0.027), and higher PD-1 on TILs (P < 0.001) were associated with poorer disease-free survival (DFS). However, lower PD-L1 expression on TILs was related to superior DFS only in the univariate Cox analyses (P = 0.002).

Conclusion: Higher LAG-3 and PD-1 on TILs, and higher PD-L1 expression on TCs, and pathological type III were identified as independent risk factors for poorer DFS in NPC patients. Our data demonstrate that LAG-3 is a promising inhibitory receptor that may play an important role in anti-NPC therapy.
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http://dx.doi.org/10.1186/s12935-021-02162-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403354PMC
August 2021

Response to: The Role of Dual Inhibition of EGFR and Vascular EGF(R) in the Treatment of NSCLC With EGFR Mutation.

J Thorac Oncol 2021 09;16(9):e72-e76

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, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2021.07.013DOI Listing
September 2021

Anticancer bispecific antibody R&D advances: a study focusing on research trend worldwide and in China.

J Hematol Oncol 2021 08 16;14(1):124. Epub 2021 Aug 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, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China.

Background: The bispecific antibody (bsAbs) research around the world has undergone great changes. We analyzed the global trend of bsAbs research and compared the differences in clinical research of bsAbs between China and worldwide.

Methods: BsAbs research clinical trials information was retrieved through the online open-resource clinical trial registration platform. Research information including organizations, identity numbers, locations, phases, participating centers, conditions, status, enrollment, targets, spectrums of mechanism of action (MOA), and start date was collected. Clinical trials were divided into two categories based on the attributes of pharmaceutical companies (international or China-initiated or involved).

Results: From 1997 to 2020, 272 clinical trials regarding bsAbs research were retrieved. Twenty-nine percent of the studies were contributed by companies from Chinese institutions, which followed the USA and ranked second. The clinical trials of bsAbs are mainly concentrated on phase I (n = 161), phase I/II (n = 54), and phase II (n = 51), and the number of phase III trials is still rare (n = 4). Tumor species distribution analysis shows that there are significantly higher focuses on gastric cancer (n = 18), esophageal/gastroesophageal junction cancer (n = 16), bladder cancer (n = 10), biliary malignant tumor (n = 8), nasopharyngeal cancer (n = 6), and thymic cancer (n = 2) in China. BsAbs target and spectrums of MOA analysis showed that international companies mainly focus on bsAbs with CD3-based (n = 63) target with MOA of T-cell redirection, while researches in China pay more attention to PD-1 (n = 9)/PD-L1 (n = 7) axises with MOA of double immune checkpoint blocking.

Conclusion: Global bsAbs research increased rapidly during the 1997 to 2020 period. The developed countries in America and Europe are leading the trend of bsAbs research. Anticancer bsAbs clinical research in China is booming and chasing after the world trend.
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http://dx.doi.org/10.1186/s13045-021-01126-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369643PMC
August 2021

Clinical Significance of Kinetics of Low-Density Lipoprotein Cholesterol and Its Prognostic Value in Limited Stage Small Cell Lung Cancer Patients.

Cancer Control 2021 Jan-Dec;28:10732748211028257

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, People's Republic of China.

Objectives: To investigate the clinical significance of dynamic alteration of serum lipids in limited stage small cell lung cancer (LS-SCLC) patients and the risk that different lipid profiles poses to patients' health.

Methods: We retrospectively analyzed the variation trends and prognostic values of serum lipids in 310 LS-SCLC patients who had received standard chemotherapy between 2002 and 2017. In addition to serum lipid level, which were measured at the time of pretreatment, after-chemotherapy and during disease progression and later analyzed, the dynamic lipid alteration trend and its correlation to progression-free survival (PFS) and overall survival (OS) were also statistically analyzed using Log-rank test and COX regression analyses.

Results: A significant decrease in HDL-C level was observed after standard chemotherapy (Post-CT baseline = -0.08 ± 0.34, < 0.001), and this trend of reduction was further enhanced by thoracic radiotherapy ( = 0.046). Increase in LDL-C level was also observed to be associated with higher likelihood of disease progression ( = 0.003). Moreover, the extent of the increase in LDL-C was also associated with the number of progression sites, as patients with higher increase in LDL-C in exhibiting a progression at more than 2 sites outside thorax ( = 0.037). The patients' median PFS and OS were 14.04 months (95%CI: 25.12-33.81) and 22.40 months (95%CI: 33.19-42.13), respectively. For both PFS and OS, LDL-C elevation remained an independent prognostic factor in the multivariate model ( = 0.007 and = 0.022, respectively).

Conclusion: Overall, for LS-SCLC patients, standard chemotherapy decreases the level of HDL-C, the level of increase in LDL-C could predict disease progression and even the number of progression sites, and LDL-C elevation could be an independent prognostic factor for poor OS and PFS.
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http://dx.doi.org/10.1177/10732748211028257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246505PMC
December 2021

Targeting immunometabolism of neoplasms by interleukins: A promising immunotherapeutic strategy for cancer treatment.

Cancer Lett 2021 10 18;518:94-101. Epub 2021 Jun 18.

Department of Microbiology, Immunology & Pathology, Des Moines University, Des Moines, IA, USA; Department of Surgery, University of Missouri School of Medicine, Columbia, MO, USA. Electronic address:

In recent years, tumor metabolism has become a prevalent research topic for scientists and pharmaceutical companies. As research in the field has progressed, the metabolism-based therapy of tumors has ushered in new opportunities. Most tumors emerge and evolve under selective pressure from their microenvironment, which promotes the diversification of both neoplastic and non-neoplastic compartments of the tumor microenvironment (TME), and finally reaches a certain degree of intratumoral heterogeneity. As a result of the tumor intratumoral heterogeneity, tumor cells often possess a complex energy metabolism phenotype. During tumor progression, the metabolism for both tumor parenchyma and stroma is reprogrammed. The tumor stroma mainly consists of the extracellular matrix, fibroblasts, and immune cells. Interestingly, tumor-infiltrating immune cells utilize different metabolites based on their subtype and function, and these immunometabolic pathways can be modified in the TME. In particular, interleukins play a vital role in the activation and differentiation of immune cells and have exhibited multiple effects on tumor cell neoplasia, invasion, and metastasis. In this review, we summarize the common mechanisms of interleukins affecting the tumor and tumor-infiltrating immune cells metabolically and discuss how these mechanisms may lead to novel therapeutic opportunities. This review might contribute to the novel development of cancer immunotherapy.
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http://dx.doi.org/10.1016/j.canlet.2021.06.013DOI Listing
October 2021

Baseline and early changes in circulating Serum Amyloid A (SAA) predict survival outcomes in advanced non-small cell lung cancer patients treated with Anti-PD-1/PD-L1 monotherapy.

Lung Cancer 2021 08 28;158:1-8. Epub 2021 May 28.

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

Background: Systemic inflammation plays an important role in carcinogenesis and is associated with overall survival in patients with different cancer types, including those treated with immune checkpoint blockade (ICB). Serum Amyloid A (SAA) is an acute-phase protein and a marker of persistent inflammation. We hypothesized that circulating SAA may predict outcomes in advanced non-small cell lung (aNSCLC) patients treated with PD-1/PD-L1 ICB.

Materials And Methods: This retrospective study included 91 aNSCLC patients who received anti-PD-(L)1 monotherapy in Sun Yat-sen University Cancer Center (Guangzhou, China) between August 2016 and June 2018. We examined the impact of circulating SAA at baseline and 8 (±2) weeks later on overall survival (OS). X-tile program was used to determine the cut-off values which optimized the significance of the split between Kaplan-Meier survival curves. Kaplan-Meier methodology and Cox regression analyses were conducted for survival analyses.

Results: The optimal cut-off value of baseline SAA for OS stratification was 137.6 mg/L. In univariate analysis, both high level of baseline SAA (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.47-5.18; P = 0.002) and lack of early SAA descent (HR, 1.51; 95% CI, 1.11-2.06; P = 0.009) were significantly associated with inferior OS. In multivariate analysis, gender, smoking status, performance status, liver metastasis, neutrophil-to-lymphocyte ratio, baseline SAA and early changes in SAA independently predicted OS (all with P < 0.05). A combined baseline SAA ≥ 137.6 mg/L and without early SAA descent identified a small cohort with remarkably worse OS (median, 3.2 months).

Conclusions: Both high baseline and lack of early decline in circulating SAA are significantly associated with inferior outcomes in aNSCLC patients treated with PD-1/PD-L1 ICB. Combined these two SAA indexes provided improved risk stratification. The prognostic value of this simple, readily-available, and cost-effective biomarker warrants larger, prospective validation before definitive recommendation can be made.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.030DOI Listing
August 2021

Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706).

J Thorac Oncol 2021 09 24;16(9):1533-1546. Epub 2021 May 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, People's Republic of China. Electronic address:

Introduction: Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC.

Methods: Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance.

Results: A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation.

Conclusions: Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL.

Trial Registration: NCT02824458.
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http://dx.doi.org/10.1016/j.jtho.2021.05.006DOI Listing
September 2021

Effect of Stirring Pin Rotation Speed on Microstructure and Mechanical Properties of 2A14-T4 Alloy T-Joints Produced by Stationary Shoulder Friction Stir Welding.

Materials (Basel) 2021 Apr 13;14(8). Epub 2021 Apr 13.

State Key Laboratory of Advanced Welding and Joining, Harbin Institute of Technology, Harbin 150001, China.

In this study, 2A14-T4 Al-alloy T-joints were prepared via stationary shoulder friction stir welding (SSFSW) technology where the stirring pin's rotation speed was set as different values. In combination with the numerical simulation results, the macro-forming, microstructure, and mechanical properties of the joints under different welding conditions were analyzed. The results show that the thermal cycle curves in the SSFSW process are featured by a steep climb and slow decreasing variation trends. As the stirring pin's rotation speed increased, the grooves on the weld surface became more obvious. The base and rib plates exhibit W- or N-shaped hardness distribution patterns. The hardness of the weld nugget zone (WNZ) was high but was lower than that of the base material. The second weld's annealing effect contributed to the precipitation and coarsening of the precipitated phase in the first weld nugget zone (WNZ1). The hardness of the heat affect zone (HAZ) in the vicinity of the thermo-mechanically affected zone (TMAZ) dropped to the minimum. As the stirring pin's rotation speed increased, the tensile strengths of the base and rib plates first increased and then dropped. The base and rib plates exhibited ductile and brittle/ductile fracture patterns, respectively.
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http://dx.doi.org/10.3390/ma14081938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068919PMC
April 2021

[Chinese Experts Consensus on Immune Checkpoint Inhibitors 
for Non-small Cell Lung Cancer (2020 Version)].

Zhongguo Fei Ai Za Zhi 2021 Apr 26;24(4):217-235. Epub 2021 Apr 26.

Cancer Center, Eastern Theater General Hospital of the Chinese PLA, Nanjing 210002, China.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2021.101.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105610PMC
April 2021

Therapeutic Repurposing of Biguanides in Cancer.

Trends Cancer 2021 08 14;7(8):714-730. Epub 2021 Apr 14.

Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Electronic address:

Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and preclinical laboratory models have demonstrated that biguanides possess antitumor activities that suggest their repurposing for cancer prevention and treatment. However, a better understanding of how these biguanides behave as antitumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their antitumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent.
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http://dx.doi.org/10.1016/j.trecan.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295194PMC
August 2021

Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma.

J Immunother Cancer 2021 03;9(3)

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: Anti-programmed death (PD)-1 therapy has recently been used in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The long-term survival and its biomarkers responding to anti-PD-1 treatment in patients with R/M NPC remain unclear.

Methods: Patients with R/M NPC were enrolled between March 2016 and January 2018 from two phase I clinical trials. The median follow-up period was 24.7 months. Eligible patients progressed on standard chemotherapy had measurable disease by Response Evaluation Criteria in Solid Tumor V.1.1. Non-obligatory contemporaneous tumor samples were collected for whole-exome sequencing. The primary outcome was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary outcomes assessed in all patients.

Results: Among 124 evaluable patients, anti-PD-1 therapy achieved an ORR of 29.8% and a durable clinical benefit rate of 60.5%. The median OS (mOS) was 17.1 months (95% CI 14.2 to 24.7), median PFS (mPFS) was 3.8 months (95% CI 3.4 to 6.0), and median DOR was 9.5 months. Significant OS benefit from treatment was observed in patients without liver metastasis (23.8 vs 13.3 months, p=0.006). Copy number deletion in genes encoding granzyme B or granzyme H () was associated with poor treatment outcome (mPFS altered vs wildtype: 1.7 vs 3.6 months, p=0.03; mOS altered vs wildtype: 10.1 vs 18 months, p=0.012).

Conclusions: Anti-PD-1 treatment provided promising clinical benefit in pretreated patients with R/M NPC. Copy number loss in either or genes was associated with reduced survival.
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http://dx.doi.org/10.1136/jitc-2020-002014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978327PMC
March 2021
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