Publications by authors named "Caicun Zhou"

384 Publications

Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC: a multicenter phase-II trial.

Signal Transduct Target Ther 2021 Oct 15;6(1):355. Epub 2021 Oct 15.

Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

This multicenter phase-II trial aimed to investigate the efficacy, safety, and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC. Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled. Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles, followed by the maintenance of toripalimab and pemetrexed. The primary endpoint was objective-response rate (ORR). Integrated biomarker analysis of PD-L1 expression, tumor mutational burden (TMB), CD8 + tumor-infiltrating lymphocyte (TIL) density, whole-exome, and transcriptome sequencing on tumor biopsies were also conducted. Forty patients were enrolled with an overall ORR of 50.0% and disease-control rate (DCR) of 87.5%. The median progression free survival (PFS) and overall survival were 7.0 and 23.5 months, respectively. The most common treatment-related adverse effects were leukopenia, neutropenia, anemia, ALT/AST elevation, and nausea. Biomarker analysis showed that none of PD-L1 expression, TMB level, and CD8 + TIL density could serve as a predictive biomarker. Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type. Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC. DSPP mutation might serve as a potential biomarker for this combination. A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing (NCT03924050).
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http://dx.doi.org/10.1038/s41392-021-00751-9DOI Listing
October 2021

Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial.

JAMA Oncol 2021 Oct 14:e214761. Epub 2021 Oct 14.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Metastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations.

Objective: To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC.

Design, Setting, And Participants: This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort).

Interventions: Mobocertinib 160 mg once daily.

Main Outcomes And Measures: The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety.

Results: Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash.

Conclusions And Relevance: In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.

Trial Registration: ClinicalTrials.gov Identifier: NCT02716116.
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http://dx.doi.org/10.1001/jamaoncol.2021.4761DOI Listing
October 2021

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer.

Front Oncol 2021 15;11:708294. Epub 2021 Sep 15.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types ( < 0.001). DDR mechanisms attach great importance to the determination of patients' prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692-0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including and than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 ( = 0.01), CD28 ( = 0.020), HLA-DRB6 ( = 0.014) in adenocarcinoma, lower TNFRSF4 ( = 0.017), and TGFB1 expressions ( = 0.033) in squamous carcinoma, and higher CD40 ( = 0.012) and TNFRSF14 expressions = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma ( = 0.044) and M2 macrophage in squamous carcinoma ( = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.
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http://dx.doi.org/10.3389/fonc.2021.708294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479169PMC
September 2021

A novel lanthanide-based NIR-II nanoprobe for lung squamous cell carcinoma identification.

Biomater Sci 2021 Sep 28;9(19):6568-6573. Epub 2021 Sep 28.

Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, P. R. China.

The morbidity and mortality of lung cancer, particularly squamous cell carcinoma and non-small-cell lung cancer (NSCLC), is significantly higher than other malignant tumors. Currently, there is a lack of a real-time, nonradioactive detection method for early-stage squamous non-small-cell lung cancer diagnosis. In this study, we introduced fluorescence imaging in the second near-infrared (NIR-II) window to identify lung squamous cell carcinoma for the first time. A novel nanoprobe is constructed based on downconversion nanoparticles (DCNPs) with a fluorescence core (NaErF) and an inert shell (NaYF) coated the successive layer-by-layer strategy. The existence of the inert shell reduces the surface defects of DCNPs and inhibits the solvent-quenching effect. Therefore, hydrophilic DCNPs exhibit strong NIR-II fluorescence. After modification with an efficient antibody to the squamous cell carcinoma antigen, [email protected] nanoprobes exhibited low cytotoxicity and good biocompatibility. These probes can accurately identify lung squamous carcinoma with high tumor-to-normal-tissue ratio as well as high spatial resolution.
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http://dx.doi.org/10.1039/d1bm00766aDOI Listing
September 2021

Chemotherapy Should Be Combined With Checkpoint Inhibitors in the Treatment of Patients With Stage IV EGFR-Mutant NSCLC Whose Disease Has Progressed on All Available Tyrosine Kinase Inhibitors.

J Thorac Oncol 2021 10;16(10):1622-1626

Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, School of Medicine, Tongji University, Shanghai, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2021.07.011DOI Listing
October 2021

Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.

Lancet 2021 Oct 20;398(10308):1344-1357. Epub 2021 Sep 20.

Department of Medicine, Division of Oncology, Stanford University School of Medicine and Stanford Cancer Institute, Stanford, CA, USA.

Background: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients.

Methods: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting).

Findings: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).

Interpretation: IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC.

Funding: F Hoffmann-La Roche and Genentech.
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http://dx.doi.org/10.1016/S0140-6736(21)02098-5DOI Listing
October 2021

The efficacy and safety of immunotherapy in thymic epithelial tumors: more effective, more risky: a systematic review.

J Thorac Dis 2021 Aug;13(8):5093-5103

Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

Background: Thymic epithelial tumors (TETs) are rare malignant neoplasms originating from thymic epithelial cells. The current treatment for localized TETs is surgical removal. However, 20-30% of thymomas and 70-80% of thymic carcinomas are unresectable, recurrent, or metastatic at the time of detection. The standard therapy for these patients is chemotherapy, but the effect is limited. With a deeper understanding of tumor immunity, immunotherapy for various cancers has rapidly developed. Antibodies against cytotoxic T-lymphocyte antigen-4, programmed death-1, and programmed death-ligand 1 have been approved for the treatment of many solid tumors. Compared with traditional treatments, these immune checkpoint inhibitors (ICIs) have better efficacy and lower toxicity. Recently, ICIs have been used more enthusiastically in the treatment of TETs. However, due to the unique biological characteristics of the thymus, immunotherapy usually causes severe immune-related adverse events (irAEs). Most previous studies on immunotherapy in TETs had small sample sizes and reported diverse conclusions.

Methods: We collected relevant studies in PubMed during the last five years and analyzed the available data to discuss the efficacy and safety of ICIs in TETs.

Results: According to 14 previous studies in the past five years, all TETs showed expression of programmed death-ligand 1, while thymic carcinomas showed 100% expression. The best median progression-free survival (mPFS) among the five studies was 6.5 months, and the best median overall survival (mOS) was 24.9 months. In addition, the most common irAEs were myasthenic symptoms, liver enzyme elevation, and elevated creatine phosphokinase levels.

Conclusions: ICIs can be used in TET treatment, especially for thymic carcinomas, in the absence of standard second-line treatment. However, more attention should be paid to irAEs.
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http://dx.doi.org/10.21037/jtd-21-290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411126PMC
August 2021

Case Report: Abscopal Effect of Microwave Ablation in a Patient With Advanced Squamous NSCLC and Resistance to Immunotherapy.

Front Immunol 2021 3;12:696749. Epub 2021 Aug 3.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Currently, immunotherapy has been a backbone in the treatment of advanced non-small cell lung cancer (NSCLC) without driver gene mutations. However, only a small proportion of NSCLC patients respond to immune checkpoint inhibitors, and majority of patients with initial response will develop acquired resistance at 5 years, which usually manifests as oligo-progression or oligo-metastases. Evidence from multiple clinical trials indicates that local consolidative therapies could improve the prognosis of oligometastatic NSCLC patients. Herein, we reported a case of advanced squamous lung cancer which showed a durable abscopal effect from microwave ablation after acquired resistance of immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.696749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368438PMC
August 2021

The Role of Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Front Oncol 2021 21;11:671874. Epub 2021 Jul 21.

Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

Background: The use of circulating tumor DNA (ctDNA) to reflect clinical benefits of advanced non-small cell lung cancer (NSCLC) patients during immune checkpoint inhibitor (ICI) therapy remains controversial. This study aimed to determine the association of pre-treatment and early dynamic changes of ctDNA with clinical outcomes in advanced NSCLC patients treated with ICIs.

Methods: Electronic databases (PubMed, Embase, Web of Science, and Cochrane) were systematically searched to include relevant studies published in English up to November 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS) and the secondary outcome was objective response rate (ORR) with RECIST criteria.

Results: A total of 1017 patients from 10 studies were identified. The baseline ctDNA levels (detected not detected) showed no significant association with clinical outcomes regarding OS (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.93-1.51), PFS (HR, 0.98; 95% CI, 0.80-1.21), and ORR (odds ratio [OR], 0.89; 95% CI, 0.54-1.46). Interestingly, when taken early longitudinal assessment of ctDNA into consideration, the early reduction of the concentration of ctDNA was associated with significant improvements of OS (HR, 0.19; 95% CI, 0.10-0.35), PFS (HR, 0.30; 95% CI, 0.22-0.41) and ORR (OR, 0.07; 95% CI, 0.03-0.18). Further subgroup analyses revealed that the reduction magnitude did not significantly impact the association between ctDNA and clinical outcomes, suggesting that both patients with decreased ctDNA or a ≥50% reduction of ctDNA was associated with improved OS, PFS and ORR.

Conclusion: Early reduction of ctDNA was associated with improved OS, PFS and ORR in advanced NSCLC patients treated with ICIs.

Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, CRD42021226255.
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http://dx.doi.org/10.3389/fonc.2021.671874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335591PMC
July 2021

Human leukocyte antigen class II-based immune risk model for recurrence evaluation in stage I-III small cell lung cancer.

J Immunother Cancer 2021 Aug;9(8)

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, School of Medicine, Tongji University, Shanghai 200092, China.

Background: Immunotherapy has revolutionized therapeutic patterns of small cell lung cancer (SCLC). Human leukocyte antigen class II (HLA class II) is related to antitumor immunity. However, the implications of HLA class II in SCLC remain incompletely understood.

Materials And Methods: We investigated the expression patterns of HLA class II on tumor cells and tumor-infiltrating lymphocytes (TILs) by immunohistochemistry staining and its association with clinical parameters, immune markers, and recurrence-free survival (RFS) in 102 patients with stage I-III SCLC with radical surgery. Additionally, an HLA class II-based immune risk model was established by least absolute shrinkage and selection operator regression. With bioinformatics methods, we investigated HLA class II-related enrichment pathways and immune infiltration landscape in SCLC.

Results: HLA class II on tumor cells and TILs was positively expressed in 9 (8.8%) and 45 (44.1%) patients with SCLC, respectively. HLA class II on TILs was negatively associated with lymph node metastasis and positively correlated with programmed death-ligand 1 (PD-L1) on TILs (p<0.001) and multiple immune markers (CD3, CD4, CD8, FOXP3; p<0.001). Lymph node metastasis (OR 0.314, 95% CI 0.118 to 0.838, p=0.021) and PD-L1 on TILs (OR 3.233, 95% CI 1.051 to 9.95, p=0.041) were independent predictive factors of HLA class II on TILs. HLA class II positivity on TILs prompted a longer RFS (40.2 months, 95% CI 31.7 to 48.7 vs 28.8 months, 95% CI 21.4 to 36.3, p=0.014). HLA class II on TILs, PD-L1 on TILs, CD4, and FOXP3 were enrolled in the immune risk model, which categorized patients into high-risk and low-risk groups and had better power for predicting the recurrence than tumor stage. Pathway enrichment analyses showed that patients with high HLA class II expression demonstrated signatures of transmembrane transportation, channel activity, and neuroactive ligand-receptor interaction. High-risk SCLC patients had a higher proportion of T follicular helper cells (p=0.034) and a lower proportion of activated memory CD4-positive T cells (p=0.040) and resting dendritic cells (p=0.045) versus low-risk patients.

Conclusions: HLA class II plays a crucial role in tumor immune microenvironment and recurrence prediction. This work demonstrates the prognostic and clinical values of HLA class II in patients with SCLC.
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http://dx.doi.org/10.1136/jitc-2021-002554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351500PMC
August 2021

Differences in treatment effect size between progression-free survival and overall survival in anti-PD-1/PD-L1 inhibitors-based trials in advanced NSCLC: a systematic review and meta-analysis.

Transl Lung Cancer Res 2021 Jun;10(6):2562-2572

Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Background: To investigate the differences in treatment effect sizes between progression-free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) treated with programmed cell death 1 (PD-1) and its ligand (PD-L1) blockade-based treatments.

Methods: The differences in treatment effect sizes between PFS and OS were assessed by using a ratio of hazard ratio (rHR): the HR for PFS to that for OS. A random effects meta-analysis across trials was conducted to generate the combined rHR. We also evaluated the feasibility of adopting PFS as the surrogate of OS by using Spearman correlation coefficient () between logHR and logHR.

Results: A total of 27 randomized controlled trials (RCTs) with 15,590 patients were included. Treatment effect sizes were comparable, on average, for OS than for PFS (pooled rHR, 0.98; 95% CI, 0.91 to 1.08). Subgroup analysis revealed that treatment effect sizes were greater for OS than for PFS for trials with immunotherapy as second or above line treatment (rHR, 1.17; 95% CI, 1.06 to 1.29), while the differences were greater for PFS than for OS for trials with immunotherapy as first-line setting (rHR, 0.91; 95% CI, 0.84 to 0.99; P<0.01). The coefficient of determination was 40% and R was 0.63 between logHR and logHR. Subgroup analysis showed that coefficient of determination and R were 62% and 0.79 in trials with immunotherapy as first-line setting, 22% and 0.47 in trials with immunotherapy as second or above line treatment, respectively.

Discussion: Treatment effect sizes between PFS and OS were roughly consistent in trials with different anti-PD-(L)1 inhibitor-based therapies. PFS could be a potential alternative endpoint for OS in trials with immunotherapy as first-line setting, but PFS should be cautiously interpreted without OS data for trials with immunotherapy as second or above line treatment.
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http://dx.doi.org/10.21037/tlcr-21-199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264319PMC
June 2021

Artificial intelligence-based analysis for immunohistochemistry staining of immune checkpoints to predict resected non-small cell lung cancer survival and relapse.

Transl Lung Cancer Res 2021 Jun;10(6):2452-2474

Center for Thoracic Oncology, Mount Sinai Cancer, New York, NY, USA.

Background: Conventional analysis of single-plex chromogenic immunohistochemistry (IHC) focused on quantitative but spatial analysis. How immune checkpoints localization related to non-small cell lung cancer (NSCLC) prognosis remained unclear.

Methods: Here, we analyzed ten immune checkpoints on 1,859 tumor microarrays (TMAs) from 121 NSCLC patients and recruited an external cohort of 30 NSCLC patients with 214 whole-slide IHC. EfficientUnet was applied to segment tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs), while ResNet was performed to extract prognostic features from IHC images.

Results: The features of galectin-9, OX40, OX40L, KIR2D, and KIR3D played an un-negatable contribution to overall survival (OS) and relapse-free survival (RFS) in the internal cohort, validated in public databases (GEPIA, HPA, and STRING). The IC-Score and Res-Score were two predictive models established by EfficientUnet and ResNet. Based on the IC-Score, Res-Score, and clinical features, the integrated score presented the highest AUC for OS and RFS, which could achieve 0.9 and 0.85 in the internal testing cohort. The robustness of Res-Score was validated in the external cohort (AUC: 0.80-0.87 for OS, and 0.83-0.94 for RFS). Additionally, the neutrophil-to-lymphocyte ratio (NLR) combined with the PD-1/PD-L1 signature established by EfficientUnet can be a predictor for RFS in the external cohort.

Conclusions: Overall, we established a reliable model to risk-stratify relapse and death in NSCLC with a generalization ability, which provided a convenient approach to spatial analysis of single-plex chromogenic IHC.
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http://dx.doi.org/10.21037/tlcr-21-96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264317PMC
June 2021

An immune-based risk-stratification system for predicting prognosis in pulmonary sarcomatoid carcinoma (PSC).

Oncoimmunology 2021 13;10(1):1947665. Epub 2021 Jul 13.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Pulmonary sarcomatoid carcinoma (PSC) is an uncommon subtype of lung cancer, and immune checkpoint blockade promises in clinical benefit. However, virtually nothing is known about the expression of common immune checkpoints in PSC. Here, we performed immunohistochemistry (IHC) to detect nine immune-related proteins in 97 PSC patients. Based on the univariable Cox regression, random forests were used to establish risk models for OS and DFS. Moreover, we used the GSEA, CIBERSORT, and ImmuCellAI to analyze the enriched pathways and microenvironment. Univariable analysis revealed that CD4 ( = 0.008), programmed cell death protein 1 (PD-1; = 0.003), galectin-9 (Gal-9) on tumor cells (TCs; = 0.021) were independent for DFS, while CD4 ( = 0.020), PD-1 ( = 0.004), Gal-9 ( = 0.033), and HLA on TILs ( = 0.031) were significant for OS. Meanwhile, the expression level of CD8 played a marginable role in DFS ( = 0.061), limited by the number of patients. The combination of Gal-9 on TC with CD4 and PD-1 on TILs demonstrated the most accurate prediction for DFS (AUC: 0.636-0.791, F1-score: 0.635-0.799), and a dramatic improvement to TNM-stage ( < 0.001 for F1-score of 1-y, 3-y, and 5-yDFS). A similar finding was also observed in the predictive ability of CD4 for OS (AUC: 0.602-0.678, F1-score: 0.635-0.679). CD4 was negatively associated with the infiltration of neutrophils ( = 0.015). PDCD1 (coding gene of PD-1) was positively correlated to the number of exhausted T cells (Texs; = 0.020) and induced regulatory T cells (iTregs; = 0.021), and LGALS9 (coding gene of Gal-9) was positively related to the level of dendritic cells (DCs; = 0.021). Further, a higher combinational level of CD4, PDCD1 on TILs, and LAGLS9 on TCs were proved to be infiltrated with more M1-type macrophages ( < 0.05). We confirmed the expression status of nine immune-related proteins and established a TNM-Immune system for OS and DFS in PSC to assist clinical risk-stratification.
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http://dx.doi.org/10.1080/2162402X.2021.1947665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279095PMC
August 2021

Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial.

Lancet Respir Med 2021 09 21;9(9):1021-1029. Epub 2021 Jul 21.

Thoracic Surgery Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Icotinib has provided survival benefits for patients with advanced, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). We aimed to compare icotinib with chemotherapy in patients with EGFR-mutant stage II-IIIA NSCLC after complete tumour resection. Here, we report the results from the preplanned interim analysis of the study.

Methods: In this multicentre, randomised, open-label, phase 3 trial done at 29 hospitals in China, eligible patients were aged 18-70 years, had histopathogically confirmed stage II-IIIA NSCLC, had complete resection up to 8 weeks before random assignment, were treatment-naive, and had confirmed activation mutation in exon 19 or exon 21 of the EGFR gene. Participants were randomly assigned (1:1) with an interactive web-based response system to receive either oral icotinib 125 mg thrice daily for 2 years or four 21-day cycles of intravenous chemotherapy (vinorelbine 25 mg/m on days 1 and 8 of each cycle plus cisplatin 75 mg/m on day 1 of each cycle for adenocarcinoma or squamous carcinoma; or pemetrexed 500 mg/m plus cisplatin 75 mg/m on day 1 every 3 weeks for non-squamous carcinoma). The primary endpoint was disease-free survival assessed in the full analysis set. Secondary endpoints were overall survival assessed in the full analysis set and safety assessed in all participants who received study drug. This trial is registered with ClinicalTrials.gov, NCT02448797.

Findings: Between June 8, 2015, and August 2, 2019, 322 patients were randomly assigned to icotinib (n=161) or chemotherapy (n=161); the full analysis set included 151 patients in the icotinib group and 132 in the chemotherapy group. Median follow-up in the full analysis set was 24·9 months (IQR 16·6-36·4). 40 (26%) of 151 patients in the icotinib group and 58 (44%) of 132 patients in the chemotherapy group had disease relapse or death. Median disease-free survival was 47·0 months (95% CI 36·4-not reached) in the icotinib group and 22·1 months (16·8-30·4) in the chemotherapy group (stratified hazard ratio [HR] 0·36 [95% CI 0·24-0·55]; p<0·0001). 3-year disease-free survival was 63·9% (95% CI 51·8-73·7) in the icotinib group and 32·5% (21·3-44·2) in the chemotherapy group. Overall survival data are immature with 14 (9%) deaths in the icotinib group and 14 (11%) deaths in the chemotherapy. The HR for overall survival was 0·91 (95% CI 0·42-1·94) in the full analysis set. Treatment-related serious adverse events occurred in two (1%) of 156 patients in the icotinib group and 19 (14%) of 139 patients in the chemotherapy group. No interstitial pneumonia or treatment-related death was observed in either group.

Interpretation: Our results suggest that compared with chemotherapy, icotinib significantly improves disease-free survival and has a better tolerability profile in patients with EGFR-mutant stage II-IIIA NSCLC after complete tumour resection.

Funding: Betta Pharmaceuticals TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2213-2600(21)00134-XDOI Listing
September 2021

Outcomes of switching from crizotinib to alectinib in patients with advanced non-small cell lung cancer with anaplastic lymphoma kinase fusion.

Ann Transl Med 2021 Jun;9(12):1014

Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Background: Alectinib and crizotinib have been approved as first-line therapies for advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene fusion. However, the therapeutic efficacy and side effects are still largely unknown of patients who switched to next-generation ALK tyrosine kinase inhibitors (ALK-TKIs), such as alectinib, after experiencing no disease progression with initial crizotinib treatment.

Methods: This prospective real-world study enrolled patients who were treated with alectinib after experiencing no disease progression with initial crizotinib treatment. The patients' baseline characteristics, objective response rate (ORR) of crizotinib and alectinib, size change of target tumor lesions, treatment regimen and adverse events (AEs) were collected and analyzed.

Results: The study included 53 patients, the majority of whom (96.2%) had non-squamous NSCLC. The median age was 51 (range, 31-80) years old. The ORR of first-line crizotinib was 54.7%. The ORR of sequential alectinib was 73.6%, and 90.5% of patients showed further tumor shrinkage after the alectinib treatment. The median progression-free survival was not reached, and 90.5% of patients were still enrolled in the study at the last follow-up. Among them, 34.0% of patients switched to alectinib treatment due to the toxicity. Crizotinib was associated with a higher frequency of AEs of grades 3 and 4 than alectinib (15.1% 0%). Neither group had any AEs resulting in death.

Conclusions: Switching to alectinib might be an option for patients who do not experience disease progression with initial crizotinib therapy, and may promote better treatment compliance.
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http://dx.doi.org/10.21037/atm-21-2769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267309PMC
June 2021

The modification of T description according to visceral pleural invasion and tumor size from 3.1 cm to 4.0 cm in non-small cell lung cancer: A retrospective analysis based on the SEER database.

Lung Cancer 2021 08 10;158:47-54. Epub 2021 Jun 10.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address:

Objectives: As a poor prognostic factor, visceral pleural invasion (VPI) was incorporated into non-small cell lung cancer (NSCLC) staging system. For modifying the T description of NSCLC, the prognostic value of VPI was assessed.

Materials And Methods: From 2010-2015, data on stage pT2N0M0 NSCLC patients with tumor size (TS) from 3.1 cm to 5.0 cm who received surgery from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled retrospectively. Propensity score matching was utilized to balance the baseline factors according to different TS intervals. Overall survival (OS) was assessed by the Kaplan-Meier method and log-rank test. Univariate and multivariate analysis were applied to identify the prognostic factors. The risk factors of VPI were calculated by logistic regression model.

Result: The sum of 4005 resected stage pT2N0M0 NSCLC patients with TS from 3.1 cm to 5.0 cm were recruited, which had 1084 patients with VPI and 2921 patients without VPI respectively. As TS interval of 3.1-4.0 cm, the 5-year OS of patients without VPI was significantly better than those with VPI (62.6 % vs 58.7 %, P = 0.015), while the 5-year OS of patients with VPI and TS interval of 3.1-4.0 cm had no significant difference compared with patients whose TS interval of 4.1-5.0 cm (58.7 % vs 58.8 %, P = 0.918). Logistic regressive analysis manifested that older age, female, worse differentiation grade and larger TS had higher incidence of VPI (OR = 1.01, 1.25, 1.25, 1.16, respectively; P < 0.05 for all).

Conclusion: This study underlined the prognostic effect of VPI and suggested that early-stage NSCLC with VPI and TS interval of 3.1-4.0 cm could be appropriately upstaged from pT2a (stage pIB) to pT2b (modified stage pIIA).
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http://dx.doi.org/10.1016/j.lungcan.2021.06.003DOI Listing
August 2021

ICI plus chemotherapy prolonged survival over ICI alone in patients with previously treated advanced NSCLC.

Cancer Immunol Immunother 2021 Jun 7. Epub 2021 Jun 7.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433, People's Republic of China.

Objectives: Immune checkpoint inhibitors (ICI) monotherapy was standard of care in second-line treatment of patients with advance non-small cell lung cancer (NSCLC). This study aims to investigate the efficacy of ICI plus chemotherapy in patients with previously treated advanced NSCLC.

Patients And Methods: An investigator-initiated trial (IIT) aiming to evaluate the efficacy and safety of ICI in combination with chemotherapy as second line and beyond for patients with advanced NSCLC was undergone at Shanghai Pulmonary Hospital (ChiCTR1900026203). Patients who received ICI monotherapy as second or later line setting during the same period were also collected as a comparator.

Results: From April 2018 to June 2019, 31 patients were included into this IIT study, simultaneously 51 patients treated with ICI monotherapy were selected as a comparator. ICI plus chemotherapy showed a significantly higher ORR (35.5% vs. 15.7%, p=0.039), prolonged PFS (median: 5.6 vs. 2.5 months, p = 0.013) and OS (median: NE vs. 12.6 months, p = 0.038) compared with ICI alone. In the subgroup of negative PD-L1 expression (9 patients in combination group and 12 patients in monotherapy group), ICI plus chemotherapy also had a favorable ORR (44.4% vs. 8.3%, p = 0.119), longer PFS (median: 6.5 vs 3.0 months, p < 0.05) and OS (median: NE vs. 8.2 months, p = 0.117). Meanwhile, the addition of chemotherapy did not increase immune-related adverse events.

Conclusions: ICI plus chemotherapy showed superior ORR, PFS and OS than ICI alone patients with previous treated advanced NSCLC. These findings warrant further investigation.
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http://dx.doi.org/10.1007/s00262-021-02974-9DOI Listing
June 2021

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC.

Theranostics 2021 13;11(14):7092-7109. Epub 2021 May 13.

Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zhengmin Road, Yangpu District, Shanghai 200433, China.

Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.
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http://dx.doi.org/10.7150/thno.58039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171101PMC
August 2021

Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12).

J Thorac Oncol 2021 09 25;16(9):1501-1511. Epub 2021 May 25.

Medical Science and Strategy Oncology, Innovent Biologics Inc., Suzhou, People's Republic of China.

Introduction: The standard chemotherapy for squamous NSCLC (sqNSCLC) includes platinum plus gemcitabine. Sintilimab, an anti-programmed cell death protein 1 antibody, plus platinum and gemcitabine (GP) has revealed encouraging efficacy as first-line therapy for sqNSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to further compare the efficacy and safety of sintilimab with placebo, both in combination with GP.

Methods: ORIENT-12, a randomized, double-blind, phase 3 study, was conducted at 42 centers in the People's Republic of China (ClinicalTrials.gov, number NCT03629925). Patients with locally advanced or metastatic sqNSCLC and without EGFR-sensitive mutations or ALK rearrangements were enrolled in the study. The stratification factors included clinical stage, choice of platinum, and programmed death-ligand 1 tumor proportion score. The patients, investigators, research staff, and sponsor team were masked to treatment assignment. Eligible patients were randomized 1:1, using an integrated web-response system, to receive sintilimab 200 mg or placebo plus GP every 3 weeks for four or six cycles, followed by sintilimab or placebo as maintenance therapy until disease progression or 2 years. The primary end point was progression-free survival (PFS), assessed by an independent radiographic review committee.

Results: Between September 25, 2018 and July 26, 2019, a total of 543 patients were screened, of whom 357 patients were randomized to the sintilimab-GP group (n = 179) and the placebo-GP group (n = 178). After a median follow-up period of 12.9 months, sintilimab-GP continued to reveal a meaningful improvement in PFS than placebo-GP (hazard ratio = 0.536 [95% confidence interval: 0.422-0.681], p < 0.00001). Treatment-emergent adverse events of grade 3 or worse occurred in 86.6% patients in the sintilimab-GP group and in 83.1% in the placebo-GP group. The incidence of treatment-emergent adverse event leading to death was 4.5% and 6.7% in the two treatment groups, respectively.

Conclusions: Regarding PFS, sintilimab plus GP reveals clinical benefit than GP alone as first-line therapy in patients with locally advanced or metastatic sqNSCLC. The toxicity was acceptable, and no new unexpected safety signals were observed.
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http://dx.doi.org/10.1016/j.jtho.2021.04.011DOI Listing
September 2021

Adenocarcinoma of High-Grade Patterns Associated with Distinct Outcome of First-Line Chemotherapy or EGFR-TKIs in Patients of Relapsed Lung Cancer.

Cancer Manag Res 2021 17;13:3981-3990. Epub 2021 May 17.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People's Republic of China.

Purpose: High-grade patterns (micropapillary/solid/complex gland) are associated with a higher recurrence rate and shorter disease-free survival. Thus far, it remains unclear whether the efficacy of first-line anticancer therapy is different from that of the other adenocarcinoma subgroups for patients with high-grade patterns. The study aimed to investigate the association between an adenocarcinoma with high-grade patterns with the outcomes of first-line treatment in patients with lung cancer.

Patients And Methods: Patients with a high-grade pattern adenocarcinoma (more than 20% of micropapillary/solid components/complex glandular patterns) were retrospectively analyzed between June 2015 and June 2017. Patients' clinical characteristics and treatment outcomes were compared with those of the remaining control adenocarcinoma subgroups.

Results: In total, 239 patients with adenocarcinoma, including 115 (48.1%) high-grade patterns and 124 (51.9%) control groups, were enrolled. Patients' clinical characteristics such as age, sex, smoking status, and stage were similar between the two groups. Among them, 108 patients received first-line chemotherapy, and 131 received epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). In the chemotherapy group, adenocarcinoma of high-grade patterns had a significantly lower objective response rate (ORR; 15.6% vs 36.4%, P=0.045), shorter progression-free survival (PFS; median 4.1 vs 5.4 months, P=0.007) and overall survival (OS, median 19.6 vs 23.8 months, P=0.048) compared with the control group. As for these treated with EGFR-TKIs, a similar ORR (70.7% vs 72.1%, P=0.703), PFS (median 11.3 vs 13.9 months, P=0.065) and OS (median 34.1 vs 29.6%, p=0.575) were observed between these two groups.

Conclusion: An adenocarcinoma with high-grade patterns is associated with inferior outcomes to first-line chemotherapy in relapsed lung cancer. Patients who received chemotherapy had a significantly shorter PFS and OS and lower ORR than control subjects, while there was no difference in the EGFR-TKI cohort. This study is the first to report the distribution of adenocarcinoma with high-grade patterns.
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http://dx.doi.org/10.2147/CMAR.S302545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139732PMC
May 2021

Distinct patterns of somatic genomic alterations and mutational signatures in central and peripheral-type small-cell lung cancer.

Transl Lung Cancer Res 2021 Apr;10(4):1747-1760

Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Generally, small-cell lung cancer (SCLC) can be classified into central and peripheral-type. Genomic landscape and genetic heterogeneity between central and peripheral-type SCLCs is scarce.

Methods: We conducted whole-exome sequencing (WES) of 41 tumor/control pairs of SCLC samples. In all cases, 8,186 genes with non-synonymous mutations were identified, as well as significantly mutated genes (SMGs), tumor mutation burden (TMB), weighted genome instability index (wGII) and somatic copy number alteration (SCNA), the driver recurrent SCNA, and mutational signatures between central and peripheral-type SCLCs.

Results: TMB of peripheral-type SCLCs were higher than central-type. Smoking patients had significantly higher wGII and CNA burden than the non-smokers in SCLCs, these alterations were more obviously in central-types. Furthermore, the driver SCNA regions of central and peripheral-type SCLCs were different. Central and peripheral-type SCLCs had no common recurrent amplification (AMP) cytobands or genes, but had collective recurrent deletion (DEL) including four cytobands and five genes. Interestingly, the AMP 12q24.31 was negative correlated with overall survival (OS) in central but not peripheral-type SCLCs. Moreover, a mutational signature A was found significantly higher in peripheral than central-type SCLCs. In parallel, signature D was predictive of poor outcome, which was mainly in peripheral SCLC patients. COSMIC signatures analysis revealed that the association with signature D and OS was similar to the positive relationship between signature 13 and outcome.

Conclusions: Central and peripheral-type SCLCs were different in immunotherapy response, genome instability, the driver SCNAs and mutational signatures, which leaded to differences of prognosis.
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http://dx.doi.org/10.21037/tlcr-20-1096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107737PMC
April 2021

FOXP3-based immune risk model for recurrence prediction in small-cell lung cancer at stages I-III.

J Immunother Cancer 2021 05;9(5)

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai 200433, China

Background: Immunotherapies may prolong the survival of patients with small-cell lung cancer (SCLC) to some extent. The role of forkhead box protein P3 (FOXP3) in tumor microenvironment (TME) remains controversial. We aimed to examine FOXP3-related expression characteristics and prognostic values and to develop a clinically relevant predictive system for SCLC.

Methods: We enrolled 102 patients with histologically confirmed SCLC at stages I-III. Through immunohistochemistry, we determined the expression pattern of FOXP3 and its association with other immune biomarkers. By machine learning and statistical analysis, we constructed effective immune risk score models. Furthermore, we examined FOXP3-related enrichment pathways and TME traits in distinct cohorts.

Results: In SCLC, FOXP3 level was significantly associated with status of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), CD4, CD8, and CD3 (p=0.002, p=0.001, p=0.002, p=0.030, and p<0.001). High FOXP3 expression showed longer relapse-free survival (RFS) than the low-level group (41.200 months, 95% CI 26.937 to 55.463, vs 14.000 months, 95% CI 8.133 to 19.867; p=0.008). For tumor-infiltrating lymphocytes (TILs), subgroup analysis demonstrated FOXP3 and PD-1, PD-L1, lymphocyte activation gene-3, CD3, CD4, or CD8 double positive were significantly correlated with longer RFS. We further performed importance evaluation for immune biomarkers, constructed an immune risk score incorporating the top three important biomarkers, FOXP3, TIL PD-L1, and CD8, and found their independently prognostic role to predict SCLC relapse. Better predictive performance was achieved in this immune risk model compared with single-indicator-based or two-indicator-based prediction systems (area under the curve 0.715 vs 0.312-0.711). Then, relapse prediction system integrating clinical staging and immune risk score was established, which performed well in different cohorts. High FOXP3-related genes were enriched in several immune-related pathways, and the close relationships of interleukin-2, , basic excision repair genes , , , and oxidative phosphorylation related gene cytochrome c oxidase subunit 8A with FOXP3 expression were revealed. Moreover, we found low-immune risk score group had statistically higher activated CD4 memory T cells (p=0.014) and plasma cells (p=0.049) than the high-risk group. The heterogeneity of tumor-infiltrating immune cells might represent a promising feature for risk prediction in SCLC.

Conclusion: FOXP3 interacts closely with immune biomarkers on tumor-infiltrating cells in TME. This study highlighted the crucial prognostic value and promising clinical applications of FOXP3 in SCLC.
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http://dx.doi.org/10.1136/jitc-2021-002339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137193PMC
May 2021

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma.

Onco Targets Ther 2021 4;14:2953-2965. Epub 2021 May 4.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People's Republic of China.

Introduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in -mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.

Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.

Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (=0.026), gender (=0.041) and mutation status (=0.015), and in -mutant patients we found a lower proportion of patients with mutated and . Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (=0.007). And the mutational frequencies of and were significantly different among three immune phenotypes.

Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having mutation. And mutational frequencies of and were lower in -mutant patients. Furthermore, and might involve in the formation of immune phenotypes.
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http://dx.doi.org/10.2147/OTT.S294993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106479PMC
May 2021

Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer.

Nat Commun 2021 05 5;12(1):2540. Epub 2021 May 5.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Lung cancer is a highly heterogeneous disease. Cancer cells and cells within the tumor microenvironment together determine disease progression, as well as response to or escape from treatment. To map the cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment in advanced non-small cell lung cancer (NSCLC), we analyze 42 tissue biopsy samples from stage III/IV NSCLC patients by single cell RNA sequencing and present the large scale, single cell resolution profiles of advanced NSCLCs. In addition to cell types described in previous single cell studies of early stage lung cancer, we are able to identify rare cell types in tumors such as follicular dendritic cells and T helper 17 cells. Tumors from different patients display large heterogeneity in cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network and phenotype dominance. Our study also reveals a correlation of tumor heterogeneity with tumor associated neutrophils, which might help to shed light on their function in NSCLC.
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http://dx.doi.org/10.1038/s41467-021-22801-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100173PMC
May 2021

Immune Checkpoint Inhibitors in EGFR-Mutated NSCLC: Dusk or Dawn?

J Thorac Oncol 2021 08 26;16(8):1267-1288. Epub 2021 Apr 26.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address:

Although immune checkpoint inhibitors (ICIs) that target programmed cell death protein-1/programmed cell death ligand-1 axis have significantly shifted the treatment paradigm in advanced NSCLC, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Several predictive biomarkers (e.g., programmed cell death ligand-1 expression, tumor mutation burden), which have been validated in EGFR-wild type NSCLC, however, are not efficacious in EGFR-mutated tumors, suggesting the unique characteristics of tumor microenvironment of EGFR-mutated NSCLC. Here, we first summarized the clinical evidence on the efficacy of ICIs in patients with EGFR-mutated NSCLC. Then, the cancer immunogram features of EGFR-mutated NSCLC was depicted to visualize the state of cancer-immune system interactions, including tumor foreignness, tumor sensitivity to immune effectors, metabolism, general immune status, immune cell infiltration, cytokines, and soluble molecules. We further discussed the potential subpopulations with EGFR mutations that could benefit from ICI treatment. Lastly, we put forward future strategies to adequately maximize the efficacy of ICI treatment in patients with EGFR-mutated NSCLC in the upcoming era of combination immunotherapies.
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http://dx.doi.org/10.1016/j.jtho.2021.04.003DOI Listing
August 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

High discrepancy in thrombotic events in non-small cell lung cancer patients with different genomic alterations.

Transl Lung Cancer Res 2021 Mar;10(3):1512-1524

Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

Background: Acute complications, such as venous thromboembolism (VTE), are common in patients with advanced severe lung cancers. However, current VTE risk scores cannot adequately identify high-risk patients with non-small cell lung cancer (NSCLC). The study proposed to elucidated the incidence of thromboembolism (TE) in patients with different oncogenic aberrations and the impact of these aberrations on the efficacy of targeted therapy in patients with NSCLC.

Methods: A systemic review was conducted in Web of Science, PubMed, Embase and the Cochrane Library to evaluate the incidence of TE in different molecular subtypes of NSCLC. Data from patients diagnosed of advanced NSCLC who harboring anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) rearrangements since 2016 to 2019 were also retrospectively collected. A meta-analysis with random-effects model, sensitivity analysis and publication bias were performed. The principal summary measure was incidence of thrombotic events in NSCLC patients. And the efficacy of tyrosine kinase inhibitor (TKI) therapy was compared between the two subgroups.

Results: A total of 5,767 cases from 20 studies were included in the analysis of the incidence of thrombosis in patients with different oncogenic alterations. The pooled analysis showed a higher risk of thrombosis in ROS1-fusion types (41%, 95% CI: 35-47%) and ALK-fusion types (30%, 95% CI: 24-37%) than in EGFR-mutation (12%, 95% CI: 8-17%), KRAS-mutation (25%, 95% CI: 13-50%), and wild-type (14%, 95% CI: 10-20%) cases. A high prevalence of thrombosis (ALK: 24.4%; ROS1: 32.6%) was observed in the Shanghai Pulmonary Hospital (SPH) cohort of 224 patients with ALK or ROS1 fusion. Furthermore, patients with embolism had significantly shorter progression-free survival (PFS) after TKI therapy than those without embolism, both in the ALK+ cohort (5.6 12.9 months, P<0.0001) and in the ROS1+ cohort (9.6 17.6 months, P=0.0481).

Conclusions: NSCLC patients with ALK/ROS1 rearrangements are more likely to develop thrombosis than patients with other oncogenic alterations. Thrombosis may also be associated with an inferior response and PFS after TKI therapy.
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http://dx.doi.org/10.21037/tlcr-20-1290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044490PMC
March 2021

Concurrent use of metformin enhances the efficacy of EGFR-TKIs in patients with advanced EGFR-mutant non-small cell lung cancer-an option for overcoming EGFR-TKI resistance.

Transl Lung Cancer Res 2021 Mar;10(3):1277-1291

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Resistance is almost inevitable and is still a major obstacle in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Only limited relevant clinical studies evaluated the therapeutic effects by combing metformin and EGFR-TKIs in non-small cell lung cancer (NSCLC) patients. Therefore, we evaluated the efficacy of concurrent use of metformin with EGFR-TKIs, and assessed whether the addition of metformin may improve clinical outcomes and delay the occurrence of EGFR-TKI resistance.

Methods: We conducted cell proliferation and apoptosis assay for investigation of metformin in combination with EGFR-TKIs to overcome EGFR-TKI resistance . Furthermore, we retrospectively reviewed clinicopathological characteristics and therapeutic outcomes of EGFR-mutant advanced NSCLC diabetic patients who received EGFR-TKIs with or without concurrent use of metformin.

Results: experiment, metformin showed synergistic interaction both with gefitinib in PC9R (CI =0.77) and with osimertinib in PC9R/OR (CI =0.77) in proliferation inhibition assay. Metformin can also augment apoptosis effect of these TKI-resistant cells to EGFR-TKIs. In retrospective cohort, a total of 85 patients were identified (cohort A), in which 28 patients had concurrent use of metformin. The objective response rate in metformin use group was significantly higher (85.7% 47.4%, P=0.001). The median progression-free survival (PFS) and overall survival (OS) in metformin use group were significantly longer (21.6 9.2 months, P=0.000; 48.4 36.6 months, P=0.049). Further analysis revealed that metformin obviously prolonged the median PFS2 of osimertinib treatment among patients who progressed to prior line EGFR-TKIs due to secondary EGFR T790M mutation (cohort B).

Conclusions: Our study suggest that concurrent use of metformin could be beneficial to EGFR-mutant NSCLC patients treated with either first-line EGFR-TKIs or second-line osimertinib.
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http://dx.doi.org/10.21037/tlcr-20-1153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044488PMC
March 2021

Peripheral Blood Autoantibodies Against to Tumor-Associated Antigen Predict Clinical Outcome to Immune Checkpoint Inhibitor-Based Treatment in Advanced Non-Small Cell Lung Cancer.

Front Oncol 2021 16;11:625578. Epub 2021 Mar 16.

Department of Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Background: Peripheral blood biomarkers to immunotherapy have attracted more and more attentions owing to noninvasive nature. This study was designed to identify a panel of tumor associated autoantibodies (TAAbs) in plasma to predict the clinical outcome of ICIs-based treatment in advanced NSCLC patients and correlation between TAAbs and checkpoint inhibitor pneumonitis (CIP) would also be investigated.

Materials And Methods: Baseline plasma was collected from patients with advanced NSCLC before receiving ICIs-based treatment. ELISA was used to detect concentration of autoantibodies. Clinical efficacy was evaluated according to RECIST v1.1.

Results: We have identified a panel of five-TAAbs to predict responses of ICIs-based treatment in a discovery cohort (n = 37), and confirmed its predictive value in a validation cohort (n = 129). In the validation cohort, the positivity of this 5-TAAbs panel was significantly associated with better response (ORR: 44.4% vs. 13.6%, < 0.001) and longer PFS (7.6 vs. 3.3m, < 0.001). This significant association was remained in subgroup of patients treated with combination therapy (ORR: 43.8% vs. 13.7%, = 0.004,PFS: 6.7 vs. 3.7m, = 0 .017). Furthermore, this 5-TAAs panel worked better in patients who received subsequent-line treatment (ORR: 42.4% vs. 7.7%, = 0.001, PFS: 6.2 vs. 3.0m, = 0.004) than those received first-line treatment (ORR: 46.7% vs. 35.7%, = 0.345, PFS: NR vs. 10.48m, = 0.146). In addition, the CIP incidence in patients with 5-TAAbs positive was significantly higher comparing to negative patients (20.4% vs. 5.9%, = 0.015).

Conclusion: Our 5-TAAbs panel is a potential predictive biomarker for responses and toxicities to ICIs-based treatment in patients with advanced NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.625578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010683PMC
March 2021
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