bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating nucleosomes to identify non-smoker subjects at risk of lung cancer and triage them for low-dose CT scan.
Authors: Tsai Tung-Ming , Hardat Nathalie , Pamart Dorian , Herzog Marielle , Chen Jin-Shing
Published: June 2022

e20558

Background: Lung cancer (LC) is the leading cause of cancer death worldwide and the most frequently occurring in men and the second most diagnosed cancer in woman after breast cancer. The primary risk factor leading to LC is tobacco smoke. Nevertheless, several studies in the US, UK and Asia reported an increasing rate of LC in non-smokers. 15-20% of LC patients worldwide are non-smokers with this percentage rising to 60% in non-smoking women in Asia. Current LC screening guidelines recommend a CT scan only for high-risk smokers. Despite there being no guidelines to recommend LC screening in non-smokers those with increased risk factors could be monitored. Therefore, a blood-test could offer a simple way to identify non-smokers at high-risk of LC and triage them to go for low-dose CT scan. Methods: We measured circulating levels of nucleosomes and CEA in 722 non-smoker subjects referred for CT scan at National Taiwan University Hospital. The patients were later confirmed to have either a LC (n = 509, including 401 patients at stage 0-1), non-malignant nodules (n = 142), or no-nodules (n = 71). Whole blood was collected in EDTA plasma tubes for analysis by six different Nu.Q chemiluminescent magnetic microparticle immunoassays (Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K9Me3-, H3K27Me3-, H3K36Me3-, H3K9Ac-, H3K14Ac-nucleosomes). CEA was analyzed on the Abbott ARCHITECT analyzer. We defined by logistic regression the best combination of biomarkers to identify LC cases in this non-smoking population in a rule-in approach. Results: At 95% specificity, none of the individual biomarkers exceed 24.8% of sensitivity for LC vs non-malignant nodules and no nodules. A combination of 2 nucleosome biomarkers: H3K9Me3- and H3K9Ac-nucleosomes with CEA in a logistic regression model showed improved sensitivity detecting 32.4% of LC in the non-smoker subjects at 95% specificity for LC vs non-malignant nodules and no nodules (area under the curve (AUC): 0.76, R2: 19.1%). In a non-smoking women sub-group by adding a third nucleosome biomarker: H3K36Me3-nucleosomes to the model we could detect 34.3% of the women who have lung cancer at 95% specificity (AUC: 0.75; R2: 20.2%). Conclusions: Our results indicate that a blood test combining circulating nucleosomes targeting different epigenetic modifications with CEA allow the detection of LC cases in a non-smokers population. This blood test could be part of the screening criteria for the non-smoking population at risk to develop LC and could help to triage them for low-dose CT scan.
Association of TP53 polymorphisms with the acquisition of EGFR T790M mutations in patients with first- or second-generation EGFR-TIK progression.
Authors: Dong Huajie , Zhou Tong , Li Peng , Wu Changling , Lu Hongjun , Zhao Lele , Yang Xueyu , Deng Wanglong , Qi Chuang
Published: June 2022

e20560

Background: Lung cancer is the leading cause of cancer death worldwide. EGFR tyrosine kinase inhibitors (TKIs) has transformed management in those patients. However, the majority of patients will become resistant to EGFR-TKIs after a period of time. The T790M acquired mutation in exon 20 of the EGFR is the predominant molecular mechanism of acquired resistance. In first-line treatment of global patients with NSCLC, osimertinib had better efficacy compared to first-generation TKIs. In the FLAURA study, the median PFS with first-line osimertinib in Asians was only 16.5 months, compared to 18.6 months in the global population. Moreover, the OS benefit in the Asian population was relatively small. At the same time, the mechanism of resistance to osimertinib is very complex and patients have limited treatment options after first-line osimertinib resistance. A variety of factors can influence the decision for first-line treatment in EGFR mutation-positive patients, including follow-up regimens, the presence of brain metastases, and tolerability, all of which should be considered in the long-term treatment plan. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions. Previous studies have shown that TP53 Arg72Pro polymorphism (rs1042522) is associated with the risk and prognosis of lung cancer. Currently, the association between EGFR mutations and TP53 polymorphisms is unclear, but previous reports have suggested that patients with EGFRmutation demonstrated a higher rate of TP53 mutation than EGFR wild type patients. Therefore, this study aim to explore the association of TP53 polymorphisms (rs1042522) with EGFR T790M acquired mutations, considering the value of T790M in lung cancer treatment. Methods: We analyzed two independent cohorts of patients with EGFR-mutant NSCLC who progressed after first-line EGFR-TKIs treatment from 2013 to 2021 (cohort 1: n=108; cohort 2: n=148). All patients were tested with plasma next-generation sequencing (NGS). Results: The acquired T790M mutation rate was 36%, 30% and 43% in all patients (n = 256), cohort 1 and cohort 2, respectively. Logistic regression analysis showed that TP53 rs1042522 polymorphism was significantly associated with an increased risk of T790M acquired mutation in cohort 1 (GG versus CC: OR (95% CI) = 3.57 (1.15-12.2), P = 0.033) and cohort 2 (GG versus CC: univariable OR (95% CI) = 3.53 (1.30-10.3), P = 0.016; multivariable OR (95% CI) = 2.94 (1.04-8.87), P= 0.047). Conclusions: We found that the TP53 rs1042522 polymorphism GG was associated with EGFR T790M acquired mutations. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions.
Dysregulated Th1 cells in lung squamous cell carcinoma.
Authors: Wang Jiahui , Zhou Qiuru , Yan Cihui , Hui Zhenzhen , Wang Tao , Zheng Liuqing , Xiao Shanshan , Zhou Jian , Zhao Yu , Wang Zhe , Ren Yulin , Wang Hao , Ren Xiubao
Published: June 2022

e20566

Background: Lung squamous cell carcinoma (LUSC) is one of the most common subtypes of lung cancer which lacks of effective treatments compared to lung adenocarcinoma. The Th1 subset in CD4+ T cells plays an indispensable role in antitumor immune responses. However, there are few studies on Th1 cells in LUSC. Methods: Firstly, we used single-cell RNA-seq to analyze the gene expression in 8 LUSC patients’ tissues, including tumor tissues, paracancerous tissues, normal tissues, lymphoid tissues, pre-treatment blood samples and pre-operative blood samples. A total of qualified 44969 CD4+ T cells and 22971 Th1 candidate cells (Because STAT1, STAT4 and T-bet can promote IFN-γ expression. We define CD4+ T cells with one or more of above four indicators as Th1 candidate cells (Th1 CDD cells)) were identified. Then, we validated Th1 CDD cells and CD8+ T cells of tumor sites in 32 patients with LUSC by using multiplex immunofluorescence staining and immunohistochemistry. Finally, we used flow cytometry to detect the IFN-γ of CD4+ T cells in human PBMCs which were co-incubated with the supernatant derived from LUSC cell lines to simulate the tumor inhibitory microenvironment. Results: Single cell RNA-seq results showed IFN-γ+ Th1 CDD cells only account for about 25.28% of the total Th1 CDD cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the differentially expressed genes (DEGs) between IFN-γ+ Th1 CDD cells and IFN-γ- Th1 CDD cells demonstrated that the decreased level of IFN-γ expression was associated with ribosomes, antigen presentation, cell-to-cell interactions, apoptosis, endoplasmic reticulum stress (ER stress) and so on. According to multiplex immunofluorescence staining and immunohistochemistry, there was a positive correlation between the IFN-γ+ STAT1+ T-bet+ Th1 CDD cells and CD8+ T cells in tumor stromal compartment. Flow cytometry showed decreased level of IFN-γ in Th1 cells co-incubated with LUSC-derived supernatant. Conclusions: The function of Th1 CDD cells is suppressed in LUSC. In our study, we found that the decreased function of Th1 CDD cells is associated with ER stress by single cell RNA-seq, which requires further research. Overall, this may highlight a new target for the treatment of LUSC.
Impact of pretreatment clinical factors and DVH parameters on radiation pneumonitis and survival after intensity-modulated radiotherapy for lung cancer.
Authors: Liang ZiBin , Xu Xiaolu , Guo Shuanshuan , Niu Xiaoli , Yan Lubin , Zou Yanfei , Lin Zhong , Peng Peijian , Wang Zhihui , Hu Liyang
Published: June 2022

e20571

Background: The aim of this study was to investigate the relationship between clinical factors and dose-volume histogram parameters regarding Overall Survival (OS) and Radiation-Pneumonitis-Free Survival (RPFS) in lung cancer patients. Methods: We retrospectively reviewed clinical data of lung cancer patients from 2018 to 2020. Demographic, clinical, and treatment-related data were collected for all patients. OS was defined as the duration from pathological diagnosis to death or last follow-up. RPFS was defined as the duration from the start of radiation therapy to occurrence of grade≥3 Radiation-Pneumonitis, or final follow-up. RPFS and OS rates were estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox regression model was used to estimate the hazard ratio (HR) and the corresponding 95% confidence interval (CI) for univariate and multivariate analysis. Results: A-hundred patients were included in this study. The median follow-up period after completion of radiotherapy was 42.9months (range: 2.0–152.1). In multivariate study, low serum sodium after RT, V5ipsi≥51%, V20ipsi≥28%, V30ipsi≥22% and MLDipsi≥15.99 Gy were independent predictive factors for poor OS, respectively ( p ＜0.05). MLD≥10.20 Gy suggested a poorer RPFS ( p ＜0.1) in this cohort. Conclusions: The independent significant risk factors of radiation pneumonitis were V20, V5 and MLD. In addition, the V20 and V5 of the ipsilateral lung should be more strictly limited to less than 28% and 51% when determining radiotherapy especially in this era of immunotherapy. Some blood indexes of low nutritional status were very important to determine the occurrence of high-risk radiation pneumonitis.
Exploratory radiomic analysis of stage III non-small cell lung cancer CT images: Correlation with clinical-pathological characteristics.
Authors: Pasello Giulia , Ferro Alessandra , Scagliori Elena , Gennaro Gisella , Costa Matilde , Sepulcri Matteo , Schiavon Marco , Bonanno Laura , Frega Stefano , Caumo Francesca , Calabrese Fiorella , Rea Federico , Guarneri Valentina
Published: June 2022

e20574

Background: Recent evidences have suggested potential applications of radiomics in early diagnosis, prognostic stratification and treatment outcome prediction of Non-Small Cell Lung Cancer (NSCLC) patients. The purpose of this study is to evaluate the ability of radiomic analysis to discriminate between different clinical-pathological conditions in patients with stage III NSCLC. Methods: Baseline CT studies from 59 patients with stage III NSCLC referred to our Institution from 2010 and 2020 were retrospectively reviewed, and the segmentation of the main lung lesion and the extraction of 517 radiomic features performed using a commercial software. The number of features was reduced to 46 by means of principal component analysis applied using the R package “RadAR” (Radiomics Analysis with R). The Kruskal-Wallis test was applied to all the radiomic features in order to evaluate which of them can discriminate between 7 clinical dichotomous characteristics: tumor stage, type, presence of mutation, treatment response, relapse free survival (RFS), smoking habit, patient outcome. P < 0.05 means that there is a statistically significant difference between the two subgroups. Results: The median age at diagnosis was 69 years (range 43-83). Most patients were males (40/59 = 67.8%) and heavy smokers (36/59 = 61.0%). Adenocarcinoma was the most common histology (41/59 = 70.7%), while cases were almost equally splitted between stage IIIA (45.8%) and stage IIIB or IIIC (54.2%). Most selected radiomic features (29/46 = 63.0%) showed a statistically significant difference between patients with and without mutations. Ten (10/46 = 21.7%) radiomic features were associated with patient sex. Seven features (7/45 = 15.2%) were “sensitive” to the tumor clinical stage (stage IIIA vs. stage IIIB+IIIC), 4 (4/46 = 8.7%) to the histological type, and 2 (2/46 = 4.3%) to the patient outcome. None of the selected radiomic features was able to discriminate between responder and non-responder patients, current/previous smokers and never smokers, and patients with RFS lower than 12 months versus RFS equal or higher than 12 months. Conclusions: This preliminary analysis showed that radiomics has the potential of identifying mathematical features associated with clinical and histopathological characteristics in stage III NSCLC patients, which might feed multiparametric predictive models. Larger datasets and further analysis are necessary in order to confirm initial results.
Characterizing node-negative non-small cell lung cancer patients with similarity networks: A CancerLinQ Discovery analysis.
Authors: Moen Erika L , Chen Zoe , Schaefer Andrew , Bhimani Alisha , O'Malley James , Dragnev Konstantin H.
Published: June 2022

e20585

Background: Patients with node-negative non-small cell lung cancer (NSCLC) whose tumors are completely resected account for approximately 17% of all patients with lung cancer, and disease recurrence occurs in approximately 1 in 5 of these patients. The lack of consensus on factors associated with risk of disease recurrence among node-negative NSCLC patients is a significant barrier to applying precision medicine strategies in this patient population. Clustering similar patients based on distances between various features of data is an emerging topic in precision medicine. Patient similarity networks represent a new model for clustering patients based on heterogeneous data, whereby any data type is converted into a similarity network by defining a similarity measure. The objective of this study was to examine the utility of patient similarity networks to identify NSCLC patients at higher risk of adverse outcomes. Methods: We conducted a retrospective, observational study of 6,020 node-negative NSCLC patients with an initial diagnosis in 2011-2014 in the CancerLinQ Discovery database. A patient similarity network was assembled based on comorbidities and network communities of patients with similar comorbidities at diagnosis were identified. Using Cox proportional-hazards modeling, we examined the extent to which patient age, sex, race, ethnicity, and network community predicted 2-year disease recurrence and 2-year mortality. Results: In the adjusted analyses, patients in the network community enriched for renal disease and congestive heart failure had an 83% increased risk of mortality (95% CI = 1.39-2.41). Patients in the network community enriched for pulmonary disease had a 37% increased risk of mortality (95% CI = 1.06-1.74) yet a lower risk of recurrence (HR = 0.5, 95% CI = 0.34-0.75). After adjusting for comorbidity network community, male patients had a 14% increased risk of mortality (95%CI = 1.02-1.28) and a 21% increased risk of recurrence (95% CI = 1.05-1.40) and black patients had a lower mortality risk (HR = 0.71, 95% CI = 0.58-0.86). Conclusions: Future studies applying patient similar networks to integrate additional diverse and high dimensional data types may afford more clarity in assigning risk of adverse outcomes.
Phase 1 first-in-human trial of MTB-9655, the first oral inhibitor of ACSS2, in patients with advanced solid tumors.
Authors: Perets Ruth , Geva Ravit , McKean Meredith , Goutopoulos Andreas , Erez Omri , Phadnis Monica , Youssoufian Hagop , Schwartz Brian E. , Kansra Vikram , Fattaey Ali
Published: June 2022

e20609

Background: ACSS2 catalyzes the ligation of acetate with Co-enzyme A to generate Acetyl-CoA. Selection to an acetate dependent state has been demonstrated and is associated with the induction of ACSS2 gene expression in certain human cancers. The ACSS2 gene is amplified in human breast cancers, and its expression is up-regulated in human colorectal, breast, ovarian and lung cancers. MTB-9655 is a potent (IC50 = 0.15nM in biochemical, and EC50 = 3nM in cellular assays) oral inhibitor of ACSS2 and induces anti-tumor effects in xenograft mouse models of human colorectal, breast and lung cancers that express high levels of ACSS2. Methods: Using a combined accelerated (single patient for the first two dose levels) and 3+3 dose escalation and dose expansion design, MTB-9655 was administered on a once daily (QD) schedule in 21-day cycles in a Phase 1 trial to assess safety, tolerability, PK and potential anti-tumor activity in patients with advanced solid tumors. Re-staging was performed every 2 cycles. Results: To-date, 10 subjects have received MTB-9655 at doses up to 225mg. MTB-9655 was absorbed rapidly post oral dosing with a half-life of 6-12 hours. Dose proportional exposure was observed on day 1 of the first dosing cycle, and steady-state exposure was noted between day 8 and day 1 of the second dosing cycle. Dose limiting toxicities or Grade 3 treatment-related adverse events (AEs) have not been observed up to the 225mg dose level. The most common AE was nausea (29%). Low grade increase in bilirubin levels was observed in 1 patient at 225mg dose, without changes in other liver enzyme levels. Increased bilirubin levels were readily reversed with dose interruption. As MTB-9655 is a 729nM inhibitor of the UGT1A1 enzyme, the increase in bilirubin levels is likely attributed to off-target UGT1A1 inhibitory activity. Conclusions: MTB-9655 has been well tolerated, and the safety profile was predictable based on preclinical studies in rodents and non-human primates. Dose proportional plasma drug levels were observed and predicted to have reached biologically active levels. Expected increase in bilirubin levels was observed in 1 patient, which may be used as a marker of significant drug exposure. MTD has not reached up to the 225mg dose and the dose escalation is continuing. Development of MTB-9655 is planned as a single agent, and based on animal model studies, in combination with standard of care platinum-based agents and gemcitabine. Clinical trial information: NCT04990739.
Effect of EGFR amplification on survival of patients with EGFR mutation-positive non-small cell lung cancer.
Authors: Xu Yiquan , Wang Haibo , Zheng Xinlong , Lin Gen
Published: June 2022

e21000

Background: Epidermal growth factor receptor (EGFR) mutation is a common mutation in non-small cell lung cancer (NSCLC). Patients with EGFR mutation generally respond well to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR mutation are often co-occurring with EGFR amplification. However, the effect of EGFR amplification on the survival of patients with EGFR mutations remained unclear. Methods: Treatment-naïve adult patients with advanced NSCLC and EGFR mutation confirmed by next generation sequencing (NGS) at Fujian Provincial Hospital between April 2017 and October 2021 were enrolled in this retrospective clinical study. The patients’ clinical characteristics, gene mutations, treatment and clinical outcomes were extracted. progression-free survival (PFS) and overall response rate (ORR) were compared between EGFR amplification and non-EGFR amplification groups using the Kaplan-Meier method and log-rank test. Results: EGFR amplification and non-EGFR amplification were identified in 55 patients (36.67%) and 95 patients (63.33%), and there were no significant differences in clinical characteristics. No significant differences between the EGFR amplification and non-EGFR amplification groups in median PFS (247 vs. 214 days, P = 0.605). The ORR in EGFR amplification group is higher than non-EGFR amplification group (60.87% vs 32.69%). Conclusions: There is a tendency that EGFR amplification might not be a well predictor in EGFR mutation positive NSCLC patients treated with EGFR-TKIs.
ALK fusion typing and response to crizotinib in ALK+ lung cancer-naive patients.
Authors: Zhou Xinliang , He Liyuan , Fan Zhisong , Zuo Jing , Feng Li , Wang Long , Han Jing , Liu Jiayin , Zhang Xue , Li Dan , Liu Feiran , Zhao Honghui , Wang Yudong
Published: June 2022

e21008

Background: Anaplastic lymphoma kinase (ALK) is one of the major oncogenic driver genes in lung cancer, and fusion as the main mutation type, of which EML4 is the most common fusion ligand. With the development of next-generation sequencing (NGS), some other rare fusion ligands and complex fusions have been discovered. The prognosis of patients with EML4-ALK fusion, non EML4-ALK fusion and multiple ALK fusion was different. Methods: We retrospectively analyzed NGS (including tissue, blood, or other body fluid samples) in 61 patients with ALK[+] lung cancer, including 59 patients with NSCLC and 2 patients with SCLC. Grouping was determined according to whether it was EML4-ALK fusion and multiple fusion. Results: In our data, the partner fused to the ALK gene are diverse, including EML4, KIF5B, TSN and others. Among them, EML4 was the most common ligand in ALK[+] NSCLC, accounting for 93.2% (55/59). Among the different fusion sites of EML4-ALK, V1 (E13:A20) and V3 (E6:A20) mutations were the most common, accounting for 45.5% (25/55) and 41.8% (23/55), respectively. Several novel ALK fusion partners were discovered in this study, including MCFD2, LINC01251, MVP17, CREG2, LINCO1498 and so on. In addition, the incidence of intergenic sequence-ALK fusions was 16.4% (10/61), such as ANXA4-ALK(A[intergenic]:A20), CREG2-ALK (C[intergenic]:A20), HCN1-ALK(H[intergenic]:A20), TSN-ALK(T[intergenic]:A20), RSAD2-ALK(R [intergenic]:A20) and so on. 19.0% (12/61) of the patient had multiple fusion, of which only one patient had multiple fusion of EML4-ALK (V2+V5'+V3a/b), and the remaining patients had co-fusion of EML4-ALK and non EML4-ALK (Table). V3 were more likely to coexist with non EML4-ALK fusions than V1 or other variants (P = 0.047). Multiple fusions were more likely to occur with non EML4-ALK fusions (P < 0.000). Compared with EML4-ALK fusion, mPFS treated with crizotinib in non EML4-ALK fusion were significantly shorter (18.2 vs. 8.5 months, P = 0.035). In the context of crizotinib treatment, multiple fusions were associated with worse mPFS compared with single fusions (13.8 vs. 8.4 months, P = 0.008). In addition, For SCLC patients with ALK fusion (n = 2), the PFS of crizotinib treatment were 8.0 and 30.6 months, respectively. Conclusions: Due to the heterogeneity of tumor development resulting in the diversity of ALK fusions, non EML4-ALK fusions and multiple fusions imply a poorer response to crizotinib. ALK gene status prior to ALK-TKI therapy helps predict drug efficacy and patient prognosis.[Table: see text]
Screening of FGFR patients for FGFR directed clinical trials in Network Genomic Medicine (NGM): Real-world data.
Authors: Scharpenseel Heather , Malchers Florian , Terjung Inken , Hillmer Axel , Merkelbach-Bruse Sabine , Scheel Andreas H. , Siemanowski Janna , Scheffler Matthias , Riedel Richard , Eisert Anna , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Weber Jan-Philip , Westphal Theresa , Kron Anna , Sueptitz Juliane , Thomas Roman K. , Buettner Reinhard , Wolf Juergen , Nogova Lucia
Published: June 2022

e21013

Background: The fibroblast growth factor receptor (FGFR) 1-4 genes show a heterogenic landscape of alterations in non-small cell lung cancer (NSCLC) whereas only a small amount is yet considered to have oncogenic potential. The frequency of activating FGFR alterations is low, counting for approximately 2% of NSCLC. We have screened NSCLC patients (pts) for FGFR translocations/mutations within NGM and analysed them on FGFR alteration frequency, patient characteristics and outcome. Methods: From 04/2019 to 01/2020 we screened 472 squamous NSCLC for FGFR gene alterations and from 02/2020 to 12/2021 an additional 5286 patients including all NSCLC cases. Of these 5286 pts, 1097 pts were analysed for FGFR fusions. We used DNA-NGS for FGFR-mutations and RNA-NGS for FGFR–translocations. Activating mutations were defined according to the publicly available molecular data bases and published data. Results: Within the cohort of 5758 NSCLC patients, we found 316 (5.5%) patients with FGFR alterations. Sixty-six (20.9% of FGFR, 1.1% of NSCLC) patients had alterations classified as activating, of whom 39 had FGFR point mutations and 27 FGFR translocations. Concerning the patients with activating alterations, they had UICC stage III or IV at time of diagnosis; 22 were females; 58 patients had squamous cell carcinoma, 6 patients had adenocarcinoma and 2 had large cell neuroendocrine carcinoma. Fifty-three patients (80.3%) with activating FGFR alteration had a co-mutation: TP53 (inactivating) co-mutation was seen in 41 cases (62.1%) and 19 cases had either PTEN (7 pts), KRAS (4), EGFR (3), PIK3CA (2), ROS1 (1), ALK (1) or BRAF (1) mutations. Ten patients were included in a FGFR-targeted trial. Sixty patients were available for follow-up. The median overall survival (mOS) was 21.4 month (95%CI: 16.8–25.9) for all patients with activating FGFR alteration, whereas mOS was 18.5 month (95%CI: 13.2-23.9) for FGFR mutation and 25.3 months (95%CI: 17.8-32.9) for FGFR fusions. Conclusions: FGFR 1-4 gene alterations are rare. Large molecular and clinical networks are necessary to identify these pts. Prognostic factors of FGFR patients are currently not defined. Further assessments on molecular and clinical features in FGFR altered NSCLC are needed to identify sensitivity to FGFR inhibition. Clinical trials with specific FGFR inhibitors are ongoing.
MIF improves immune microenvironment of Lewis lung cancer brain metastases after radiotherapy via reducing M2 macrophages.
Authors: Wang Ying , Dong Xiaorong
Published: June 2022

e21026

Background: Our previous studies showed that inhibition of MIF/CD74 signaling pathway can promote the transformation of intracranial macrophages from M2 to M1 type after radiotherapy in brain metastases(BMs). It is reported that M2 macrophages are the main components of tumor immunosuppression microenvironment, and the surface marker, ARG-1, can decompose the Arginine which is essential in the growth and development of T cells. Therefore, this paper will focus on the mechanism of MIF regulating tumor infiltrating lymphocytes (TILs) by inducing macrophage phenotype transformation. Methods: MIF-Knockdown in Lewis cells were constructed by lentiviral shRNA interference technique. The expression levels of MIF in Lewis and iNOS (M1 type marker), Arg-1 (M2 type marker) in BV2 cells were detected by WB. The RNA expression levels of M1 and M2 tags were detected by qPCR. The expression of iNOS, Arg-1 and Iba-1 in lung cancer BMs model mice was detected by IF. The content of arginine in tumor tissue and clinical patient specimens were detected by Arginine kit. The proportion of TILs in vivo was measured by flow cytometry. BMs tumor growth in mice was observed by Small Animals Imaging Technology. Results: In animal experiments, WB、PCR and IF results showed that MIF knockdown (sh-MIF) combined with whole brain irradiation(IR) can raise the expression of iNOS, while the Arg-1 lessend, suggesting that downregulation of MIF can promote M1 phenotype and reduce M2 phenotype. Flow cytometry results showed that sh-MIF combined with IR increased the proportion of CD8+T/CD4+T cells . After clearance of macrophage, Flow cytometry showed no difference between the sh-MIF group and the control group (NC). Small Animals Imaging results also showed that the inhibition of tumor growth by sh-MIF was less significant than macrophages presence. It is indicated that down-regulation of MIF expression combined with irradiation promote T cell infiltration and inhibit tumor may be mediated by macrophages. Arginine kit results showed that the content of arginine increased after IR or sh-MIF, while it increased overall after macrophage clearance, but the difference between each groups was not significant, suggesting that IR or sh-MIF could increase the content of arginine by reducing M2-type macrophages. Flow cytometry and animals imaging results showed that the CD8+/CD4+TILs ratio was increased and tumor growth was inhibited after the addition of exogenous arginine. In clinical samples, the content of arginine in CSF decreased after radiotherapy, which suggests that arginine supplementation has the potential to improve the effect of radiotherapy. Conclusions: Inhibitory MIF expression can reduce the expression of Arg-1 from M2 type macrophages in BMs, thus raise the content of arginine, promote the infiltration of lymphocytes, improve the immune microenvironment, achieve radiotherapy sensitization finally.
Is recent FDA guidance on HRQoL clinical significance a barrier to clinician/patient treatment risk/benefit discussions: An example using EORTC scale endpoints in a randomized, phase 3 trial.
Authors: Podger Lauren , McManus Shauna , Iaconangelo Charles , Serrano Daniel
Published: June 2022

e21066

Background: Recent FDA guidance on clinical significance thresholds (CSTs) may adversely affect the evaluation of EORTC endpoints, thereby altering clinician/patient discussions about treatment (Tx) risk/benefit for emerging Tx. Specifically, FDA now rejects historic CSTs for EORTC measures (e.g., Osoba, 1998 10-point change). FDA’s guidance implies that EORTC function/symptom CSTs should be ±33.331; in addition, Tx arms must separate at the CST. Few, if any, EORTC domains are likely to achieve CSTs 3 times those of Osoba (1998). Holding health-related quality of life (HRQoL) endpoints to this standard may limit detection of clinically meaningful patient-centric Tx benefits & clinician/patients dialogue about HRQoL for emerging cancer Tx. The NCI-conducted Sunitinib trial data (NCT00693992), obtained through Project DataSphere, was used to generate revised deterioration thresholds for EORTC scales under an anchor-based meaningful change approach. This this Phase 3 trial met it’s primary PFS endpoint. Evidence from this research highlights the potential implications of the FDAs position on COA-based CSTs. Methods: The Sunitinib trial was a randomized, phase 3 study comparing the efficacy & safety of Sunitinib versus placebo as a maintenance therapy in non-progressing patients following chemotherapy in advanced non-small cell lung cancer. Symptoms & HRQoL were measured by EORTC LC13. The analysis population consisted of 107 patients in the HRQoL substudy completing the QLQ-C30 Global Health/QoL scale (GHS). The GHS was used to categorize patients into: no change (0 pt. change), deterioration (≤-1 pt. change) & improvement (≥1 pt. change). Deterioration thresholds were estimated as the mean LC13 scale change-scores & visualized with empirical cumulative distribution functions (eCDFs). Results: See Table. Within this population, interpretable mean deterioration CSTs were found Dyspnea, Diarrhea, and Nausea/Vomiting. At these CSTs, Tx arms separated in eCDFs except for Dyspnea. However, while Dyspnea & Diarrhea CSTs exceeded Osoba’s CSTs, none met the FDA criterion of + 33.33 points change. Conclusions: The LC13 scores had interpretable CSTs; evidence suggests FDA’s CST criterion may be unachievable for EORTC scales & may thereby affect HRQoL endpoints. This research was limited by the use of the GHS as an anchor variable rather than a PGIS. The main risk is that FDA’s CST criterion may limit the characterization of truly meaningful Tx benefits for patients & clinician communication with patients about HRQoL for emerging Tx. Clinical trial information: NCT00693992. [Table: see text]
Outcomes of cardiac tamponade in patients with lung cancer.
Authors: Aung Pyi Phyo , Park Kyeeun , Nge Htoo Myat
Published: June 2022

e21083

Background: Cardiac tamponade is a serious complication of pericardial effusion and life-threatening cardio-oncological emergency. The prevalence of malignant pericardial effusion varies between 1% and 20% in autopsy studies. Primary lung cancer is the most common cause of metastatic tumor involving the pericardium. The common triggers for pericardial effusion in patients with lung cancer include cancer itself, chemotherapy and radiation therapy. The outcomes of cardiac tamponade in patients with lung cancer remain to be elucidated. Methods: We conducted a retrospective analysis of the 2016 to 2018 Nationwide Inpatient Sample. Adult patients with lung cancer and cardiac tamponade (age ≥ 18) were selected using the ICD-10 diagnosis code. Discharge-level weight analysis was used to produce a national estimate. A univariate and multivariable hierarchical regression analysis was performed to calculate the odds ratio (OR). Results: During the study period, 1,207,580 patients were admitted due to lung cancer of which 7,105 (0.6%) developed cardiac tamponade. Patients with cardiac tamponade tended to be younger (63.2 SE 0.3 vs 69.1 SE 0.2), male (54.5% vs 51.2%) and large proportion of radiation treatment (0.9% vs 0.7%), and smaller proportion of diabetes (18.5% vs 24.2%), chronic kidney disease (4.5% vs 7.6%) and heart failure (15.9% vs 16.2%). After adjusting for age, sex, comorbidity burden and heart failure, cardiac tamponade increased the risk for in-hospital mortality (OR 2.1; 1.9 – 2.5; p < 0.001), major adverse cardiac events (OR 1.6; 1.3 – 2.1; p < 0.001) and acute respiratory failure (OR 2.3; 2.0 – 2.5; p < 0.001). Furthermore, cardiac tamponade was associated with longer length of stay (8.6 SE 0.2 vs 6.0 SE 0.01, p < 0.001) and higher total hospital cost ($118,708.0 SE $4,027.1 vs $65,369.8 SE $170.6). Conclusions: In conclusion, patients with lung cancer who developed cardiac tamponade were associated with poor outcomes including higher in-hospital mortality, MACE, acute respiratory failure, a longer length of stay by 2.6 days, and higher cost of hospitalization. Cardiac tamponade was more common in males and patients who received radiation therapy. Further studies are warranted to develop an optimal management guideline for this cardio-oncological emergency.
Bone metastasis reduces responsiveness to EGFR-TKIs in patients with EGFR-mutated advanced lung adenocarcinoma.
Authors: Jiang Kan , Lin Gen , Zheng Xinlong , Long Feng
Published: June 2022

e21085

Background: The response of epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) to bone metastasis site in patients with EGFR mutated lung adenocarcinoma remains to be determined. Methods: This is a retrospective analysis of the efficacy of EGFR-TKIs for lung adenocarcinoma patients with EGFR mutations, comparing patients with bone metastases (BM) and those with no bone metastases (NBM). BM patients need extra imaging to assess the efficacy of bone metastasis sites . Overall response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and progression patterns were evaluated. Results: Of the 502 patients, 175 were enrolled (BM 96, NBM 79) from January 2012 to December 2017. 125 patients had disease progression on January 31, 2018. The clinical characteristics of the two groups were not significantly difference. The median PFS was 11.0 months in NBM group and 7.0 months in BM group ( P= 0.013) . The median PFS in patients with multiple BM (≥ 4) was significantly lower than that in patients with oligometastases (1-3) and NBM (7.0 months vs 10.0 months vs 11.0 months, P = 0.003). Multivariate analysis confirmed that bone metastasis was an independently negative predictor of PFS for EGFR-TKIs ( P = 0.017). The ORR and DCR of NBM group were higher than those of BM group (70.9% vs 56.3%, P = 0.046 and 96.2% vs 85.4%, P= 0.017). Bone was one of the frequently progressive sites of EGFR-TKIs therapy, accounting for 52 of 125 (41.6%). The incidence of bone progression in NBM patients was significantly lower than that in BM patients(11.8% vs 62.2%, P < 0.001). Conclusions: Bone metastasis, especially multiple bone metastasis, reduces the response to EGFR-TKIs for lung adenocarcinoma with EGFR mutations. Bone metastasis monitoring should be a routine clinical practice for BM patients.
Obesity diabetes and dyslipidemia as determinants of immune checkpoint inhibitors response in non-small cell lung cancer.
Authors: Awidi Muhammad , Osataphan Soravis , Jan Yu Jen , Frankenberger Edward , Mariano Melissa , Stafford Katherine Ann , Kolnick Aleksandra , Ghazalah Hind , Patti Mary-Elizabeth , Gunturu Krishna Soujanya , Lam Prudence B.
Published: June 2022

e21104

Background: Immune checkpoint inhibitors (ICI) are standard of care in the treatment of non-small cell lung cancer (NSCLC). Predictive markers of response to ICI are being studied extensively. Obesity has been correlated with a better response to ICI in NSCLC and other types of cancer. This may in-part be related to high circulating leptin or impaired T-cell fatty acid oxidation within the tumor microenvironment. We aim to further explore the effects of obesity, dyslipidemia and other components of the metabolic syndrome such as diabetes on treatment outcomes on NSCLC patients receiving ICI. Methods: We conducted a retrospective cohort study in patients with NSCLC treated with pembrolizumab, nivolumab, durvalumab, cemiplimab or atezolizumab as monotherapy or combined with chemotherapy at Mount Auburn and Lahey Hospital between January 2016 to June 2021. Obesity was defined as body mass index (BMI) > 30 kg/m2, dyslipidemia and type 2 diabetes were defined by ICD-10 diagnosis codes. Overall survival was evaluated. Kaplan-Meier survival analysis and cox proportional hazards regression were used to assess correlation between overall survival and obesity, dyslipidemia, type 2 diabetes, metformin use and statin use. These were adjusted for age, biological sex, cancer stage, ECOG and smoking status. Patients with BMI < 18.5 were excluded. Results: We identified 408 patients with NSCLC who were treated with ICIs. Of these, 66.7% had adenocarcinoma, 29.1% had squamous and 4.2% had either adenosquamous, large cell or poorly differentiated carcinoma. Among these patients 23.3% were classified as obese, 55.6% had dyslipidemia and 23% had type 2 diabetes. Of these, 66% of patients received ICIs as monotherapy. Median survival was 840 days in obese patients compared to 483 days in non-obese patients (HR 0.66, CI 0.42-0.92, p = 0.014). Conversely, within this cohort, median survival in patients with dyslipidemia was 483 days when compared to 762 days in controls (HR 1.37, CI 1.07-1.81, p = 0.013). Overall survival was not significantly different between type 2 diabetes, metformin use or statin use. Conclusions: Our study shows a trend towards a better survival in obesity and poor survival associated with dyslipidemia. Obesity and dyslipidemia may be important markers of ICI response in patients with NSCLC regardless of treatment strategies. Further studies are needed to explore the molecular mediators within the metabolic syndrome that may provide a synergistic effect with immune checkpoint inhibitors.
Low infiltration of CD8+ FOXP3+ T cells associated with favorable clinical outcomes after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma patients.
Authors: Liu Kejun , Tan Quanquan , Peng Kai-Cheng , Chen Shiyuan , Su Junwei , Zhang Chanyuan , Chen Yuqing , Wu Ligang , Zheng Xue , Zheng Hongbo , Mao Beibei , Zhang Shihao , Jia Jun , Yang Jin-Ji
Published: June 2022

e21107

Background: As the standard first-line treatment for NSCLC patients with EGFR-sensitive mutation, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) were proved to be highly effective and less toxic compared to traditional chemotherapeutic regimens. But little is known about the correlation between tumor-infiltrating immune cells in the tumor microenvironment and clinical outcomes. This study was designed to investigate the association between tumor-infiltrating immune cells and the clinical outcome after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma (LUAD) patients. Methods: A total of 26 advanced LUAD patients with EGFR exon 21 mutation who received first-generation EGFR-TKIs as initial therapy between January 2017 and October 2019 were included in this study. All the patients were treated at Affiliated Dongguan Hospital, Southern Medical University, China. Patients who progressed within 12 months after first-line EGFR-TKIs therapy were defined as experiencing early progression (EP), and patients who progressed after 12 months or without progression were defined as experiencing late progression (LP). We analyzed immune markers in biopsy from these patients before treatment with EGFR-TKIs and examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD56/CD68/CD163/FOXP3/PD-L1 antibodies. Results: In this cohort, we observed that after first-line EGFR-TKIs therapy in EGFR exon 21 mutated LUAD patients, the density of CD8+ FOXP3+T cells infiltrated in tumor area of LP group was significantly lower than EP group (P = 0.038). However, the difference of the density of the other infiltrated immune cells including CD8+T cells, FOXP3+Treg cells, CD8+PD-L1+T cells, CD68+CD163+M2macrophages, etc., were not significant between LP group and EP group (P > 0.05). The “optimal” cutoff value for CD8+ FOXP3+T cells infiltrated in tumor area was 5.45 (n/mm2) using the survminer package in R software according to PFS. Kaplan-Meier analysis suggested that the density of CD8+ FOXP3+T tell infiltrated in tumor area contributed to risk factor for PFS (HR = 5.56, P = 0.00054). Taking 5.45 (n/mm2) as the cutoff value, the percent of LP patients in low density of CD8+ FOXP3+T cells infiltrated in tumor area group was close to being statistically significant higher than high density of CD8+ FOXP3+T cells group (47% vs. 0%. P = 0.058). Conclusions: This study indicated that the low density of CD8+FOXP3+ T cells infiltrated in tumor area was associated with favorable clinical outcome in EGFR exon 21 mutated LUAD patients treated with first-generation EGFR-TKIs at first-line.
Actionability of comprehensive genomic profiling (CGP) compared to single-gene and small panels in patients with advanced/metastatic non-small cell lung cancer (aNSCLC): A real-world study.
Authors: Bapat Bela , Sweetnam Connor , McBratney Ashleigh , Izano Monika A. , Schroeder Brock , Walters Sheetal , Chen William , Febbo Phillip G. , Berry Anna B.
Published: June 2022

e21114

Background: Biomarker testing for patients with aNSCLC includes testing for specific alterations in single genes, hotspot multigene panels, or CGP. Historically, CGP has been used following progression on early lines of systemic therapy to identify genomic alterations not captured by single-gene/hotspot testing, or to determine clinical trial(CT) eligibility. We compared the proportion of patients with genomic alterations for which FDA has approved targeted therapies(TT) (actionable alterations) identified through CGP vs. single-gene/small panel(“small panel”) testing in the real-world setting. Methods: In a retrospective study, patients initially diagnosed-with/progressed-to aNSCLC between 1/1/2015-12/31/2020, treated in the US community health setting, were categorized based on small panel or CGP testing. Patients were followed until the earliest of last contact/death/study-end on 9/30/2021. Testing between 30 days prior to initial NSCLC diagnosis and end of follow-up was used to determine actionability based on OncoKB levels, and eligibility for two basket-CTs(ASCO-TAPUR, NCI-MATCH). Results: Of 7,242 aNSCLC patients in this study, 5,154 (72%) received molecular testing (50% only small panel; 14% CGP; and 7% with an unknown size panel), 22% of patients remained untested and 7% were tested for only PD-L1. Among CGP-tested patients evaluated for tumor mutational burden (TMB), 18% were classified as TMB-High. > 75% of patients presented with advanced cancer at initial diagnosis, 51% were female, 50% were White, and median age was 68 years. Molecular testing rate increased from 9% to 20%(CGP) and 42% to 51%(small panel) between 2015–2020. The proportion of patients with ≥1 actionable biomarker was significantly higher with CGP than small panels (34%vs.15%; p < 0.001). Of tested patients. the proportion of CT eligible patients was also significantly greater for CGP than small panels (56%vs.4%; p < 0.001). The proportion of tested patients that received an FDA-approved TT or immunotherapy(IO) within 30 days of testing was higher in CGP cohort compared to small panel (9%vs.3%; p < 0.001). Conclusions: Although rates of CGP and small panel testing are increasing over time, overall molecular testing remains underutilized, and the proportion of patients who received TT/IO post-testing is low. Use of CGP is associated with higher identification of actionable biomarkers and patients receiving TT/IO, and CT eligibility.
Phase Ib/IIa study evaluating the safety and clinical activity of osimeritinib combined with anlotinib in EGFRm, treatment-naive advanced NSCLC patients (AUTOMAN).
Authors: Han Baohui , Yan Bo , Gu Aiqin , Chu Tianqing , Zhang Wei , Wang Huiming , Zhong Hua , Shi Chunlei , Zhang Xueyan
Published: June 2022

e21140

Background: Limited data is known regarding osimertinib plus anlotinib as first line treatment in EGFRm advanced NSCLC patients. Earlier we have reported that osimertinib in combination with anlotinib was well tolerated. Here we further present the efficacy and safety profile of the combined therapy. Methods: In this phase Ib/IIa, open-label study, treatment-naïve patients with an activating EGFR mutation, advanced or metastatic lung adenocarcinoma were eligible. Patients with stable CNS metastases were allowed to enroll. Patients were treated with anlotinib at dose of 8mg, 10mg and 12mg, all patients received osimertinib 80mg. Primary endpoint was objective response rate (ORR) by investigator using RECIST v1.1. Secondary endpoints include disease control rate (DCR), depth of response, median progression free survival, overall survival rate at 12 months and safety profile. Data cut-off: Nov. 23rd, 2021. Results: From November 2020 through June 2021, 25 patients were enrolled in the study and started treatment. Median age was 59 years (38-77years), 11 (44%) were female, 24 (96%) were ECOG PS 1. 24 (96%) patients were stage IV and 6 (24%) had CNS metastases. At DCO, 18 (72%) patients remained on treatment. Among 23 response evaluable patients, the overall ORR was 65.2% (95%CI 42.7,83.6), DCR was 95.7% (95%CI 78.0,99.9) and median depth of response was -40.7% (range, -70.6 to 49.7). Adverse events (AEs) were observed in 21 (84%) patients. The most common AEs were platelet count decreased (56.5%), thyroid-stimulating hormones increased (39.1%) and diarrhea (30.4%), no unexpected AEs occurred. Grade≥3 AEs and SAEs were experienced by 5 (20%) and two (8.0%) patients, respectively. Dose reduction occurred in 8 (32%) patients and all were related to anlotinib. There was no fatal AE event reported in this study. Conclusions: Osimertinib in combination with anlotinib as first-line treatment for naïve EGFRm advanced NSCLC patients showed encouraging antitumor activity with manageable safety profile. The study is ongoing and more results will be updated in the future. Clinical trial information: NCT04770688.