bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel parameter reflecting the interaction between CD8+ T cells and cancer-associated fibroblasts.
Authors: Zheng Xinlong , Xiao Weijin , Zeng Dongqiang , Peng Wenying , Long Feng , Jiang Kan , Bai Jing , Zheng Xiaobin , Miao Qian , Mok Tony S. K. , Lin Gen
Published: June 2022

e20536

Background: Accumulating evidence reveal complicated crosstalk amongst cancer-related fibroblasts (CAFs) and immune cells in tumor microenvironment (TME). However, interaction within CAFs and immune cells, and their relationship with clinical outcomes remain largely undetermined. Methods: Interaction between CAFs and immune cells was evaluated by the CD8+ T cells/CAFs ratio (CFR), denoting great difference within single-sample gene-set enrichment analysis (ssGSEA) scores. Association of CFR with survival was examined in TCGA/GEO lung cancer and TCGA pan-cancer cohorts. Correlation between CFR and immunotherapeutic efficacy was determined in five independent cohorts including melanoma, lung cancer and urothelial cancer. orrelations between CFR and objective response rates (ORR) reported in the literature following pembrolizumab monotherapy were calculated in 20 TCGA cancer cohorts. To translate the in silico findings into clinical use, immunohistochemically-detected CD8/α-SMA ratio was used as prognostic and immuno-therapeutically predictive biomarker in two lung cancer cohorts. Furthermore, correlation within CFR, TMB, PD-L1, and molecular/genomic characteristics of CFR subgroups was also evaluated. Results: A moderately positive correlation existed between CAFs and immune cells infiltration in various cancer types. Higher immune cells/CAFs ratios indicated favorable prognosis regardless of distinct immune cells. Higher CFR, an independent risk factor and complementary factor to PD-L1 and TMB, was strongly associated with improved survival in melanoma, lung cancer and urothelial cancer immunotherapy cohorts (log-rank test, P < 0.05). Moreover, CFR averages across cancer types provided a higher correlation coefficient with the ORR following pembrolizumab monotherapy when compared to PD-L1 expression and TMB, r = 0.65 versus 0.36 and 0.31, respectively. Finally, in the clinical setting, CD8/α-SMA ratio was validated as an independent prognostic and predictive biomarker of immunotherapy efficacy in non-small cell lung cancer (HR, 0.21, 95% CI, 0.12-0.37, P < 0.001; HR, 0.37; 95% CI, 0.19-0.75; P < 0.001). Low CFR was associated with upregulation of hypoxia, TGF-β signaling, epithelial-mesenchymal transition and angiogenesis. Conclusions: CFR was a promising biomarker in the prediction of immunotherapeutic efficacy across various malignancies.
Predictive value of the biomarker of peripheral blood of lung carcinoma patients responding to PD-1 treatment: A real-word study.
Authors: Su Shu , Lv Xin , Chen Fangjun , Qi Liang , Ren Wei , Yu Lixia , Yang Xiaoyan , Yan Tingting , Li Shanping , Wei Jia , Liu Baorui , Wang Lifeng
Published: June 2022

e20549

Background: The introduction of anti-PD-1 antibody has greatly improved the clinical outcomes of patients with lung cancer. Pre-treatment biomarkers in peripheral blood such as neutrophil-lymphocyte ratio, cytokine level, or clinical features such as BMI, lactate dehydrogenase, and prognostic nutrition index have been shown to be predictive markers treated by immunotherapy. Here we retrospectively analyzed the efficacy of PD-1 antibody-based therapy in patients with locally advanced un-operable or metastatic lung cancer patients and report an association between peripheral blood biomarkers with clinical response in these patients. Methods: We conducted a single-center study by including medical record data for lung cancer patients treated with PD-1 antibody first-line or posterior-line either as monotherapy or in combination with chemotherapy. The patients enrolled from March 2020 to December 2021 were treated with albumin paclitaxel or pemetrexed plus carboplatin、lobaplatin or cisplatin combined with PD-1 antibody. The clinical response were assessed after 2 circles of therapy. Peripheral blood were drawn prior to therapy and post therapy. Multiple Th1 and Th2 cytokines levels in the blood serum were evaluated and phenotype of T cells of peripheral blood were also analyzed. The association between cytokines levels, T cells phenotype and clinical response were investigated. Results: 61 patients with stage IIIA-IV lung cancer were enrolled in the study. 40 non-squamous NSCLC patients, 15 Squamous NSCLC patients and 6 SCLC patients received PD-1 antibody with chemotherapy. 40(65.6%)patients were first-line therapy and 21(34.4%) were posterior-line treatment. 42(68.9%) patients achieved partial response(PR), 7 (11.5%) patients were stable(SD) and 12(19.6%) patients had progressed disease (PD). The disease control rare(DCR) was 80.4%. In DCR group, higher levels of IFN-γ(P = 0.023,P < 0.05), TNF-α(P = 0.007,P < 0.05)and IL-5 (P = 0.002, P < 0.005) were detected in peripheral blood prior to the treatment comparing to PD group. Besides, the reduction of lymphocyte absolute counts in peripheral blood after PD-1 antibody-based therapy was associated with disease progression(P = 0.023,P < 0.05). Furthermore, higher CD8+CD27+T cells in peripheral blood before therapy was associated with worse clinical response(P = 0.019,P < 0.05) and higher ratio of CD4+CD45RO+CD62L+/ CD4+CD45RO+CD62L-seems to related with better clinical response, though without statistic difference due to limited sample size. Conclusions: These results suggest for the first time that serum IFN-γ, TNF-α and IL-5 levels could predict clinical efficacy with anti-PD-1 blockade therapy in lung cancer patients. Other biomarkers include lymphocyte counts or phenotype may also have predictive value. Large prospective studies need to further clarify the value of these biomarkers.
Immune-related gene set prediction model contributes to the evaluation of prognosis in lung adenocarcinoma patients.
Authors: Zhang Liwen , Liu Yang , Lu Leilei , You Dong
Published: June 2022

e20550

Background: In recent years, rapid progress of immunotherapy (I/O therapy) development brings new hope to LUAD patients. The subtypes and/or quantality of TIL-IC cells were closely related to the prognosis and to the I/O therapy’s response in patients with a variety of solid tumors. In order to stratify high-risk and low-risk LUAD patients, we herein established a prognostic prediction model based on the expression of large-scale immune infiltration genes in LUAD patients. Methods: RNA sequencing data and relevant clinical information of LUAD patients ( n = 501) were obtained from the TCGA cohort. Stromal and immune scores were calculated using ESTIMATE algorithm. The differentially expressed immune-related genes (IRGs) were identified using the “DESeq2” package in R platform. Patients were randomly divided into training set and validation set with a ratio of 8:2. Univariate and Lasso Cox regression analyses were performed to identify overall survival (OS)-related IRGs. Next, stepwise multivariate Cox regression analysis was carried out to establish an optimal risk model of immune-related prognostic gene sets in the training cohort. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were used to examine the predictive performance of the model in the validation cohort. Results: A total of 643 IRGs were identified in these LUAD patients, of which 140 IRGs were significantly associated with OS by univariate Cox regression analysis (P < 0.05). Lasso Cox and stepwise multivariate Cox regression analysis identified IRGs as independent prognostic factors, including C20orf197, SPRR1B, CHRNA5, SLC14A2, RP11-284F21.9, IGLV9-49, IGF2BP1, and C5orf64. The final immune-related gene set model was as follow: risk score = −0.13 * expression level of C20orf197 + 0.074 * expression level of SPRR1B + 0.23 * expression level of CHRNA5 − 0.11 * expression level of SLC14A2 + 0.11 * expression level of RP11-284F21.9 - 0.076 * expression level of IGLV9-49 + 0.048 * expression level of IGF2BP1 - 0.42 * expression level of C5orf64. Patients were divided into high-risk group and low-risk group with the median risk score. Kaplan–Meier survival analysis showed that the high-risk group had a significantly poor prognosis, when compared to the low-risk group in the training set ( HR 2.77, 95%CI; [1.96 - 3.93], P < 0.0001). The ROC curve analysis equally revealed that the area under curves for OS in the first and fifth year were 0.82 and 0.81, respectively, in the validation cohort. Taken together, the eight IRGs risk prediction model could effectively stratify LUAD patients according to prognosis. Conclusions: We constructed a prognostic prediction model for LUAD patients, which consisted of a robust signature of eight IRGs. This model could effectively stratify high-risk and low-risk LUAD patients and help to customize personalized treatment plans.
Influence of ancestry in racial disparities of squamous cell lung cancer.
Authors: Choi David , Lee Michelle Jeung-Eun , Jain Sanjay R.
Published: June 2022

e20554

Background: Significant progress has been made in the screening, diagnosis, and treatment of squamous cell carcinomas of the lung (LUSC). Despite the advancements, African American populations continue to experience worse disease burden and poorer overall survival, even after controlling for patient and tumor characteristics. While the interplay of various social determinants of health is well known to contribute to racial disparities in cancers, the molecular basis of racial disparity is less understood. Given the diversity of the US population that comprise of genetically admixed groups, understanding the role of ancestry and its influence on biology of cancers that drive incidence and prognosis is paramount to reducing racial disparities. Therefore, in this study, we aimed to investigate the influence of African (AFR) ancestry in genetic mutations of LUSC. Methods: We utilized The Cancer Genome Ancestry Atlas (TCGAA) to obtain data on the genetic ancestry and ancestral composition of 504 LUSC patients. The dataset contained 459 self-reported whites, 32 blacks, and 11 Asians. The percentage of each patient’s ancestral composition (European, AFR, Asian, and Native American) was revealed via the LAMP technique. The dominant ancestry was defined as those with genetic composition of ≥50% from one of four ancestral backgrounds. Genetic alteration profiles and clinical data of patients were obtained from LUSC TCGA PanCancer Atlas through GDC data portal. Of those with AFR dominant ancestry, we analyzed the differences in the gene mutation frequency based upon the proportion of AFR ancestry. Results: Ancestry analysis uncovered 30 AFR ancestry dominant cases with a mean AFR composition of 78.4%. We found 14 subjects with > 80% AFR ancestry and 16 subjects with 50-80% AFR ancestry. Two patients from the > 80% were excluded from the mutational analyses due to absence of genetic profiles in the data portal. TP53 was the most frequently mutated gene with a rate of 91.7% and 87.5% in > 80% and 50-80% AFR groups, respectively. Evaluation of the classic genetic mutations that drive disease pathology in LUSC (EGFR, ALK, PIK3CA, NRAS, KRAS) revealed 25% of > 80% AFR ancestry subjects carried mutations in at least one of these genes compared to 6.3% in the 50-80% AFR ancestry subjects. Also, a trend towards worse overall survival (OS) was seen in those with greater proportion of AFR ancestry (median OS of 27.2 months in > 80% group vs 43.9 months in 50-80% group). Conclusions: Despite the limited sample size, our study highlights substantial heterogeneity in tumor biology even within those of AFR ancestry and that genetic ancestry may impact tumor and host biology that contribute to disparities. Moving forward, engagement of the African American community into clinical trials and genomic studies are needed to explore ancestral influence on tumorigenesis, and to facilitate discovery of new actionable targets to help eradicate racial disparities in lung cancer.
Evolutions in the management of non-small cell lung cancer in the 21st century: A bibliometric analysis from the 100 most impactful articles in the field.
Authors: Chen Siyuan , Hu Yi , Liu Zhefeng
Published: June 2022

e20562

Background: The study was designed to explore the evolution of non-small cell lung cancer (NSCLC) management in the 21st century. Methods: The top 100 most-cited papers on NSCLC treatment were retrieved from the Web of Science Core Collection database. R and VOSviewer were used to extract bibliographic information, including the year of publication, countries/regions, institutions, authors, journals, keywords, impact factor, and total citations. The topic and type of papers were checked independently by authors. Bibliometric analysis was conducted and visualized with R, CiteSpace, Excel and VOSviewer to identify output dynamics, research forces, topics, hotspots, and frontiers in the field. Results: The average citation of each retrieved top 100 most-cited NSCLC management papers in 21st century was 1,725 (range: 615-7,340). Fifty-seven corresponding authors were from the United States. This country contributed the most papers (n = 76), followed by Germany (n = 34), France (n = 33), and South Korea (n = 32). The top contributors were Paz-Ares L. (n = 12) and Reck M. (n = 12). The Memorial Sloan Kettering Cancer Center published the largest number of papers (n = 20). There were two significant citation paths, indicating publications in medicine/medical/clinical journals primarily cited journals in molecular/biology/genetics fields, partly cited health/nursing/medicine fields. Top-cited papers mainly came from the New England Journal of Medicine (n = 33, citations =80427), followed closely by the Journal of Clinical Oncology (n = 28, citations = 32408). “Chemotherapy” (n = 36) was the keyword with the greatest frequency of co-occurrence. “Open-label” was the keyword with the strongest burst strength (= 4.01), followed by “nivolumab” (= 3.85), “blockade” (= 2.86), and “efficacy” (= 2.85). Conclusions: The United States as a nation and the Memorial Sloan Kettering Cancer Center as an institute contributed the most papers on this topic in 21st century. Individual authors, such as Paz-Ares L. and Reck M., have developed extensive international collaborations. The New England Journal of Medicine is the most eye-catching journal. Molecular, biological, and genetic research plays important role in this field. Hotspots of NSCLC management have almost undergone an evolution from chemotherapy and radiotherapy to targeted therapy to immunotherapy. Immunotherapy and combination therapy are research frontiers. To our knowledge, the study is the first bibliometric assessment on the evolution of NSCLC treatment from the 21st century.
Treatment patterns and prognosis in inoperable stage III NSCLC after concurrent chemoradiotherapy with or without immune checkpoint inhibition: Historical overview.
Authors: Flörsch Benedikt , Taugner Julian , Käsmann Lukas , Kenndoff Saskia , Guggenberger Julian , Tufman Amanda , Reinmuth Niels , Duell Thomas , Belka Claus , Eze Chukwuka , Manapov Farkhad
Published: June 2022

e20578

Background: To investigate the impact of treatment patterns in inoperable stage III NSCLC following concurrent chemoradiotherapy with or without immune checkpoint inhibition (cCRT±ICI). Methods: Patients were stratified by treatment year and divided into three subgroups: A (2011–2014), B (2015–2017) and C (2018–2020). Patient- and treatment-related characteristics regarding to PFS and OS were analyzed. Survival parameters were calculated from the last day of thoracic radiotherapy (TRT). Results: 136 consecutive enrolled patients were included. Median follow-up (FU) was 35.7 months; median age was 66.9 years. All patients completed TRT to a total dose ≥60.0 Gy; Median radiotherapy planning target volume (PTV) was 700 cc (range: 172.5–2293.2). Thirty-six (26%) patients received ICI. Median PFS in subgroups A, B and C was 8.0, 8.2 and 26.3 months (p = 0.007). Median OS was 19.9 months, 23.4 months and not reached in subgroups A, B and C (p < 0.05). In subgroup C, median PFS was 14.2 vs. 26.3 months in patients treated with and without ICI. On multivariate analysis for the entire cohort, PTV > 700cc was a negative prognosticator of PFS (HR: 1.522; p = 0.042) and OS (HR: 2.671; p = 0.001); ICI was a predictor of improved PFS (HR: 0.571; p = 0.071) and longer OS (HR: 0.401; p = 0.062). In the Non-ICI cohort, multivariate analyses revealed PTV > 700cc (HR: 1.630; p = 0.047) and SUVmax > 13.75 (HR: 1.859; p = 0.012) were predictors of reduced PFS; PTV > 700cc (HR: 1.958; p = 0.017), SUVmax > 13.75 (HR: 2.405; p = 0.002) and total lung V20 > 30 (HR: 3.357; p < 0.05) were predictors of longer OS. Conclusions: Regardless of ICI, patients receiving multimodal therapy after 2018 demonstrated improved survival compared to patients treated earlier. Both PTV > 700cc and ICI were predictive for PFS and OS in the entire cohort.
Propensity-matched analysis of concurrent/sequential versus sequential immune checkpoint inhibition in inoperable stage III NSCLC patients treated with chemoradiotherapy.
Authors: Käsmann Lukas , Taugner Julian , Eze Chukwuka , Guggenberger Julian , Kenndoff Saskia , Flörsch Benedikt , Tufman Amanda , Reinmuth Niels , Belka Claus , Manapov Farkhad
Published: June 2022

e20589

Background: Durvalumab maintenance treatment after completion of concurrent chemoradiotherapy (CRT) in patients with inoperable stage III NSCLC is the international standard. In this propensity-matched analysis, we prospectively evaluated the role of concurrent/sequential versus sequential immune checkpoint inhibition. Methods: Between 10/1/2016 and 12/31/2020, 39 NSCLC patients in stage IIIA/B/C were analyzed. 11 (28%) patients received concurrent/sequential PD-1 inhibition (nivolumab) and 28 (72%) patients received sequential PD-L1 inhibition (durvalumab) up to one year after the end of CRT. A 1:2 propensity score matching (PSM) using age, gender, T category and histology was performed to reduce selection bias and address for confounding factors (n = 33, 11 patients receiving nivolumab (SIM-cohort), 22 patients receiving durvalumab (SEQ-cohort). Treatment-related adverse events were assessed weekly during the CRT and at 6 weeks, 3,6,9, and 12 months after the end of CRT. Results: The median follow-up time of the overall cohort, SIM-I cohort, and SEQ-I cohort was 27.6, 33.3, and 26.5 months after CRT, respectively. For the entire cohort median survival (OS) was not reached; median progression-free survival (PFS) achieved 26.3 months. In the SIM-cohort, median PFS was 22.8 months and median OS was not reached. In the SEQ-cohort, neither median PFS nor OS was reached. PFS at 12/24 months was 82/44% in the SIM-cohort and 57/57% in the SEQ-cohort (p = 0.714), respectively. In the SIM-cohort, 18.2% of patients showed grade III pneumonitis; in the SEQ-cohort 13.6% (p = 0.735). Grade 4 and 5 toxicities were not observed. Conclusions: Both concurrent/sequential and sequential immune checkpoint inhibition shows a favorable side effect profile and promising survival in terated patients. Concurrent immunotherapy did not result in an improved outcome (PFS, OS) compared to sequential approach. However, our propensity-matched analysis found that concurrent immunotherapy was associated with a non-significant moderate increase in grade III pneumonitis.
Molecular parameters impacting the success rate of a lung cancer PDX model.
Authors: Li Ziyi , Hubert Shawna Marie , Zhang Ran , Song Xingzhi , Karpinets Tatiana , Weissferdt Annikka , Little Latasha , Mohammad Mohammad , Gumbs Curtis , Negrao Marcelo Vailati , Zhang Jianhua , Pataer Apar , Swisher Stephen , Vaporciyan Ara A. , Roth Jack A. , Heymach John , Sepesi Boris , Gibbons Don Lynn , Fang Bingliang , Zhang Jianjun
Published: June 2022

e20592

Background: Patient-derived xenograft (PDX) models can provide renewable cancer tissue resources, are being increasingly utilized for the molecular characterizations of cancers and preclinical studies on drug activities, and have the potential to advance biomarker identification. Previous research has demonstrated that PDX tumors preserve the histologic and morphologic characteristics and gene expression and mutation patterns of primary tumors, and correlate to patient survival. Tumor histological subtypes and differentiation grades are known to contribute to the success of PDX intake, but little is known about how molecular features associate with the success of PDX engraftment or whether PDX preserves subclonal architecture of primary tumors. Methods: To fill this void, we analyzed 252 primary tumor samples from the SPORE/ICON project at MD Anderson Cancer Center that were used for generating PDXs and had comprehensive genomic, transcriptomic, and immune profiling data available to evaluate the parameters impacting the intake success of lung cancer PDXs. In order to establish the impact of molecular features on PDX intake success we also assessed the fidelity of PDX in representing the molecular features of this cohort of primary tumors. Results: Only 36% of the primary tumors in this study successfully generated a PDX, with Squamous Cell Carcinoma PDX demonstrating an intake rate of 67% and Adenocarcinoma PDX demonstrating an intake rate of 21%. Genomic architecture derived from whole exome sequencing showed not only 43% (38-48%) of mutations shared, but also similar clonal architecture between primary tumors and PDX. Higher copy number aberration burden, high tumor purity and low immune infiltration in primary tumors were found to be associated with successful intake of PDX. Transcriptomics revealed 6,103 genes differentially expressed between primary tumors with successful PDX intake versus those which were unsuccessful. Pathway analysis of these genes indicated that inhibition of cell proliferation, signaling, and migration as well as DNA replication, recombination and repair were associated with PDX intake failure regardless of histology. Conclusions: These findings indicate that PDX intake success is regulated by molecular features and multiomic evaluation of lung cancer primary tumors can be used as a marker for determining which samples to use for PDX model generation.
Malignant pleural mesothelioma in Brazil: An analysis of public databases between 2000 and 2017.
Authors: Costa Guilherme Jorge , Favato Barcelos Isabella , Taveira Gabriela Monte Tenorio , De Marchi Pedro , Montella Tatiane Caldas , Thuler Luiz Claudio Santos , Ferreira Carlos G. M.
Published: June 2022

e20597

Background: malignant mesothelioma is a rare tumor with about 31,000 new cases diagnosed annually worldwide. Malignant pleural mesothelioma (MPM) is recognized as an occupational cancer, and past exposure to asbestos represents its main risk factor. Little is known about the epidemiological and clinicopathological profile in developing countries. Methods: this is a cross-sectional study that analyzed the incidence and mortality rates and the clinicopathological profile of MPM in Brazil, from Brazilian public databases: Population-Based Cancer Registries (PBCRs - for incidence), Hospital Cancer Registry (HCR - for clinicopathological profile) and National Mortality Information System (SIM - for mortality). Results: In thirty PBCRs, from 23 of 26 states (average covered of 17% of the Brazilian population), 310 new MPM cases were reported, from 2000 to 2015. The mean age at diagnosis was 62.8 years. Incidence crude rate reached its maximum of 8.96 per 1.000.000 men in the 75-79 age group, and of 3.34 per 1.000.000 women in the 80+ age group. The clinicopathological profile registered in the HCR, from 2000 to 2017, showed a majority of men (70.2%), smoker/former smoker (62.7%) and alcohol users (58.2%). Regarding histology, 59% were described as mesothelioma, NOS (not otherwise specified), 30.6% as epithelioid, 7% as fibrous mesothelioma and 3.4% as biphasic. 54.4% were stage IV at diagnosis, 27.5% stage III and 18.1% stages I or II. A quarter of the patients received neither local nor systemic treatment. From 2000 to 2017 512 deaths related to MPM were registered in SIM database, an average of 28 deaths per year (mean age of death 63.7 years). The age-adjusted mortality rate remained statistically stable over all analyzed period. Conclusions: According to our study, most MPM patients in Brazil are elderly men, stage IV at diagnosis, with mesothelioma NOS. A considerable percentage do not receive any specific treatment for the disesase. Understanding the scenario of MPM in Brazil is important to design prevention, diagnosis and treatment strategies.
Population kinetics assessment of limited small cell lung cancer (L-SCLC).
Authors: Stewart David J.
Published: June 2022

e20602

Background: For most advanced malignancies, progression free survival (PFS) and overall survival (OS) curves approximate first order kinetics.1 PFS and OS half-lives can be calculated by curve exponential decay nonlinear regression analysis (EDNLRA). Curve characteristics vary significantly with treatment and malignancy type.1 On log-linear plots, PFS curves are significantly more likely to be convex for extensive SCLC than for other malignancies, with late acceleration of tumor growth after completion of 1st line therapy.1,2 Here we assess L-SCLC by EDNLRA. Methods: We used https://apps.automeris.io/wpd/ to digitize PFS curves from L-SCLC studies published from 1990 to 2021. We analyzed curves for study arms having > 50 patients. We used GraphPad Prism 7 for 1 and 2 phase decay EDNLRA as previously described.1 We also constructed log-linear plots. Results: We analyzed 55 L-SCLC PFS curves from 34 published trials. Median PFS half-life was 15 months for studies published 1990 to 2010 vs 19.5 months for 2011 to 2021 (P = 0.003). This improvement over time might be explained in part by stage migration (eg, with PET scanning). Of 55 log-linear plots, 53 (96%) had an inflection to the right. The curve inflection indicates there are 2 distinct subpopulations: namely progressing patients vs cured patients. Of the 55 curves, 46 fit 2 phase decay EDNLRA models. Across these 46 2-phase decay curves, EDNLRA calculations indicated that the progressing subgroup comprised 86% of the total population and had a PFS half-life of 10.5 months. The cured subgroup accounted for the other 14% of the population, with a PFS half-life greater than 15 years. The proportion cured increased from a median of 12% for 1990-2010 studies to 22% for 2011-2021 studies (p = 0.01). Stage migration might again explain this difference. For patients who are progression-free at any time point, one can also use these EDNLRA data to calculate the proportion who would eventually progress in the future. Of those still progression free at 12, 24, 36, 48, 60 and 120 months, respectively, the proportion that would eventually progress would be 73%, 56%, 36%, 20%, 10%, and 0.2%. As with extensive SCLC, all 55 L-SCLC PFS log-linear curves displayed early convexity, with a downward inflection after a period of relative stability. This downward inflection occurred at a median of 4.4 months, in keeping with acceleration of progression after completion of planned systemic therapy. Conclusions: Population kinetic assessments permit calculation of probability of eventual progression for L-SCLC patients who remain progression-free at different time points after initiation of therapy. Of L-SCLC patients who remain progression-free at 60 months, approximately 10% are nevertheless destined to eventually relapse. References: Stewart DJ et al. Crit Rev Oncol Hematol. 2020;153:103039. Stewart DJ et al. Proc American Soc Clin Oncol 2020. Abstract # e21101.
Outcomes of anti-PD-L1 blockades plus etoposide and platinum (EP) as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC) with brain metastasis (BM).
Authors: Tian Yaru , Ma Ji , Zhu Hui , Yu Jinming
Published: June 2022

e20607

Background: Anti-PD-L1 blockades plus EP is the standard first-line therapy for ES-SCLC from IMpower133 and CASPIAN. Subgroup analyses of the two trials indicated that patients (pts) without BMs could benefit from atezolizumab and durvalumab, while those with BMs could not. The aim of the retrospective study is to further investigate the clinical efficacy of the first-line anti-PD-L1 blockades plus EP for ES-SCLC with BMs. Methods: Between 2017 and 2021, pts with newly diagnosed ES-SCLC and baseline BM confirmed by CT or MRI at Shandong Cancer Hospital and Institute were enrolled. According to whether combined with anti-PD-L1 blockades (atezolizumab or durvalumab) or not, pts were assigned to anti-PD-L1+EP group and EP group, respectively. Response was assessed by RECIST 1.1 and survival analyses were conducted using Kaplan-Meier and log-rank tests. Results: A total of 56 pts were enrolled in the current study. Eighteen pts were allocated to anti-PD-L1+EP group and 38 were allocated to EP group. The median follow-up time was 18.17 months. Overall response rate (ORR) was 72.22% vs 78.95% ( P= 0.83) and disease control rate (DCR) was 100% vs 97.37% in the two groups, respectively. And for BMs, the intracranial ORR and DCR were 50.00% vs 68.42% ( P= 0.18) and 72.22% vs 78.95% ( P= 0.83), respectively. Progression-free survival (PFS) was numerically prolonged with anti-PD-L1 blockades, but the significance was not achieved (median: 9.4m vs 7.3m, P = 0.146, HR = 0.63 (95%CI, 0.35-1.13)). The intracranial PFS was not improved, neither (median: 8.2m vs 7.9m, P= 0. 943, HR = 1.02 (0.53-2.00)). However, overall survival was significantly prolonged with anti-PD-L1 blockades (median: NR vs 15.53m, P = 0.012, HR = 0.20 (0.09-0.46)). Conclusions: Collectively, we found that the addition of the first-line anti-PD-L1 blockades to EP brought about a significant survival benefit compared with EP alone for ES-SCLC with BMs.
First-in-human study of pelcitoclax (APG-1252) in combination with paclitaxel in patients (pts) with relapsed/refractory small-cell lung cancer (R/R SCLC).
Authors: Qin Angel , Kalemkerian Gregory Peter , Mohindra Nisha Anjali , Patel Jyoti D. , Karapetis Christos Stelios , Carlisle Jennifer W , Sands Jacob , Spira Alexander I. , Gao Bo , Amin Harshad , Paudyal Bishnuhari , Frank Genevieve , Sun Xuemei , Xu Yang , Wang Cunlin , Fu Tommy , Winkler Robert , Liang Zhiyan , Yang Dajun , Zhai Yifan
Published: June 2022

e20612

Background: Targeting BCL-2/BCL-xL proteins is considered an important approach for anticancer drug development. Investigational pelcitoclax (APG-1252) as a single agent is a novel BCL-2/BCL-xL dual inhibitor, which has demonstrated synergistic antitumor activity in combination with chemotherapy preclinically through targeting both BCL-xL and MCL-1 pathways. The phase I study of pelcitoclax suggested promising antitumor activity and a favorable safety profile. Methods: The primary aim of this study was to determine the safety and preliminary efficacy of pelcitoclax combined with paclitaxel in patients with R/R SCLC. Patients received pelcitoclax 160 mg or 240 mg IV infusion on Days 1, 8, and 15 plus paclitaxel 80 mg/m2 on Days 1 and 8 of a 21-day cycle. The primary endpoint of phase Ib was to characterize the safety and tolerability of the combination. The primary endpoint of phase 2 was the objective response rate (ORR) of pelcitoclax at the RP2D plus paclitaxel using RECIST v1.1. Results: On December 20, 2021, 28 pts (median age, 63 [range, 37-77] years) were enrolled. The median (range) duration of treatment was 84 (7-259) days. The RP2D of pelcitoclax was determined to be 240 mg. A total of 26 pts experienced any grade treatment-related adverse events (TRAEs), including anemia (32.1%); ALT or AST elevation (28.6% each); neutropenia (25%); fatigue, leukopenia, or thrombocytopenia (21.4% each); peripheral neuropathy, nausea, or alopecia (17.9% each); peripheral sensory neuropathy or decreased appetite (14.3% each); and lymphopenia, hyponatremia, or dizziness (10.7% each). A total of 15 pts had at least one ≥ grade 3-4 TRAE, and 11 (39.3%) had serious AEs. No dose-limiting toxicity was reported. A total of 5 of 20 evaluable pts (4 pts in the 240 mg cohort and 1 in the 160 mg cohort) reported PR (ORR 25%), with a median response duration of 83 days. The pharmacokinetics profile showed that pelcitoclax systemic exposure increased between 160 and 240 mg, with an average terminal half-life of 3.7 to 7.4 hours and without any drug-drug interaction. Conclusions: Pelcitoclax was well tolerated at doses of up to 240 mg/week. Treatment with pelcitoclax 240 mg and paclitaxel 80 mg/m2 demonstrated modest antitumor activity in pts with R/R SCLC. Further clinical exploration, preferably in selected patient populations with relevant biomarkers, is warranted to fully elucidate the clinical activity of pelcitoclax. Clinical trial information: NCT04210037.
Peripheral blood T-cell receptor repertoire profiling of advanced non-small cell lung cancer patients receiving PD-1/PD-L1 treatment.
Authors: Tseng Diane , Chiou Shin-Heng , Nair Viswam , Martins Renato G. , Santana-Davila Rafael , Lee Sylvia , Eaton Keith D. , Baik Christina S , Houghton A. McGarry
Published: June 2022

e21004

Background: Whether peripheral blood T cell receptor (TCR) repertoire profiling can serve as a biomarker to predict clinical benefit from anti-PD-1/PD-L1 checkpoint immunotherapy is not well understood. Moreover, it is not known which methods for TCR repertoire analysis are most clinically meaningful. To address this, we have performed TCR repertoire analysis of patients with advanced/metastatic non-small cell lung cancer (NSCLC) receiving PD-1/PD-L1 treatment. Methods: We analyzed 29 patients receiving PD-1/PD-L1 monotherapy or combination therapy in any line of treatment, excluding patients with EGFR mutations or Alk alterations. Genomic DNA was extracted from peripheral blood examples, and CDR3 regions of the rearranged TCR beta genes were amplified and sequenced using the immunoSEQ platform (Adaptive Biotechnologies, Seattle, WA). Libraries were sequenced using Illumina HiSeq 2500. TCR clonality, diversity, evenness, and the percentage of high-frequency clones (> 0.1% of the repertoire) were calculated at pre-treatment and post-treatment (1 – 3 months) timepoints. Morisita’s overlap index was calculated for 25 paired pre- and post-treatment samples. Metrics were compared in patients with and without durable clinical response at 6 months using the Mann-Whitney test. Results: There were no statistically significant differences in TCR repertoire clonality, diversity, evenness, or high-frequency clones between patients with and without durable clinical benefit, either at pre-treatment or post-treatment time points (p > 0.05). Conclusions: TCR repertoire metrics including clonality, diversity, evenness, percentage of high-frequency clones, and Morisita’s overlap index do not predict immunotherapy responses in this cohort of advanced/metastatic NSCLC patients receiving PD-1/PD-L1 monotherapy or combination therapy. Limitations of this study include sample size and heterogeneity of the patient cohort. This highlights the need for advanced TCR repertoire metrics, for example, considering shared TCR specificities and clonal identity. In ongoing work, we are defining TCR specificity groups and TCR clones in NSCLC as biomarkers of immunotherapy responsiveness.
Identification and validation for biological characteristics and prognosis of tumor microenvironment subtypes in patients with lung adenocarcinoma.
Authors: Yao Yi , Zhou Jin , Zhang Haohan , Wu Jie , Zhao Yaqi , Liu Zheming , Xu Bin , Song Qibin
Published: June 2022

e21006

Background: Immunotherapy has brought a great revolution to treatment of patients with lung adenocarcinoma (LUAD). However, the infiltrating cells in the tumor microenvironment (TME) could influence immunotherapy outcomes. This study aimed to investigate the TME subtypes based on 50 immune, stromal, and stem cell types in TME. Methods: The xCell algorithm was used to infer the enrichment scores in TME. We performed the k-mean consensus clustering to identify TME subtypes for LUAD patients. The ESTIMATE, ABSOLUTE, LUMP, and CPE algorithms were used to compare tumor purity and immune infiltration of TME subtypes. The genomic mutations and copy number variants were also calculated by “maftools” R package and GISTIC 2.0. We established a neural network model, based on the TCGA dataset and verified it in GEO datasets by the Kaplan-Meier curve and Cox regression analyses, to prove the stability of TME subtypes. Using prophetic algorithm, ridge regression model was established to predict the sensitivity of drugs in all datasets. In addition, TIDE score and submap analyses were used to speculate the potential response of patients in immunotherapy. Results: In our study, 50 types of cells, including immune (including lymphocyte and myeloid cells), stem, and stromal cells in TME, were included for analysis. Based on cell scores, 504 LUAD patients were divided into four different subtypes (C1, C2, C3 and C4). In univariable Cox regression, the hazard ratio (HR) value of C2 vs. C1 was 2.066 (95%CI: 1.313 - 3.250), the HR value of C3 vs. C1 was 1.821 (95%CI: 1.067- 3.108), and that of C4 vs. C1 was 2.313 (95%CI: 1.461 - 3.662). Then, a neural network model was established (the area under the curves in the testing cohort: 0.911) to validate our conclusions in external sets and similar results were observed. Through pseudotime trajectory, we discovered there were potential connections among clusters from C1 to C4. The C2 and C3 were the intermediate forms of C1 and C4, and thus, the survival, immunological, and metabolic status of C2 and C3 may be intermediate between C1 and C4. By comparing the cell infiltration and immune gene expression of the four clusters, we found that C1 and C3 may have a similar immune phenotype which was opposed to that of C2 and C4. Meanwhile, the enrichment scores of cell proliferation-related pathways were progressively increased in the four clusters, which may be related to survival outcomes of them. We noticed that C1 harbored a unique EGFR mutation compared to other clusters, which may be sensitive to erlotinib. Patients of C4 had lower TIDE scores, which indicated that these patients may get higher benefits from immunotherapy. Conclusions: In conclusion, we identified four TME subtypes with distinct clinical outcomes and biological features, including tumor immunity, TME status, tumor mutations, and responses to chemotherapy and immunotherapy.
Use of next-generation sequencing (NGS) to study the impact of demographic variables on prevalence of driver mutations in non-small cell lung cancer (NSCLC).
Authors: Choi WonSeok William , Haroun Faysal
Published: June 2022

e21030

Background: The management of NSCLC is rapidly evolving with the discovery of new driver mutations and the introduction of targeted therapies (TT). The list of targets with FDA-approved TT is estimated to cover over half of the cases of non-squamous NSCLC. The prevalence of driver mutations varies significantly depending on several demographic variables such as smoking status, race, and sex. This abstract presents data obtained from a unique, racially diverse cohort of patients in the Washington, DC metropolitan area. Methods: Retrospective review of circulating tumor DNA NGS data from 2 commercial testing companies (Guardant and Tempus) and demographic data from our health records on 66 patients with NSCLC treated at the George Washington University Medical Faculty Associates between October 2017 and November 2021 was performed. Demographic information including age, sex, race, and smoking history, as well as histology, stage at diagnosis, and driver mutations were collected. Only patients with non-squamous NSCLC and identifiable mutations were included. Results: Mean age was 67. Most patients in this cohort were female (56.1%, male 43.9%), African-American (62.1%, Caucasian 25.8%, African 9.1%, Asian 3.0%), had smoking history (former smoker 48.5%, current smoker 25.8%, never smoker 25.8%), had adenocarcinoma (78.8%, other NSCLC (not squamous cell carcinoma or adenocarcinoma) 21.2%) with advanced stage (stage 4 62.1%, stage 3 28.8%, stage 1 3.0%, unknown 6.1%). Mutations are listed as follows: KRAS 28.8% (G12C accounted for 58% of all KRAS mutations), EGFR 19.7% (exons 19 and 21 mutations such as del19 and L858R accounted for 69%), MET 9.1% (MET amplification made up 83%), Her2 3.0% (2/66), ALK 3.0% (2/66), RET 1.5% (1/66), non-targetable mutations 34.8% (23/66). A table at the end of this abstract shows the frequency of three most prevalent mutations in this cohort distinguished by race, sex, and smoking status. Conclusions: KRAS was the most prevalent driver mutation in this cohort, followed by EGFR and MET. In concordance with the existing literature, EGFR was more prevalent in non-smokers and females, while KRAS was more common among smokers. Interestingly, a larger percentage of Africans had EGFR mutations compared to African-Americans. Given the small sample size, however, a larger scale study is needed to investigate this further. These findings show that demographic factors influence the prevalence of driver mutations which can have therapeutic implications in patients with NSCLC.[Table: see text]
Genetic mutations-based criteria to distinguish multiple primary lung cancers from intrapulmonary metastasis in patients with lung tumors.
Authors: Li Zhenhua , Lv Huilai , Zhang Fan , Zhu Ziming , Guo Qiang , Wang Mingbo , Huang Chao , Guo Lijie , Meng Fanfei , Yuan Shaohua , Shi Xiaoliang , Tian Ziqiang , Pang Fei
Published: June 2022

e21038

Background: Patients with multiple primary lung cancers (MPLC) and intrapulmonary metastasis (IPM) are considered as different clinical stages and require different treatment strategies. At present, the molecular identification criteria employed for distinguishing MPLC and IPM still need to be improved. Therefore, there is an unmet medical need in regards to a diagnostic standard that could effectively distinguish MPLC from IPM. Methods: Between December 2014 and April 2020, a total of 35 patients, with more than two lung lesions, were selected and divided into a training cohort (N = 22) and a validation cohort (N = 13). Imaging, anatomical evidence, pathological results, and histological examinations of the primary tumor, as well as histological subtypes, were used to differentiate MPLC from IPM. Genomic profiles obtained using a targeted sequencing with 450 cancer-related genes panel were analyzed. Modified diagnostic criteria for MPLC and IPM were established based on Martini and Melamed criteria, as well as molecular profiles. Results: We developed interpretation criteria using a flowchart that distinguishes MPLC from IPM, as follows: 1) MPLC can be determined using the following aspects: no common mutations are present; one lesion has no mutations (tumor = 2); two common high frequency driver gene mutations are present, or one driver gene mutation and one rare mutation comprising the p53 mutation are present; and only one common mutation is present. 2) IPM can be determined using the following aspects: one driver gene mutation and one rare mutation comprising the p53 mutation (concordance rare ≥ 50%) are present; two driver gene mutations (concordance rare ≥ 60%) are present; all mutations are common; and more than three common mutations are present. 3) Undetermined results are based on the following aspects: no mutations in one tumor are present (tumor > 2); no mutations are identified in all tumors; or two rare mutations are present. Undetermined patients were identified by combining histological identifications. Subsequently, to verify the criteria, 13 patients were recruited as a validation cohort. Eight MPLC and 5 IPM patients were identified, and the results were 100% consistent with independent imaging and pathological diagnoses. Conclusions: In this work, we proposed more comprehensive and detailed molecular identification criteria for MPLC and IPM, and it suggested that genetic alterations may be an effective method for diagnosing MPLC and IPM. We also determined that NGS may be a useful tool for assisting with differential diagnoses. Key words: Multiple lung cancer, Multiple primary lung cancer, Intrapulmonary metastasis, Next-generation sequencing, molecular classification.
Low-dose selenite synergizes with KRAS inhibitor as a dual apoptotic and ferroptotic agent in lung adenocarcinoma.
Authors: Chan Lok Seng , Liu Johnson , Li Lili , Tao Qian , Mok Tony S. K.
Published: June 2022

e21039

Background: Selenium, an essential trace element, has long been investigated as a pro-apoptotic and DNA demethylation agent. It sensitizes the response to chemotherapy in patients refractory to cytostatic agents. Meanwhile, ferroptosis is a novel approach in cancer treatment by triggering cell death and reversing drug resistance. However, the role of selenite in targeted therapy of lung adenocarcinoma (LUAD) and its underlying mechanism to demethylation and ferroptosis are largely unknown. Methods: EGFR- and KRAS-mutant LUAD cells (H1975 EGFR p.L858R and p.T790M and H358 KRAS p.G12C) were treated with selenite for 72 hours to examine its effect on DNA methylation, apoptosis and ferroptosis by western blot, C-11 BODIPY staining, methylation-specific PCR and transcriptome sequencing validated by qPCR and western blot. Cell proliferation and apoptosis of both cells treated with selenite and osimertinib in H1975 or adagrasib in H358 were assessed by MTS assay and western blot. Results: We confirmed selenite to be a dual apoptotic and ferroptotic agent in LUAD, associated with the activation of the p38-ATF4-CHOP axis in the unfolded protein response. This pathway linked ferroptosis with apoptosis by the upregulation of BH3-only proteins. Selenite also altered the DNA methylation machinery by downregulating DNMT1 and upregulation of TET1. We further found that low-dose selenite synergized with adagrasib in KRAS-mutant H358 but only yielded additive interaction at a high dose. Conclusions: Selenite is a dual apoptotic and ferroptotic agent with dose-dependent, oncogenic driver-dependent therapeutic effects in LUAD. These data suggest that low-dose selenite should be a potential drug candidate for the treatment of KRAS mutation-positive lung cancer.