bluuebunny/crossref_metadata_2025 huggingface dataset:
Somatic aberrations detected in tumor tissue and plasma in Chinese patients with stage I single-lesion and multi-lesions lung cancer.
Authors: Pei Guotian , Yang Yingshun , Li Mingwei , Ma Xiaoxue , Qin Jiayue , Cao Shanbo , Liu Qiang , Wang Shuai , Huang Yuqing
Published: June 2023

e20600

Background: Recent studies show that the use of circulating tumor DNA (ctDNA) has potential to guide precision medicine and transform the management of early-stage lung cancers. We aim to investigate whether plasma is suitable for detecting tumor‐derived DNA in patients with stage I single-lesion lung cancer and multifocal lung cancer which has rarely been investigated. Methods: Matched tumor tissues (n = 114) and plasma samples (n = 95) from Chinese patients with stage I lung cancer (n = 95), including 80 patients with single-lesion and 15 patients with multiple primary lung cancer (MPLC) diagnosed by American College of Chest Physicians (ACCP) guidelines, were analyzed by Acornmed panel with 808 cancer-related genes. Results: Using tumor tissue-based results as the gold standard, we performed variant-level assessment of the ctDNA tests. In patients with single-lesion, sequencing detected alterations in 98.8% (79/80) ctDNA and 9.3% (74/797) of variants in ctDNA were detected by corresponding tDNA. Among them, 31.3% (25/80) patients had at least one overlapping variant called by tDNA and ctDNA, and 5% (4/80) patients shared EGFR in both tDNA and ctDNA. Meanwhile, we identified 2 mutated EGFR in ctDNA that were not detected in tissues. As for multiple primary lung cancers, 86.7% (13/15) of MPLC patients had ≥1 alteration in ctDNA. In addition, 7.4% (9/122) of variants in ctDNA were detected by corresponding tDNA in MPLC. The overall concordance for all variants detected in both ctDNA and any tDNA of patients was 53.3% (8/15) in MPLC, with EGFR and KRAS as the most two frequent mutations. Furthermore, mutations consistent with ctDNA were detected in 29.4% (10/34) of the lesions in MPLC. Conclusions: Our analysis showed that plasma with high mutation detection rate and considerable concordance rate with tDNA maybe a powerful complement to tissues for molecular testing in lung cancer. Furthermore, ctDNA detection not only may be able to overcome the heterogeneity of tumors but also more comprehensively reflect the disease state of patients with multifocal lung cancer.
Differentiating ensartinib from lorlatinib and alectinib for first line use in an ALK+ non-small cell lung cancer preclinical model (ResCu).
Authors: Gadde Manasa , Hill Lindsay , Schwabe Elizabeth , Bulow Christopher
Published: June 2023

e20607

Background: The objective of this study was to determine whether Ensartinib with its high potency and resistance suppressing properties creates a more favorable treatment profile when used as first-line therapy in ALK+ non-small cell lung cancer compared to two other ALK inhibitors, Alectinib and Lorlatinib. Methods: The ResCu system, a novel culturing system, allows for long term culture of cells without the need for passaging, allowing determination of treatment resistance that can develop over time in a physiologically relevant system that conserves the resistance pathways found in patients. Two ALK-dependent lung adenocarcinoma cell lines, H3122 and H2228 were used to derive starting populations for this study. Using ResCu, we drove resistance to three ALK inhibitors: alectinib, lorlatinib, and ensartinib by using a clinically equivalent dose. The evolved cells were characterized for cross-sensitivity and resistance to a representative panel of 21 drugs. Cell viability was assessed by luminescence after 7 days of exposure to these secondary drugs. Additionally, BulkRNA Seq and WES were performed on the resistant evolved cells. Results: The ResCu system developed resistant cell populations by evolutionary steering of H3122 and H2228 cell lines treated with ensartinib, alectinib, and lorlatinib. Genetic background had a significant effect on which ALKi exhibited the most durable response. The H2228 derived cell population became resistant to alectinib and lorlatinib by 14 days while ensartinib remained effective for at least 42 days. In contrast, H3122 derived cells became resistant to all ALK inhibitors tested by 14 days. Rate of cross-resistance generation also varied between ALK inhibitors. Alectinib led to the highest levels of cross-resistance to other ALKi, approximately 3x higher. Lorlatinib led to highest levels of cross-resistance to other drug classes. Treatment with lorlatinib led to resistance in 13 other drug classes. Ensartinib led to least cross-resistance to ALKi and other drug classes. While the H3122 derived cells more rapidly evolved ALKi resistance, first line treatment with ensartinib sensitized them to lorlatinib, extending overall response to ALKi. Conclusions: The ResCu system developed two ALKi resistant cell populations from distinct genetic backgrounds under physiologically relevant conditions. In one of the two genetic background ensartinib response was durable for greater than 42 days compared to 14 days with alectinib and lorlatinib. Alectinib led to the most cross-resistance to other ALKi while lorlatinib led to the most cross-resistance to other drug classes in both backgrounds. Biomarkers of ALKi escape and cross-resistance were derived from RNA-seq, and we are currently validating these alterations against clinical samples.
Molecular profiling in a Peruvian population with advanced non-small cell lung cancer assessed by NGS.
Authors: Galvez-Nino Marco , Belmar-Lopez Carolina , Ruiz Rossana , Carrion Pamela , Diaz Diana , Chumpitaz Manuel , Gutierrez Jose Maria , Requena María , Pinto Joseph , Mas Luis
Published: June 2023

e20612

Background: The use of next generation sequencing (NGS) both at diagnosis and disease progression has allowed us to detect changes in the genetic profile of patients that are potentially targetable. In this study we will describe the genetic profile of patients both at diagnosis and disease progression using NGS in tissue sample (TS) and liquid biopsy (LB). Methods: We evaluated 403 patients diagnosed with non-small cell lung cancer (NSCLC) referred to ONCOGENOMICS laboratory from 2016 to 2022 to somatic mutation testing. NGS was performed using the Ampliseq for Illumina FOCUS panel and run on the Illumina MiSeq. The panel targets single nucleotide variants (SNVs) and insertion/deletions (indels), copy number variation (CNVs), and gene fusions in 52 genes associate to solid tumors. Raw data were processed automatically on the BaseSpace Sequence Hub (Illumina) and aligned to the hg19 reference genome The default limit of detection (LOD) was set at 5% allelic frequency (VAF) in tissue samples and 0.5% VAF in ccfDNA samples. The Human Genome Variation Society (HGVS) nomenclature guidelines (http://varnomen.hgvs.org/) were used to annotate identified variants and the ClinVar database (www.ncbi.nlm.nih.gov/clinvar/) was used to determine the biological significance of all reported variants. Results: Of the 403 patients, 351 patients had NGS at diagnosis and 52 patients in disease progression. Regarding the genetic profile at diagnosis, we analyzed 328 tissue samples and 23 liquid biopsies, the most frequent alteration was the EGFR mutation, detected in 116 (33.1%) patients (detection rate TS 32.6% and LB 39.1%), followed by KRAS (15.4%), ALK (2.6%), BRAF (1.9%), and others (4.8%). In the disease progression setting, we analyzed 34 tissue samples and 18 liquid biopsies, the most frequent alteration was the EGFR mutation, detected in 28 (53.8%) patients (TS detection rate 29.4% and LB 44.4%), followed by KRAS (15.4%), ALK (3.9%), and others (3.9%). Conclusions: Peruvian patients are a population with a high mutation rate, in this cohort almost 50% of them had a target mutation, especially the EGFR mutation. Likewise, it was found that the detection rate of the EGFR mutation was higher with NGS in liquid biopsy than in tissue samples, both in the diagnostic and in the disease progression samples. On the other hand, it is important to mention that the frequency of KRAS mutations found is higher than previous Peruvian reports.
Prevalence of delta-like ligand 3 expression in small cell lung cancer.
Authors: Pundole Xerxes , Ju Chia-Hsin , Bylsma Lauren C. , Hooda Naushin , Movva Naimisha , Elkhouly Ehab , Bebb D. Gwyn , Fryzek Jon , Balasubramanian Akhila , Jandial Danielle , Dingemans Anne-Marie C.
Published: June 2023

e20618

Background: Delta-like ligand 3 (DLL3), a ligand of the Notch-family, is a potential therapeutic target in small cell lung cancer (SCLC). High expression levels of DLL3 are observed in SCLC, however different methods and thresholds are used. A systematic literature review (SLR) was conducted to estimate the prevalence of DLL3 expression in SCLC. Methods: A comprehensive literature search was conducted in the PubMed, EMBASE, Web of Science, and Cochrane Library databases, as well as on clinicaltrials.gov, using a pre-specified search strategy. This SLR was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42022351119). Prevalence of DLL3 expression was evaluated overall and by method of DLL3 assessment and positivity threshold. Results: Of the 30 studies that met our study inclusion criteria, 22 (73.3%) were observational and 8 (26.7%) were clinical trials. Most studies (N = 21, 70%) evaluated less than 100 patient specimens (range: 20 to 1,362 patient specimens). Twelve studies (40%) were conducted in Asia, six (20%) in Europe, five (17%) in North America, five (17%) were multi-country, one in Brazil, and geographical location was not reported in one study. DLL3 testing methods varied across studies, with immunohistochemistry (IHC) being used in 26 (86.7%) studies. Two studies used real-time polymerase chain reaction, one used quantitative mass spectrometry, and one study did not report the testing method. Thirteen of the studies (13/26, 50%) that evaluated DLL3 expression by IHC used the Ventana SP347 assay. DLL3 expression was evaluated at various thresholds of tumor cell staining and showed a wide range of expression, across studies (Table). Conclusions: The SLR findings indicate that most studies assessing DLL3 in SCLC have relied on IHC methodology. Despite the range of thresholds used for evaluating positivity, DLL3 is notably expressed in SCLC. The frequency and impact of aberrant DLL3 localization was not addressed in these studies and minimal data on comparison of IHC with other methodologies exists. Results of this SLR also highlight the need to define a standardized method and threshold of evaluating DLL3 expression. [Table: see text]
Outcomes of patients with small cell lung cancer admitted to the intensive care unit.
Authors: Huang Joy , Kwon Daniel H , Brondfield Sam
Published: June 2023

e20620

Background: Small cell lung cancer (SCLC) is aggressive and carries a poor prognosis. National Comprehensive Cancer Network guidelines recommend considering systemic therapy even for patients with poor performance status, if cancer-related. However, little is known about the prognosis and effectiveness of treatment for patients with SCLC in the intensive care unit (ICU), and thus clinicians lack guidance in this scenario. Therefore, we characterized outcomes and predictors of overall survival (OS) for patients with SCLC in the ICU for cancer-related complications, with or without chemotherapy. Methods: This is a single-institution retrospective study in which we used diagnosis codes to identify all patients with SCLC who were admitted to the ICU from 2012 to 2022. We then manually selected patients admitted to the ICU for cancer-related complications and excluded those admitted for chemotherapy complications, post-operative observation, or other reasons not directly related to SCLC. Demographic and clinical data were collected via manual chart review. OS from ICU admission date was evaluated using the Kaplan-Meier method and compared between those who received chemotherapy and those who did not using the log-rank test. Multivariate analysis was performed using Cox proportional hazards regression analysis to identify predictors of OS. Sensitivity analysis was performed by excluding patients with limited stage (LS) disease. Results: Twenty-three patients met inclusion criteria, of whom 20 had extensive-stage (ES) and three had LS disease. Six patients received chemotherapy in the ICU (five with ES, one with LS) and 17 did not. Of those who received chemotherapy, two died during their stay, and four had partial responses. Median OS from ICU admission for all patients was 2.4 weeks. Median OS from ICU admission did not differ significantly between those who received chemotherapy and those who did not (21.0 vs 1.6 weeks, p = 0.12). A three-variable model significantly predicted OS: pulmonary vs non-pulmonary reason for ICU admission (HR for death = 6.18 [95% CI 2.01-19.00], p < 0.01), TNM stage IVB vs IVA or III (HR = 5.34 [1.58-18.00], p = 0.01), and Charlson Comorbidity Index (HR = 0.76 [0.56-1.04], p = 0.09). Results were similar when patients with LS disease were excluded. Conclusions: In this single-institution study of patients with SCLC admitted to the ICU for cancer-related complications, OS was short. Chemotherapy given in the ICU was not associated with longer OS. Potential clinical predictors of OS at the time of ICU admission were identified: pulmonary reason for ICU admission and TNM stage IVB were both associated with shorter OS. The trend toward improved OS associated with higher Charlson comorbidity index may reflect reversible non-malignant contributors to ICU-level illness. Conclusions apply primarily to patients with ES disease. These findings require validation in larger, multicenter studies.
Impact of systemic immune-inflammation index in patients with limited-stage small cell lung cancer.
Authors: Zhang Ziling , Li Juan , Liu Huijuan , Wang Yuxiang , Li Xiaomei , Jia Fangfei , Wen Junpeng , Zhao Yan
Published: June 2023

e20626

Background: The systemic immune-inflammation index (SII) has been suggested as a prognostic marker in several solid malignant neoplasms. However, there are few studies on the prognostic value of SII in patients with limited-stage SCLC. This study explored the impact of SII on overall survival (OS) and progression-free survival (PFS) in patients with limited-stage small cell lung cancer, and compared the predictive ability of SII and platelet/lymphocyte ratio (PLR) to find a better prognostic marker. Methods: In total, 572 patients with new diagnosis of limited-stage SCLC were included in this study. The optimal threshold of SII and PLR were determined using the outcome(OS)-based method by maximizing the log-rank test statistic and the survival differences.The predictive ability of SII and PLR were compared by drawing the continuous time-dependent receiver operating characteristic curves (time-dependent ROC). Logistic multivariable analysis was performed to identify factors associated with high SII. Propensity score matching (PSM) was used to balance confounders between groups and adjust observed selection bias. Kaplan-Meier methods and Cox proportional hazards models were used to assess the impact of pre-treatment SII on OS and PFS. Results: The median age of the whole group was 60.0 (25.0-81.0) years, and the median follow-up time was 56.5 (2.5-95.4) months. The optimal cutoff value of SII and PLR were 760.6 and 137.3, respectively. The area under the time-dependent ROC curves of SII and PLR in 1-, 2- and 3-year were 0.727, 0.708, 0.680 and 0.680, 0.669, 0.649, respectively. The high SII group was correlated with pleural effusion (P = 0.001), T stage (P = 0.009), N stage (P = 0.048), and pretreatment serum sodium (P = 0.003). The median OS and PFS of the whole group was 26.0 months (95%CI 23.8-28.2) and 13.0 months (95%CI 11.3 -14.7), and the 1-, 3-, 5-year OS rates and the 1-, 3-, 5-year PFS rates were 81.1%, 35.5%, 27.1% and 52.8%, 24.8%, 19.9%, respectively.There were 414 patients after PSM. In multivariable survival analysis, SII remained an independent prognostic factor for OS (HR1.792; 95%CI 1.416-2.268; P < 0.001) and PFS (HR1.410; 95%CI 1.043-1.906; P = 0.025). Conclusions: Elevated SII is an independent adverse prognostic factor in patients with limited-stage SCLC and is superior to PLR in terms of prognostic ability.
Combinatorial analysis of CD4+Tregs and CD8+Teff to predict response to ICI in patients with ES-SCLC.
Authors: Tsapakidis Konstantinos , Xagara Anastasia , Kokkalis Alexandros , Markou Alexandra , Aidarinis Chrysovalantis , Lazarou Alexandros , Kallergi Galatea , Papadopoulos Vasileios , Saloustros Emmanouil S. , Samaras Ioannis , Kotsakis Athanasios
Published: June 2023

e20633

Background: Recently, the antiPD-L1 agent, durvalumab, was approved in first line treatment in combination with chemo. However, there is not a clear benefit from this regimen for the majority of patients. In this study, we explored the predictive role of regulatory T-cells in response of patients with ES-SCLC treated with the aforementioned regimen. Moreover, we evaluated the potential role of inflammatory hematological indices such as Neutrophil to Lymphocyte ratio (NLR) and CRP levels to predict responders. Methods: Blood was collected before initiation of immunotherapy from 24 patients with ES-SCLC. PBMCs were isolated with Ficoll density gradient centrifugation from patients and 1O healthy donors (HD). Immunophenotyping was performed by multi-color flow cytometry using antibodies against CD3,CD8,CD45RA,CD45RO,CCR7,PD-1, for CD8 T-cells and CD3,CD4,FoxP3,CD25,CD127,CTLA-4,CD39 for Tregs. Results: High percentages of CD39+ (p = 0.0061) and CTLA-4+ (p = 0.012) Tregs were detected in circulation of ES-SCLC compared to healthy individuals. Additionally, higher percentages of CD8+ Teff were detected in SCLC patients (p = 0.027). Patients with high numbers of Teff had significant higher PFS (p = 0.021, median 183 and 97 days) and better OS (p = 0.075, median 318 and 202 days) in response to immunotherapy compared to those with low numbers. Spearman analysis revealed a significant negative correlation between Tregs and Teff (Spearman r2 = -0.39,p = 0.043) that was accompanied with significant higher PFS (p = 0.041, median 207 and 130 days ) and OS (p = 0.029, median 318 and 202 days ) in patients with high levels of Teff and low Tregs comparing to the rest. Further analysis on inflammatory clinical signatures demonstrated that patients with better clinical response to immunotherapy have significantly lower NLR (p = 0.034) while no significant difference was revealed for CRP (p = 0.401) levels before therapy initiation. Conclusions: Combinatorial analysis of Tregs and Teff cells may be used as a predictive tool for response to immunotherapy in ES-SCLC patients.
Survival outcomes of stage I small cell lung cancer (SCLC) treated with stereotactic body radiation therapy (SBRT) versus external beam radiation therapy (EBRT): An NCDB analysis.
Authors: Heckman Patrick , Hao Zhonglin , Bernard Mark Edmund , Chen Quan , Huang Bin
Published: June 2023

e20638

Background: Patients with stage I (T1/T2a, N0) SCLC have a 5-year survival of 48% after surgical resection. Unfortunately, 70% of limited stage patients are inoperable and thus reliant on definitive radiation. The use of SBRT has increased 16-fold from 2004-2013 with continued widespread acceptance due to its safety and projected efficacy; however, there is no category one evidence to support this practice. Currently NCCN guidelines cite experience of SBRT in 117 patients from two studies. The impact of SBRT versus EBRT with or without chemotherapy is not yet well defined and requires more evidence to influence treatment decisions. Methods: We used National Cancer Database (NCDB) to identify 4,012 patients with clinical stage I SCLC treated with surgery, or EBRT with chemotherapy, or SBRT with or without chemotherapy from 2011 to 2020. The primary outcome analyzed was overall survival (OS). Secondary analyses evaluated differences amongst age, gender, race, institution, and Charlson Comorbidity Index (CCI). Kaplan-Meier (KM) plots were used to examine survival outcomes and descriptive analysis was performed to examine the characteristics of clinical variables by the different treatment modalities. Cox regression analysis was used to identify factors associated with OS. Results: The utilization of surgery and SBRT in stage I SCLC has increased over the last fifteen years. As of 2020, SBRT volume has increased 657-fold and is combined with chemotherapy in more than 50% of cases. From 2010-2019, those who were treated with surgery-based therapy had a survival advantage (HR 0.64 95%CI 0.58-0.71, p < 0.01) compared to multimodality radiotherapy techniques. For those treated with definitive radiation, there was no significant difference between EBRT with chemotherapy and SBRT with or without chemotherapy (HR 1.11 95%CI 0.97-1.28, p = 0.135). Patients treated with SBRT alone experienced a significantly shorter median OS of 20.4 months compared to those who received SBRT with chemotherapy (median OS 34.3 months, HR 1.74 95%CI 1.38-2.20, p < 0.01). Multivariate analysis revealed better OS for patients under the age of 64 (HR 0.51 95%CI 0.44-0.58, p <0.01) and those with lower CCI (CCI 0, HR 0.82 95%CI 0.70-0.90, p< 0.01); worse OS for males (HR 1.26 95%CI 1.16-1.37, p < 0.01); and no difference between academic or non-academic institutions (HR 0.92 95%CI 0.84-1.01, p= 0.094), white versus black (HR 0.84 95%CI 0.71-1.00, p = 0.054) or non-white patients (HR 1.06 95%CI 0.75-1.50, p = 0.736). Conclusions: Our preliminary results suggest surgery-based multimodality therapy is associated with a higher survival for medically operable patients. There was no survival advantage of EBRT with chemotherapy compared to SBRT especially when chemotherapy is given. Further statistical analysis is underway to confirm these trends and survival differences.
The role of adjuvant chemotherapy (CT) for early stage resectable node negative small cell lung cancer with size of ≤ 2 cm post-surgical resection: A SEER plus based statistical analysis.
Authors: Budhathoki Pravash , Shah Anish Kumar , Gaire Suman , Potluri Lakshmi Bhavani , Uprety Dipesh
Published: June 2023

e20643

Background: Small cell lung cancer (SCLC) is a poorly differentiated neuroendocrine tumor accounting for 15% of all lung cancers. Surgical resection followed by adjuvant platinum-etoposide is recommended for patients with limited-stage SCLC (T1 N0M0). In this study, we sought to evaluate the survival benefit of adjuvant chemotherapy for patients with ≤2 cm size SCLC following surgical resection. Methods: We utilized Surveillance, Epidemiology and End Results (SEER) plus 18 registries to identify adult patients (≥18 years) diagnosed with small cell cancer of the lung with tumor size of ≤ 2 cm from 2010 to 2018. The study population comprised of patients who underwent surgical resection followed by adjuvant chemotherapy and patients who received surgical resection alone. Kaplan-Meier and long rank tests were used to compare overall survival between the two groups. Multivariate survival analysis was done using the Cox proportional hazards regression model. Results: 419 patients were identified, with 203 (48%) receiving adjuvant CT while 216 (52%) not receiving adjuvant CT. The population who received adjuvant chemotherapy was younger than those who did not (Median years: 67 years vs 71 years, p < 0.001). The 5-year overall survival rate was significantly higher for those receiving adjuvant CT (49% vs 40.9%, P value < 0.001). On multivariate analysis after adjusting for age, gender, race, and origin, adjuvant chemotherapy was associated with better overall survival (HR:0.67; 95% CI 0.54 - 0.88, p = 0.003). Conclusions: Our study demonstrates that adjuvant CT should be used for early-stage small cell lung cancer irrespective of tumor size following surgical resection.
Application of a contralateral esophageal-sparing technique to reduce radiation esophagitis in limited-stage small cell lung cancer treated with twice-daily radiotherapy and concurrent chemotherapy.
Authors: Hu Min , Yang Shuangyan , Chen Yun , Kang Jingjing , Xu Yaping
Published: June 2023

e20644

Background: Acute esophagitis (AE) is a common radiation-related toxicity after concurrent twice-daily hyperfractionated radiotherapy and chemotherapy in limited-stage small cell lung cancer (LS-SCLC) patients, which could limit dose-escalation of the target and make treatment postponed to decrease local tumor control. More esophageal protective techniques should be proposed to reduce radiation severe esophagitis of LS-SCLC patients. Methods: We retrospectively applied a contralateral esophagus sparing technique (CEST) in 20 unresectable LS-SCLC patients, who had gross tumor within 1 cm of the esophagus and received a total dose of 45 Gy of concurrent twice-daily radiation and standard chemotherapy regimen. The contralateral esophagus (CE) was contoured as an avoidance structure, and the feasibility of CEST on promoting a steep dose falloff beyond the target volume near esophagus was analyzed. The appropriate dose constraints of CE were also investigated. The AE events were recorded according to the RTOG acute toxicity grading system. Results: We performed CEST in 20 LS-SCLC consecutive patients, among whom three patients experienced severe AE after concurrent chemoradiotherapy. Each treatment plan of eligible patients assured high radiation doses delivering, with the planning and gross tumor volume covered by 95% and 100% of the prescription dose. Among these patients, the median maximum esophagus dose declined from 47.9 Gy (range, 46.6-49.7 Gy) to 41.3 Gy (range, 35.9-48.2 Gy), as well as V30 and V36 of esophagus decreased from 9.22 Gy (range, 0.42-17.71 Gy) and 7.39 Gy (range, 0-16.19 Gy) to 2.40 Gy (range, 0-5.68 Gy) and 0.53 Gy (range, 0 -2.69 Gy) after CEST applying, respectively (all p < 0.001). The CE’s median maximum dose, V30, and V36 were 41.3 Gy, 2.13 cc, and 0.24 cc, respectively. Conclusions: By using proposed CE dose constraints of Dmax≤42 Gy, V30 ≤3.5 cc and V36 ≤0.5 cc, we confirmed the feasibility and efficacy of CEST to avoid exposing the esophagus cross-section to high prescription doses in LS-SCLC patients receiving twice-daily hyperfractionated IMRT and concurrent chemotherapy. These findings support the clinical practice of CEST in LS-SCLC patients, while more prospective and large-scale studies are warranted.
Racial and ethnic differences in thymic epithelial tumors: A single-institution retrospective analysis.
Authors: Wuthrich Brice , Maniar Rohan , Heldman Emily , Laniak Louis , Davis Hannah , Ardeshir-Larijani Fatemeh , Spittler Aaron John , Kesler Kenneth , Loehrer Patrick J.
Published: June 2023

e20649

Background: Thymic epithelial tumors (TETs) are a rare, heterogeneous group of malignancies that arise from the thymus. While the etiology of TETs remains unknown, variation in incidence rates amongst racial/ethnic groups has raised the possibility of germline predispositions. Unfortunately, due to the rarity of this disease, there is a limited understanding of the impact of race/ethnicity on tumor characteristics and treatment outcomes for TET patients. We sought to characterize patient/tumor data and investigate treatment outcomes based on race and ethnicity. Methods: We conducted a single-institution, retrospective database analysis of TET patients evaluated at the IUSCCC from 1979 – 2021 from which clinical annotations were available for 477 thymoma and 164 thymic carcinoma (TC) patients. We identified 112 thymoma and 35 TC patients who were deemed to have sufficient data for evaluation of racial/ethnic characteristics. Demographic/clinical variables and therapeutic interventions, including treatment outcomes, were analyzed. Data was compiled and analyzed using descriptive statistics and the Kaplan Meier method for survival analysis via GraphPad Prism software. Results: Of the 112 thymoma patients, 29 thymoma patients presented with de novo metastatic disease at the time of diagnosis. The median age at the time of diagnosis of all patients revealed a statistically significant difference between White and Black TET patients (53.0 v. 42.0 years, *p = 0.0195). There was a trend towards significance when median age of diagnosis between White and Asian TET patients was compared (53.0 v. 48.0 years, p = 0.0633, NS). Advanced histologic subtypes, include B3 and TC, appeared predominantly in Asian and Black patients at 77.7% and 56.3%, respectively, compared to White patients (44.9%), though the finding was not statistically significant. No statistically significant differences between racial/ethnic groups regarding progression free survival for unresectable or metastatic disease were observed, regardless of histology. There was a non-significant difference in recurrence free survival for resectable thymoma in White (30.0 months) and Asian/Pacific Islander (47.0 months) patients compared to Black patients (24.0 months). Conclusions: Overall, this analysis suggests differences in the median age of diagnosis for patients with thymic malignancies based on race, raising the possibility of inherent biologic differences driving oncogenesis and symptoms at the time of presentation. While no statistically significant differences in treatment outcomes were found based on race and ethnicity, Black patients appeared to experience shorter times to recurrence after definitive surgery. Further studies to understand the mechanistic differences driving tumorigenesis and potential disparities in treatment outcomes are greatly needed in this rare tumor type.
Tumor immune microenvironment in BRAF V600E mutant lung adenocarcinoma.
Authors: Liu Yutao , Wang Mingzhao , Chen Tong , Li Weihua , Hu Xingsheng , Jiang Jun , Li Fang , Wan Zhiyi , Zhang Jie , Zhang Chunmei
Published: June 2023

e21003

Background: The efficacy of immune checkpoint inhibitors (ICIs) is closely related to tumor immune microenvironment (TIME). However, little is known about the role of BRAF V600E mutation in the TIME of lung adenocarcinoma (LUAD). Methods: Here, we analyzed the TIME of LUAD with the BRAF V600E mutation using RNA sequencing and multiplex immunofluorescent (MIF) stained with CD8, CD68, CD163, CD57, PD-1, and PD-L1 antibodies. Patients were divided into the BRAF V600E (n = 31) and driver gene ( ALK, BRAF, EGFR, HER2, KRAS, MET, RET, and ROS1) wild-type groups (WT, n = 32). Results: There were no significant differences between the BRAF V600E and driver gene WT groups in terms of immunological signature scores, including T cell–inflamed gene expression profiles, adhesion molecules, chemokines, cytolytic activity, immunocostimulators, immunoinhibitors, MHC Class I, MHC Class II, MHC Non-Class, IFNg signature, tertiary lymphoid structure, and most of infiltrating immune cell subtypes. MIF showed that the proportions of PD-L1+ cells and CD68-associated tumor-associated macrophages (TAMs) were significantly higher in the BRAF V600E group in the tumor, stroma, and total regions. Notably, the majority of CD68-associated macrophages were CD68+CD163- TAMs. However, the proportions of CD8+, CD8+PD-L1+, and CD8+PD-1+ tumor-infiltrating lymphocytes (Tils) in the BRAF V600E and driver gene WT groups were all comparable in the tumor, stroma, and total region. Conclusions: The TIME was generally similar between the BRAF V600E mutant and driver gene wild-type groups, particularly in the proportion of CD8+ Tils. This may support that BRAF V600E mutation does not affect the efficacy of immune checkpoint inhibitors in LUAD.
An exploratory analysis of lung cancer survival using NGS genetic predictors and partial least squares.
Authors: Sequero-Lopez Silvia , Martinez-Murcia Francisco Jesus , Castillo-Barnes Diego , Moreno-Garcia Javier , Segura-Perez Ana , Gallego-Molina Nicolas , Ortiz Andres , Ramirez Javier
Published: June 2023

e21007

Background: According to the IARC, lung cancer is one of the most common types of cancer worldwide (2.09 million of cases in 2018). Some genetic alterations (ALK, ROS1, EGFR, etc.) are known to play a key role in its origin. Fortunately, target therapies have been developed in the last years increasing patients Overall Survival (OS). Methods: Next-Generation Sequencing (NGS) is a powerful tool to determine which specific mutations occur in these genes. Nevertheless, despite some of them have been labeled as pathogenic, we still do not know exactly their effect on the OS. In this context, we have evaluated the NGS (Ion Torrent™ S5, kit Oncomine™ Focus Assay, Oncomine Focus-520- W3.0-DNA v5.14) results of 119 patients diagnosed with lung adenocarcinoma (89 variants in 28 genes) with a cross-validated (k = 5) schema using Partial Least Squares (PLS) and multiple repetitions to determine the coefficient variability from the genetic alterations modeling the OS. This gives us a measure of the proportion of variance in the OS (dependent variable) that is explained by the mutations (independent variables) in our statistical model. Results: Analyzing our results, alterations on ALK EML4-ALK V1 (CI -58.7 to -18.8); BRAF SNV exon15 p.Val600Glu (CI -66.1 to 0.0); CTNNB1 SNV exon3 p.Thr41Ala (CI -84.3 to 8.8) and p.Thr41Ile (CI -26.0 to 0.6); EGFR CNV (CI -68.5 to -5.1) and DEL exon19 p.Glu746-Ala750 (CI -66.9 to 16.4); KRAS SNV exon2 p.Gly12Val (CI -76.1 to -39.3) and p.Gly13Cys (CI -66.0 to -36,9); MET CNV (CI -50.0 to 1.3) and FUS exon13 to exon15 (CI -46.8 to 33.6); and PIK3CA SNV exon10 p.Glu545Lys (CI -99.0 to -35.6) have a negative impact on the OS. In contrast, mutations in CTNNB1 SNV exon3 p.Ser37Phe (CI -26.3 to 105.5); EGFR SNV exon21 p.Leu858Arg (CI -32.7 to 121.3); KRAS SNV exon2 p.Gly12Ala (CI 1.3 to 39.3); KRAS SNV exon3 p.Gln61His (CI -53.32,50,11) lead to a better prognosis on OS. Note that our analysis involved patients not treated due to their tumoral progression: CTNNB1 SNV exon3 p.Thr41Ile (1); EGFR SNV exon21 p.Leu858Arg (3); CTNNB1 SNV exon3 p.Thr41Ala (1); PIK3CA SNV exon10 p.Glu545Lys (1); ALK EML4-ALK V1 (1) and KRAS SNV exon2 p.Gly12Val (1). Conclusions: Though alterations in the EGFR and ALK genes usually present a favorable prognosis, our work suggests that some of their variants are associated with a poor survival. This study also reveals other mutations like alterations on PIK3CA and CTNNB1 genes, which may impact lung cancer prognosis and will require further exploration.
Revealing distinct immune landscape in EGFR mutant and EGFR wild type lung adenocarcinoma by using single-cell RNA sequencing.
Authors: Yin Tianwen , Liu Chao , Lei Tianyu , Wang Peiliang , Bai Menglin , Yu Jinming , Teng Feifei
Published: June 2023

e21008

Background: Non-small cell lung cancer (NSCLC) with EGFR mutations displays heterogeneity in the extent of intratumoral immunocytes infiltration compared to those with EGFR wild types, which may explain their variable responsiveness to PD-1 blockade. Here, we performed single-cell RNA sequencing (scRNA-seq) to unveil the immunescape and heterogeneity of lung adenocarcinoma (LUAD) between EGFR mutant (EGFR-mut) patients and wild type (EGFR-wt) patients. Methods: Eleven EGFR-mut and 7 EGFR-wt NSCLC tumor samples were analyzed. Immune cells (CD45+) were enriched through fluorescence-activated cell sorting (FACS) and subjected to single-cell RNA sequencing (scRNA-seq) using the 10X Genomics platform. Sequencing reads were normalized and analyzed using the R/Seurat package. Cellular components of each sample were determined based on known marker genes. Wilcox test was used to compare promotion by subtype composition and immune cell infiltrates. Results: Different immune cell compositions were observed between EGFR-mut and EGFR-wt LUAD tumor samples. We found EGFR-wt tumors are marked by an enrichment of CCL15+ tumor-associated macrophages(TAMs), which display pro-inflammatory properties and high expressions of TNF-a-signaling genes. In contrast, EGFR-mut tumors exhibit enrichment of SPARCL1+TAMs, which are involved in epithelial-mesenchymal transition (EMT) and angiogenesis. EGFR-wt tumors exhibited enrichment of CD8-Teff-MX1 and Gamma delta T cells, both of which displayed higher cytotoxic and naive features. Moreover, the high expression of Gamma delta T corresponds with a better clinical prognosis. In contrast, CD8-Teff-XCL1 and NKT-FGFBP2 were found enriched in EGFR-mut tumors, both of which contributed to higher exhaustion and decreased cytotoxic function. Additionally, NK-IL32 was found enriched in EGFR-mut tumors, showing a downregulated T cell receptor signaling and stronger exhausted features. The high expression of this subcluster correlated with poor outcomes in LUAD patients harboring EGFR mutation. Conclusions: Our study provided a deeper understanding of the immune landscape of EGFR-mut and EGFR-wt LUAD and gained better insights into the immunological mechanisms involved in the response to ICIs. The results of our study could be instructive for the development of future immunotherapy strategies for NSCLC patients harboring EGFR mutations.
Single cell RNA sequencing to reveal immune microenvironment in primary and brain metastatic lesion of non-small cell lung cancer.
Authors: Teng Feifei , Bai Menglin , Liu Chao , Li Xiaohui , Meng Xiangji , Wang Peiliang , Yu Jinming
Published: June 2023

e21009

Background: Despite immune checkpoint inhibitors (ICIs) have been proven effective in patients with advanced NSCLC, suboptimal therapeutic responses are seen in brain metastatic lesions. The heterogeneous cellular components in the tumor immune microenvironment (TIME) pose a challenge in understanding the low immune response. A comprehensive understanding of the heterogeneous TIME in primary and brain metastatic NSCLC is currently lacking, but crucial for improving ICI therapeutic responses in NSCLC patients with brain metastasis. Therefore, we use single cell RNA sequencing (scRNA-seq) to reveal distinct immune microenvironment in primary and brain metastatic lesion of NSCLC. Methods: Eight primary and nine brain metastatic NSCLC tumor samples were obtained through surgical resection. Immune cells (CD45+) were enriched through fluorescence-activated cell sorting (FACS) and subjected to scRNA-seq using the 10X Genomics platform. Sequencing reads were normalized and analyzed using R/Seurat package. Cellular components of each sample were determined based on known marker genes. Results: In our study, we observed a significant difference in the immune cell composition between primary and brain metastatic tumor samples. We found brain metastatic tumors are marked by an enrichment of TIMP1+ monocytes and PLTP+ tumor-associated macrophages (TAMs), both of which display heightened anti-inflammatory properties. In contrast, primary tumors exhibit an enrichment of FCN1+ monocytes and MARCO+ TAMs. Further analysis has revealed that the enrichment of TIMP1+ monocytes and PLTP+ TAMs is associated with a worse prognosis in patients receiving immunotherapy. Additionally, our examination of the transcriptome profile of CD8+ T cells showed an upregulation of inhibitory and exhausted signatures in brain metastatic tumor samples. Conclusions: Our study provided a comprehensive understanding of the TIME of primary and brain metastatic NSCLC and to gain deeper insights into the immunological mechanisms involved in the response to ICIs. The results of our study could prove valuable for the development of future immunotherapy strategies for NSCLC patients with brain metastasis.
Does the landscape of comprehensive genomic profiling in patients with advanced stage lung cancer in India differ from data from the western countries.
Authors: Bahl Ankur , Raizada Niti , Dhar Aparna , Agarwal Amit , Bajaj Rajat , Rohatgi Nitesh
Published: June 2023

e21011

Background: Lung cancer is one of the leading causes of cancer related deaths worldwide and India. The understanding of the molecular basis of lung cancer has led to increased number of FDA approved targeted therapies and therefore survival. Data on the molecular landscape of lung cancers has a preponderance of western and east Asia. India while may harbour one third of world new lung cancer case, the understanding of comprehensive molecular landscape of lung cancer in India is poor. Methods: We have retrospectively compared comprehensive genomic profiling of lung cancer patients across three centres over a period of two years using foundation one cdx. We aim to compare this to available data from rest of the world and present the differences and commonalities. We believe this will help understand both differences in presentations and pattern of disease as well as question if treatment algorithms should be same or different. At least on this occasion we will limit our study to foundation one CDx patients only so that comparison with western data is not confounded by differences in technology. Results: We have Highlighted 44 such patients and will be comparing their data to the available data on foundation on CDX from available literature. 27 (61.3%) patients had one of the most common targetable mutations including EGFR ALK ROS MET BRAF ERBB2 and NTRK. Surprisingly 9(20.4%) had mutations in the homologus repair pathway. 3 patients also had MSI High. We will present comparison of this Indian data to that's available across the world. Conclusions: Precision Oncology and molecular biology is cornerstone of cancer care especially in Lung Cancer. We want to deepen the understanding of the comparison of Indian cohort and believe its different with arguably more targetable abnormalities detected than in the west and similar to the eastern population of the world.
Comparison of mutation detection rate between cell pellet DNA and cell-free DNA from cerebrospinal fluid in patients with advanced lung cancer.
Authors: Hu Shukun , Wang Xue , Peisu Suo , Li Yingmei , Chen Shifu , Zhang Yi
Published: June 2023

e21014

Background: Liquid biopsy of cerebrospinal fluid (CSF) has been approved to be a promising strategy for molecular pathology testing in patients with lung cancer. Numerous studies showed that CSF-derived DNA can recapitulate the molecular characteristics of metastatic lung cancer. However, differences in mutation detection rate and the overall mutational profile between cell pellet DNA and supernatant cell-free DNA (cfDNA) from CSF in patients with lung cancer have rarely been reported. Methods: Matched CSF cell pellet and supernatant sample sets were selected from 51 lung cancer patients in our sequencing center. CSF was centrifuged (1000g, 10 min) to separate the cell pellet and supernatant components. Cellular DNA and cfDNA were extracted and underwent library preparation procedures for next-generation sequencing respectively. Cut adapter, mapping, fusion calling and cnv calling were performed for sequencing data analysis. Results: At the sample level, gene mutation could be detected in both CSF cell pellet and cfDNA, and the positive detection rate of gene mutation was consistent. The positive percent agreement (PPA) of CSF cfDNA sequencing compared with CSF cell pellet DNA was 93%. At the genetic variation level, 223 gene mutation sites were detected, and the positive rate of gene mutation in the CSF cfDNA (32.51%) was significantly higher than that in the CSF cell pellet (10.74%, p＜0.01). Additionally，the variation rate of less than 1% was defined as the low-frequency mutation range. Results showed that variant allele frequency (VAF) in CSF cfDNA were remarkably higher than those in the CSF cell pellet in both low-and high-frequency mutation ranges ( p＜0.01, p＜0.01). Conclusions: Both cell pellet DNA and cfDNA isolated from CSF can be used for molecular subtyping of lung cancer. Given that CSF is inevitably contaminated with blood cells in clinical procedures, the dynamic range of tumor cells in CSF could be quite large. CSF cfDNA better recapitulate the mutational status and is recommended to consider first for liquid biopsy in advanced lung cancer with brain metastases or suspicious brain metastases. Key words: Next-generation sequencing; CSF; cell pellet DNA; cfDNA; advanced lung cancer.
RNA sequencing to characterize pathways in EGFR-mutated non-small cell lung cancer.
Authors: Yun Nicole , Naqib Ankur D , Borgia Jeffrey Allen , Batus Marta , Fidler Mary Jo J.
Published: June 2023

e21019

Background: The purpose of our study is to explore patterns in gene expression for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Methods: 287 patients with EGFR-mutated lung cancer were identified using the Tempus Lens database. Raw RNA sequence expression data was requested from TEMPUS XT RNA analysis. Sequences were processed through the EdgeR analysis in the R programming environment. Differential abundance analysis was done to further filter out genes and Benjamini-Hochberg correction selected genes with a corrected p-value of < 0.05 for further pathway analysis. Pathway analysis was performed using GSEA (Gene Set Enrichment Analysis). Enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GSEA Molecular Signatures Database (MsigDB) was performed for overexpressed and under-expressed genes in patients. Results: Pathway analysis run against the KEGG reference database and GSEA MSigDB helped to illustrate genes shared in activated and suppressed pathways in our patient cohort. For example, using the KEGG reference database, enriched pathways meeting p value significance threshold of < 0.005 included the nicotine addiction, olfactory transduction, and cortisol synthesis and secretion pathways, amongst others. Suppressed pathways using the KEGG reference database meeting p value significance threshold of < 0.005 included fat digestion and absorption, vitamin digestion and absorption, PPAR signaling pathway, and drug metabolism by cytochrome P450 and other enzymes. Using the GSEA MSigDB, enriched pathways included G protein-coupled receptor activity, sensory perception, synaptic signaling and trans-synaptic signaling, meanwhile suppressed pathways included cytolysis by host of symbiont cells, negative regulation of very-low-density lipoprotein particle remodeling, and oxidoreductase activity. Conclusions: Patterns in gene and pathway expression were observed in our cohort of patients with EGFR-mutated NSCLC. Analyzing RNA sequencing pathways showed differential up and down regulation of multiple pathways. For example, suppression of the fat and vitamin digestion and absorption pathways may shed light on processes involved in cancer cachexia and metabolism. Though further work needs to be done, RNA sequencing results for patients with EGFR-mutated lung cancer may lead to information on cancer development and additional therapeutic targets.