bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment patterns and outcomes associated with small cell lung cancer by platinum sensitivity status in a U.S. Medicare population.
Authors: Cockrum Paul , MacEwan Joanna P. , Ramirez Robert A. 
Published: June 2022

e20617 Background: Platinum-based chemotherapy plus irinotecan or etoposide is the standard of care for first line (1L) treatment of small cell lung cancer (SCLC). Sensitivity to platinum-based chemotherapy has implications for regimen choice in subsequent lines of treatment. The goal of this study was to examine differences in patient characteristics, treatment patterns, and survival associated with the management of SCLC in a Medicare population by platinum sensitivity status, i.e., platinum sensitive (PS) or platinum refractory (PR). Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data. Patients were included if they had a record with a diagnosis of SCLC in the database from 1/1/2007 – 12/31/2017 and were ≥65 years of age at diagnosis. Patients also had continuous enrollment for ≥180 days pre-SCLC diagnosis and platinum-based 1L treatment. Patient characteristics, treatment patterns, and outcomes were stratified by PS status, which was defined as initiating 2L therapy more than 6 months after the last administration of platinum-based chemotherapy in 1L. Median overall survival (OS) was estimated using the Kaplan Meier method. Results: 7,208 patients met the study criteria and one in three (33.6%, N = 2,424) SCLC patients were PS. The PS population was majority female (64.4% vs 35.6% males), younger on average (aged 72.4 yrs vs 72.9 yrs), and more likely to be diagnosed at stage I-III than the PR patient population (50.6% vs 21.1%). Among PS patients, mean time from diagnosis to 1L treatment was 6.1 weeks versus 5.7 weeks among PR patients. Only 29.7% of PS patients initiating 1L went on to second line (2L) versus 40.4% of PR patients. 68.6% of PR patients received monotherapy in 2L, with topotecan (31.7%), paclitaxel (12.1%), and irinotecan (9.9%) being the most common monotherapy regimens. 51.7% of PS patients were retreated with platinum-based chemotherapy in 2L. Median OS from initiation of 1L was 20.2 months (95%CI: 19.3-21.1 months) among PS patients versus 6.4 months (95%CI: 6.2-6.6 months) among PR patients. 5-year survival was 20.0% among PS patients and 1.5% among PR patients. Conclusions: Approximately two-thirds of SCLC patients are refractory to platinum-based chemotherapy. These patients have fewer treatment options and shorter OS than PS patients, underscoring the ongoing need for effective therapies for SCLC.
Impact of cachexia on the efficacy of first-line immunotherapy in extensive-stage small-cell lung cancer patients.
Authors: Fan Xinyu , Li Butuo , Wang Linlin 
Published: June 2022

e20620 Background: This study was to investigate the association between cachexia and prognosis in extensive-stage small-cell lung cancer(ES-SCLC) patients who received first-line immunotherapy. And the prognostic values of some systematic inflammatory and nutritional indexes were also evaluated. Methods: Data of 123 ES-SCLC patients receiving immunotherapy as first-line treatment in one single center from June 2019 to February 2021 were analyzed. Development of cachexia after the initiation of immunotherapy was defined as patients with more than 5% weight loss over past 6 months, or more than 2% weight loss with body mass index (BMI) less than 20 kg/m2. Endpoints included response rate, progression-free survival (PFS) and overall survival (OS). Univariate and multivariate survival analysis were performed to identify the factors correlated with PFS and OS. Results: At evaluation after 6 months of initial treatment, cachexia was presented in 51 patients(41.5%). The treatment response and survival of patients with cachexia were worse than those without. The overall median overall survival (OS) was 14.4 months (95% CI 13.3–15.6). The overall median progression-free survival (PFS) was 8.1 months (95% CI 7.0–9.2). The median PFS was significantly longer in patients without bone metastases at diagnosis(HR = 2.362,95%CI:1.452-3.842;p = 0.001), without cachexia(HR = 1.802,95% CI: 1.121-2.895; p = 0.015), and with lower change of total protein(HR = 1.799,95% CI: 1.084–2.984; p = 0.023). The median OS was significantly shorter in patients with poor ECOG PS (HR = 1.904, 95% CI: 1.017-3.564; p = 0.044), higher baseline SII (HR = 2.135,95% CI: 1.117–4.080; p = 0.022), with cachexia(HR = 2.020,95% CI: 1.075-3.795; p = 0.029), advance M stage(HR = 3.111,95% CI:1.545–6.262; p = 0.001) and higher post-treatment SIRI (HR = 2.135,95% CI: 1.281–4.697; p = 0.007). Conclusions: ES-SCLC patients who develop cachexia after first-line immunotherapy have a poor prognosis. our study also confirms that baseline SII and SIRI at 6 weeks after treatment appears to be promising predictors for OS of ES-SCLC who treated with first-line immunotherapy.
Shift of tumor-infiltrating immune cells after adding immune checkpoint inhibitors to neoadjuvant chemotherapy against NSCLC.
Authors: Ren Yulin , Hui Zhenzhen , Zheng Liuqing , Wang QI , Wang Tao , Xiao Shanshan , Wang Hao , Liu Shaochuan , Ren Xiubao 
Published: June 2022

e21002 Background: Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has revolutionized the treatment strategies in multiple cancer types, including NSCLC. Anti-PD1 combined with chemotherapy was superior to chemotherapy alone, but the fundamental mechanisms underlying their synergic effect remain incompletely understood. Here, we investigated the different effects induced by neoadjuvant pembrolizumab combined with chemotherapy (NAPC) and neoadjuvant chemotherapy (NAC) on tumor immune microenvironment in patients with NSCLC. Methods: We performed single-cell RNA-sequencing (scRNA-seq) to characterize the immune cells composition in seven patients with NSCLC received NAPC or NAC and validated these findings in a large population cohort (n = 58) utilized multiplex fluorescent immunohistochemistry (mIHC). Results: The results of scRNA-seq revealed that patients with NSCLC received NAPC or NAC displayed distinct immune cell composition, with myeloid cells being the predominant cells in NAC patients, whereas T cells, B cells and NK cells were more abundant in NAPC patients. Consistent with these results, mIHC confirmed that compared to NAC, NAPC was associated with increased infiltration of CD8+ T cells, CD8+KLRG1+ effector cells, CD8+CD127+ memory cells, CD4+CD127+ memory cells, CD20+ B cells, accompanied by reduced CD66b+ neutrophils but had no effect on other immune subsets examined, including CD68+ macrophage, CD68+CD163+ M2 and mast cells. Survival analysis showed that, for both NAPC and NAC patients, CD8+ T cells, CD8+KLRG1+ effector cells, CD8+CD127+ memory cells were associated with favorable overall survival (OS), while CD66b+ neutrophils was related to inferior OS. Moreover, CD20+ B cells appear to have a more pronounced effect than CD8+ T cells on the efficacy of NAPC, but not for NAC. Conclusions: Compared to neoadjuvant chemotherapy, the addition of pembrolizumab induced a shift in tumor-infiltrating immune cells toward enhanced antitumor immunity and reduced immunosuppressive cells. In additional, post-treatment tumor-infiltrating immune cells were able to provide prognostic value.
Lung cancer patients with germline mutations have a unique fusion molecular spectrum.
Authors: Yang Zixin , Zheng Likang , Wu Yaqing , Luo Ningning , Zhang Qin , Bu Xuesong , Sun Tingting , Qi Chuang 
Published: June 2022

e21009 Background: In contrast to numerous studies of somatic mutations, the researches of lung cancer germline mutations remain smaller. Some certain germline mutations are assumed to increase susceptibility to lung cancer. However, the details of such mechanism remain to be established. In this study, DNA profiles were performed by targeted next-generation sequencing (NGS). Methods: A retrospective study of 3,421 lung cancer patients with available NGS data was performed to identify germline mutations. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, germline mutations were categorized as being pathogenic (P), likely pathogenic (LP) and other significance (Non_P). Thus, the patients were divided into two groups: patients with P or LP mutation(P&LP), and patients with Non_P mutation. Results: Of 3421 patients with lung cancer, 174 (5.09%) patients were identified to carry pathogenic or likely pathogenic germline mutations, with a median age of 62.5 years old. BRCA2, ATM, MUTYH, BRCA1 and ERCC2 were the top five genes with germline alterations, and their mutation rates were 11.5, 6.90, 6.32, 5.17 and 4.60%, respectively. Homozygous mutations were identified in only two patients, one was TP53( p.Ser215Ile), and the other was TSC2(splice site alteration). No statistically significant difference in age and sex between P&LP and Non_P group. Somatic mutation data was also involved in our study. The frequency of gene fusion events was same between these two groups. Interestingly, fusion molecular spectrum of P&LP group was different. Among all the 25 fusion events of P&LP group, 20 were unique and 19 fusion events couldn't be retrieved in the PubMed database. In total, 44 genes involved in fusion events and 5 genes were located on chromosome 17. Frequency of FAT1 single nucleotide variant (SNV) mutation was significantly higher in P&LP group (9.77% vs 5.57%, p = 0.03). Most copy number variations (CNV) were amplification, and frequency of EGFR copy number amplification was higher in P&LP group (19.5% vs 12.6%, p = 0.01). Conclusions: These data implied that genomic profile of lung patients who carried germline gene mutations could be different. Associations between germline mutation and lung cancer susceptibility, treatment will be studied further.
The genomic landscape of SMARCA4 and the clinical characteristics in Chinese NSCLC patients.
Authors: Guo Renhua , Li Jun , Xu Jiali , He Yuange , Sun Wei jie 
Published: June 2022

e21010 Background: The tumor suppressor gene SMARCA4 encodes a submit of SWI/SNF chromatin remodeling complexes and inactivated by mutations or other mechanisms. Previous studies have reported the genomic landscape of SMARCA4 and the clinical impact in Caucasian population, but the molecular and clinical characteristics in Chinese NSCLC patients have never reported. Herein, we explore the SMARCA4 profiles in Chinese population. Methods: A total of 740 patients of NSCLC with paired tumor-normal samples were collected into the study, all samples were detected by DNA based sequencing with a 1021 gene panel. Results: The incidence of SMARCA4 mutation in Chinese NSCLC patients was 7.16% (53/740), the top10 co-mutated genes were TP53, LRP1B, KEAP1, EGFR, KRAS, HGF, FGFR1, FAT1, CDKN2A, STK11. The SMARCA4 alterations were divided to functional or unfunctional mutations according to the OncoKB database (developed by MSKCC), then we compared the clinical characteristics among the SMARCA4-functional (S-F), SMARCA4-unfunctional (S-UNF) and SMARCA4-wide type (S-WT) patients. The results showed the S-F group tended to have more Male patients (88% vs. 64% vs. 55%, p = 0.004) and more smokers (68% vs. 46% vs. 34%, p = 0.015), meanwhile the age and histopathological subtype showed no significant difference among the three groups. We also analyzed the mutation burden characteristics, The S-F group have more somatic mutations (19.20 vs. 16.29 vs. 9.06, p < 0.0001) and higher TMB value (15.67 vs. 12.20 vs.5.61, p < 0.0001), indicating the patients may have more clinical benefits from immunotherapy. As recent studies revealed the SMARCA4 alterations associated with a very poor prognosis in NSCLC, according to our results, the immunotherapy may be an alternative strategy, and this need more clinical explorations. Conclusions: The patients with SMARCA4-functional mutations were associated with Male and smoker in Chinese population and tended to have more somatic mutations and higher TMB value, thus may benefit more from immunotherapy.
Molecular characteristics of EGFR exon20 mutations in NSCLC patients.
Authors: Ji Yinghua , Wang Jin , Meng Xiangli , Xie Jinling , Lu Ping , Li Mengmeng , Luo Ningning , Qi Yingxue , Zhu Xiaofeng 
Published: June 2022

e21011 Background: EGFR exon 20 mutations are associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 20 mutations are usually not present alone, suggesting a more complex subtype of exon 20 mutations. Methods: In this study, we retrospectively analyzed the different subtypes and compound mutation profiles of EGFR 20 mutations. A total of 1,233 NSCLC patients’ tumors were collected and the mutations were detected by next-generation sequencing (NGS) from May 2020 to June 2021. Results: A total of 415 NSCLC patients' tumors harbored EGFR exon 20 mutations, accounting for 33.66% of the entire EGFR mutation cohort. Among these 415 patients, most of mutations were single-nucleotide variant (SNV) (379; 91.33%), and a few were indel or insertion mutations (39; 9.40%). The insertions were all in the back of exon 20, which were resistant to EGFR-TKIs. In addition, the subtypes of SNV were concentrated in T790M (270; 71.24%), S768I (48; 12.66%) and C797S (33; 8.71%), and all T790M mutations were accompanied by other mutations. Notably, the compound mutations of exon 20 have also been analyzed in this study. EGFR exon 20 combined with other EGFR mutations were detected in 345 patients. The compound mutations of exon 20-18, exon 20-19, exon 20-20 and exon 20-21 were detected in tumors from 52 (15.07%), 163 (47.25%), 43 (12.46%) and 140 (40.58%) patients respectively. Remarkably, the compound mutation subtype of exon 20-20 was T790M/C797X (29; 67.55%) and exon 20-21 was T790M/L858R (124; 88.57%). Conclusions: Diverse patterns of SNV mutations are seen in EGFR exon 20 mutations tumors. EGFR 20 mutations often accompany other mutations, which are associated with resistance to EGFR-TKIs. These data may help avoid the resistance of future adjuvant targeted therapy.
Clinical characteristic and outcomes of KRAS G13 mutant non-small cell lung cancers.
Authors: Muthiah Arun , Chudasama Rani , Mingrino Jennifer , Olszewski Adam J , Kurt Habibe , Garcia-Moliner Maria , Khan Hina 
Published: June 2022

e21017 Background: KRAS is the most commonly mutated oncogene in lung adenocarcinoma. Different KRAS mutations (mts) have unique prognostic and therapeutic implications. New drugs to target KRAS G12C have raised interest in studying the unique clinical and molecular characteristics of the different KRAS subtypes. We sought to evaluate the clinical outcomes of KRAS G13C/D (*) mutant (mut) non-small cell lung cancers (NSCLC) patients (pts), compared to those with G12C and other non-G12C mutations. Methods: We identified 255 KRAS mt NSCLC pts at Brown University-Lifespan Cancer Institute that were diagnosed between 06/2016 to 12/2021. Demographics, therapies and outcomes were retrospectively recorded. Progression-free (PFS) and overall survival (OS) was compared using log-rank test. For clinical relevance, we divided pts into G12C, G13*, and other non-G12C groups. Treatments (tt) received were divided into chemotherapy alone and immune-checkpoint inhibitor (IO) containing regimens. Results: Across the KRAS cohort (n = 255), median age was 71 years and 62% were females. Most pts had advanced disease (85%) at diagnosis (dx) and > 90% were smokers. Most common KRAS mt was G12C (42%), and 7% of pts had G13*. Compared to other KRAS mut groups, G13 * had worse PFS counted from dx (median 4 vs 12 m, p = .037). When comparing outcomes of any tt among pts with G13*, G12C and other non-G12C KRAS mut, G13 group had the worst PFS (2.1 vs 10.3 vs 6.4 m, p = .004) and OS (4.1 vs 27.8 vs 18.1 m, p = .027). When treated with IO-based regimens, pts with G13 had also worse outcomes than those with other KRAS mts: PFS 1.8 vs 7.3 m, respectively, (p < 0.001) and OS 1.8 vs 16.5 m, respectively (p = .006). Within the G13 group, pts who received IO-based regimens had worse PFS (1.8 vs 7.9 m, p = .037) and OS (1.8 vs 16.1 m, p = .093), compared to chemotherapy alone. While response to all systemic therapies was poor in G13* group (disease control rate [DCR] 10%, p = .004), DCR was particularly low with IO-based tt in G13* (0%) compared to other groups (p = .023). Conclusions: Pts with KRAS G13C/D had poor survival and response to therapies in comparison with G12C and other non-G12C KRAS mts, particularly with IO-containing regimens. Recently (Judd et al, MCT-21-0201), STK11 and KEAP1 were reported to be frequently co-mutated with KRAS G13* (37.3 and 12.6%) compared to other KRAS mts, and this genotype may confer primary resistance to IO. We hypothesize that the poor outcomes and immune resistance in G13* mut may be secondary to higher prevalence of STK11 and KEAP1 co-mutations. Larger data sets should confirm our observations and correlate them with PD-L1 scores and co-mutations.[Table: see text]
Peripheral blood t cell responses to immunotherapy related adverse events in metastatic non-small cell lung cancer.
Authors: Amara Suneetha , Muzaffar Mahvish , Namireddy Praveen , Yang Li V. 
Published: June 2022

e21047 Background: There has been prospective and retrospective evidence for the onset of immunotherapy (IO) related adverse events (irAE) and efficacy of anti programmed death (PD1) and Programmed death Ligand 1(PD L1) antibodies. The incidence of irAE in these studies ranged anywhere from 30-44%. There have been attempts in the past to cluster irAEs into distinct subtypes by T cell profiling before and after immunotherapy. Identifying the trend of CD4/CD8 changes during irAE may aid in finding ways to mitigate the severe toxicities, so the benefits of immunotherapy can be extended to far more number of patients. Methods: We have collected blood samples from 20 patients of Non Small Cell Lung Cancer patients (NSCLC) before each cycle of immunotherapy with informed consent. We have measured the different inflammatory markers such as IL6, IL10 using ELISA and isolated cellular components such as CD4, CD8 T cells along with others using magnetic bead technique, from these samples in our research laboratory at East Carolina University. We have also collected clinical information including the adverse events with their (Common Terminology Criteria for Adverse events) CTCAE 5.0 grading, different cell counts and C- reactive Protein (CRP). Results: In the cohort of 20 patients, 9 experienced irAE, out of which 6 had grade 2, including thyroiditis, pneumonitis, dermatitis, cytokine release syndrome (CRS), 1 had grade 3 pneumonitis, 1 had grade 4 pneumonitis and 1 had grade 1 CRS. When we looked at the CD4/CD8 ratio before each cycle, the one prior to the incidence of the irAE had at least 30-40% drop in the ratio consistently although there were minor fluctuations in the ratio at other times in both directions. Conclusions: Although most irAEs can be treated and reversed with steroids and other immunosuppressive agents, prolonged immunosuppression can lead to reduced efficacy of IO and development of undue opportunistic infections. Experience with IO has shown that earlier initiation of immunosuppression shortens the required treatment. However, given the challenge in the subtility of the earlier presentation, therapies are frequently delayed. Hence, biomarker to identify the early manifestations is of critical importance for early intervention. Studies suggest there is clonal expansion of CD8 T cells preceding grade 2-3 irAEs. Studies also indicate that increased T cells in the tumor is indicative of response to immunotherapy. Our observation suggests that increased CD8 in proportion to CD4 in the peripheral blood precedes the onset of irAE. It is unclear as to how this leads to increased toxicity when the immunotherapy treatment works by affecting T cell function. One possible explanation is that the T cell response in the tumor tissue is beneficial, however, T cell response in the peripheral blood may indicate response against self antigens leading to toxicities in the form of irAE.
Short-term efficacy of furmonertinib in treatment of NSCLC patients with EGFR exon20 insertion.
Authors: Zhou Xiaoyue , Dong Huajie , Li Peng , Wu Changling , Lu Hongjun , Xiao Mingzhe , Zhou Tong 
Published: June 2022

e21063 Background: EGFR is a key driver gene of lung cancer, in which exon 20 insertion (Ex20ins) mutation accounts for about 1-5%. However, the first- and second-generation EGFR-TKI had poor efficacy on patients with Ex20ins mutation (ORR = 6.9%, mPFS = 1.9 months, mOS = 12.9 months, DCR = 44.8%). Our study retrospectively observed the short-term efficacy and safety of furmonertinib in Chinese NSCLC patients with EGFR Ex20ins mutation. Methods: The study retrospectively collected 15 NSCLC patients with EGFR Ex20ins mutant who were treated in two medical institutions in Changzhou City, Jiangsu Province from April 2021 to December 2021. All patients received targeted therapy with furmonertinib. The last follow-up time was December 30, 2021. All patients received 160 mg furmonertinib orally until disease progression, drug intolerance, patient refusal or death. EGFR Ex20ins mutation was confirmed by ARMS or next generation sequencing (NGS). The patient's gender, age, score of Eastern Cooperative Oncology Group (ECOG), smoking history, pathological type, tumor stage, gene status and other basic clinical characteristics and adverse events (AES) were collected. The clinical efficacy was evaluated according to RECIST version 1.1, and the adverse events were evaluated according to the NCI-CTCAE version 5.0. SPSS 25.0 software was used to record and analyze the data. Results: All 15 patients had received ≥2 lines of therapy. The median age was 62 (25-80) years old, and there were 8 male patients (53.3%). Most patients had no smoking history (13 cases, 86.7%). ECOG score was mostly 1 (13 cases, 86.7%). In 15 patients, we found 10 different EGFR Ex20ins variants, among which p.A767_V769dup (n = 3) and p.A767_V769dup (n = 4) were more common. By the end of follow-up, 15 patients had completed at least one efficacy evaluation, and all had different degrees of tumor regression. No patient reached CR, 8 patients had PR and 7 patients had SD. This preliminary efficacy data showed that the overall ORR was 53.5% and DCR was 100%. No grade 3 or above adverse events were observed. The 3-months PFS rate was 100%. Conclusions: The results of this study in ≥2 lines patients treated with twice the conventional dose had a good curative effect (compared with 3 times of conventional dosage in FAVOUR study), which provided more treatment options for NSCLC patients in multiple lines of treatment and could alleviate part of their economic pressure, but the PFS and OS data still need further follow-up and verification of a larger sample size. The overall findings suggested that furmonertinib is a third generation EGFR-TKI with good efficacy and acceptable safety. Given the heterogeneity of EGFR Ex20ins mutation, the efficacy of targeted therapy may vary in different mutation types and requires further investigation.