bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer (NSCLC) patients.
Authors: Fung Andrea S. , Karimi Maryam , Michiels Stefan , Seymour Lesley , Brambilla Elisabeth , Le Chevalier Thierry , Soria Jean-Charles , Kratzke Robert Arthur , Graziano Stephen L. , Devarakonda Siddhartha , Govindan Ramaswamy , Tsao Ming-Sound , Shepherd Frances A. 
Published: May 2020

e21080 Background: The prognostic and predictive role of KRAS mutations and gene copy number aberrations (CNA) in early stage NSCLC is unclear. In this study, we characterize the prognostic effect of KRAS mutation status and concomitant CN gain in early stage NSCLC, and determine the ability to predict survival benefit from adjuvant chemotherapy. We hypothesize that concomitant KRAS mutations and CN gain will be prognostic of worse survival compared to KRAS mutations alone. Methods: Clinical and genomic data from The LACE (Lung Adjuvant Cisplatin Evaluation)-BIO consortium was utilized. CNA were categorized as Gain or Neutral (Neut)/Loss; mutation status was defined as wild type (WT) or mutant (MUT). WT+Neut/Loss (reference), WT+Gain, MUT+Gain and MUT+Neut/Loss groups were compared in all patients and the adenocarcinoma subgroup. Primary endpoint was lung-cancer-specific survival (LCSS); secondary endpoints were DFS and OS. Survival curves were assessed using Kaplan-Meier and log-rank tests. Concomitant KRAS CNA and mutation status was correlated to endpoints using a Cox proportional hazards model stratified by trial and adjusted for treatment, age, gender, histology, WHO performance status, surgery type, tumor and nodal stage. A treatment-by-variable interaction was added to evaluate predictive effect. Results: 946 (399 adenocarcinoma) patients had complete KRAS mutation, CNA and clinical data: 41 (30) MUT+Gain, 145 (99) MUT+Neut/Loss, 125 (16) WT+Gain, 635 (254) WT+Neut/Loss. There was a negative prognostic effect of KRAS MUT+Neut/Loss for LCSS (HR = 1.32 [1.01-1.71]) on univariable analysis, and to a lesser extent after adjusting for covariates (HR = 1.28 [0.97-1.68]). A similar non-significant trend was observed in KRAS MUT+Gain patients for LCSS (HR = 1.34 [0.83-2.17]), DFS (HR = 1.34 [0.86-2.09]) and OS (HR = 1.59 [0.99-2.54]). There was no significant predictive effect in the overall population; however, a potential predictive effect of KRAS for OS was seen in the adenocarcinoma subgroup (interaction p = 0.046). KRAS MUT+Gain was associated with a beneficial effect of chemotherapy on DFS (HR = 0.33 [0.11-0.99], p = 0.048), with a non-significant trend also seen for LCSS (HR = 0.41 [0.13-1.33]) and OS (HR = 0.40 [0.13-1.26]). Conclusions: A small prognostic effect of KRAS mutation was identified for LCSS. A potential predictive effect of concomitant KRAS mutation status and CNA was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require further validation.
Management of medical inoperable and tyrosine kinase inhibitor-naive early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: A retrospective multi-institutional analysis.
Authors: Sun Yue Mei , Zhou Ming Xiu , Zeng Ming 
Published: May 2020

e21082 Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) and for medical inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations is not yet determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI alone and combined radiation and TKI on the survival outcomes in this patient subgroup. Methods: 132 cases of medical non-operable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among the patients, 65 cases received combined radiation and EGFR-TKI therapy (R+TKI) (49.2%), while 67 cases had EGFR-TKI (50.8%) treatment alone. All patients were followed until death. Results: For R+TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < .001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups were 24 months and 14.7 months respectively (log-rank p < .001). Multivariate analysis showed that R+TKI was independently associated with improved OS (adjusted HR: 0.420; 95% CI, 0.287 to 0.614; p < .001) and PFS (adjusted HR: 0.420; 95% CI, 0.291 to 0.605; p < .001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. Conclusions: Upfront radiation to primary sites with TKI to follow was a feasible option for patients with EGFR-mutant medical inoperable non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with TKI alone
Reconstruction of the superior vena cava in patients with thymic malignancies.
Authors: Yu Lei 
Published: May 2020

e21116 Background: Thymoma is a kind of mediastinal tumors usually with an indolent growth pattern but malignant because of potential for local invasion, pleural dissemination, and even systemic metastases. Different from other malignant tumors, thymoma is often associated with autoimmune disorder s, the most common one being myasthenia gravis (MG). Complete surgical excision has been regarded as the standard of care for patients with thymoma, esp. locally advanced thymoma. The aim of this study was to investigate the effectiveness of reconstruction (Y-shaped bypass) of the superior vena cava (SVC) to treat locally advanced thymoma with SVC syndrome. Methods: We retrospectively studied data from 24 consecutive patients with locally advanced thymoma and SVC syndrome, operated on from October. 2015 to Dec. 2018 in Beijing Tongren Hospital. Their clinical data including clinical presentation, operation procedure, postoperative drug, adjuvant radiochemotherapy and follow-up were documented. 18 cases had MG, one having dermatomyositis, and two having interstitial pneumonia. Results: There were no perioperative deaths. All patients underwent complete resection and replacement with a GORE-TEX Vascular Graft (Y-shaped bypass) of SVC. The number of typeAB, B1, B2, B3 thymoma, and thymic carcinoma in this data were 2, 2, 7, 7, and 6, respectively. 7 patients had postoperative complications: 3 (with MG) experienced myasthenia crisis, 3 had pneumonia, and one had pulmonary embolisms, respectively. Both unfractionated heparin and Warfarin were routinely used the second or third day after surgery to maintain INR (International Normalized Ratio) between 1.8 and 2.5. All patients received mediastinal radiation therapy within one month after surgery. All patients were followed up for 2 months to 42 months. There were no patients dying and recurring. Conclusions: Reconstruction of SVC (Y-shaped bypass) is an effective way to treat locally advanced thymoma with SVC syndrome. After surgery, postoperative anti-thrombotic agents should be applied to prevent acute graft occlusion.
Monitoring immunotherapy response in non-small cell lung cancer patients using 5-hydroxymethylcytosine signatures in circulating cell free DNA.
Authors: Guler Gulfem , Haan David , Ning Yuhong , Ku Jeremy , McCarthy Erin , Phillips Tierney , Antoine Michael , Bergamaschi Anna , Lloyd Paul , Scott Aaron , Ellison Chris , Levy Samuel 
Published: May 2020

e21505 Background: Liquid biopsies are gaining prominence for not only cancer diagnosis but also patient monitoring. Mutational signals derived from cell-free DNA (cfDNA) show promise to assess response to cancer treatment, including immunotherapy. However, reliance of these methods on mutational data from tissue biopsies limit their applicability when a tumor biopsy is unavailable, or when mutational landscape of tumor changes under the selective pressures of cancer drug treatment. Epigenomic approaches have the potential to address these shortcomings. Methods: Blood draws were obtained from a cohort of non-small cell lung cancer (NSCLC) patients (n = 19) who went on to anti-PD1 treatment prior to therapy start and while on therapy. cfDNA was isolated from plasma and was subsequently processed to generate 5hmC genome-wide profiles. Results: We analyzed cfDNA from NSCLC patients undergoing anti-PD1 therapy to investigate whether immunotherapy response can be detected from plasma. Using a predictive model trained on lung cancer and non-cancer samples, we were able to detect changes in prediction scores in patient treated with immunotherapy that were consistent with RECIST. Patients with progressive disease (n = 3), determined by RECIST, had prediction scores that increased while they received treatment. On the other hand, majority of the patients that exhibited partial response to treatment (n = 12) had predictive scores that decreased with treatment, again consistent with RECIST. Furthermore, score changes consistent with RECIST was observed one cycle prior to the RECIST timepoint in all except one patient, where an extra blood draw after baseline was available (n = 7). Annotation of the regions that account for differential scoring identified enhancer, 5’UTR and promoter regions. Comparison of partial responders to patients with progressive disease revealed genes involved in metastasis, oncogenes and tumor suppressors that change in opposing directions between these patient groups, consistent with the underlying biology. Conclusions: Our results suggest that 5hmC profiles from cfDNA can be used to determine immunotherapy response in non-small cell lung cancer patients. Compared with mutation based liquid biopsy methods to assess response, epigenomics-based methods have the advantage of being agnostic to starting tumor mutations, and not relying on a mutational analysis from tumor biopsy. Future work will help determine applicability of this method to other kinds of therapies and cancer types.
Clinical management of lung adenocarcinoma patients with HER2 V659E mutation.
Authors: Jia Ziqi , Liang Naixin , Wang Yadong , Wang Yanyu , Ye Junyi , Wang Weiwei , Li Bing , Han-Zhang Han , Zhao Jiaxing , Zhang Xiaochun , Peng Feng , Chen Fengxia , Chen Xueqin , Lu Yan , Ying Shenpeng , Dp Wu , Zhang Xinwei , Ma Caixia , Lai Lipeng , Ma Songling 
Published: May 2020

e21521 Background: ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i. Methods: We retrospectively screened genomic profiles of 7,812 lung adenocarcinoma (LADC) patients. Molecular docking of lapatinib, afatinib and pyrotinib with the HER2 KD was simulated with AutoDock 4.2 and the binding affinity was predicted by MMPBSA.py program in AmberTools18. Results: We analyzed NGS data of 7812 LADC patients and identified 14 patients (0.18%) with HER2 TMD mutation, mostly V659E mutation (11/7812, 0.14%); other mutations included V664F, T652M, V664F; each occurred in 1 patient. In this cohort, all adenocarcinomas harbor a dinucleotide missense mutation, including 10 TT→AA and 6 TT→AG (c.1976_1977). T P53 was the most frequently co-mutated gene (n = 4) followed by HER2 (n = 2), NSD1 (n = 2) and RARA (n = 2). Treatment history of 9 advanced LADC patients were collected and analyzed. 3 of them had chemotherapy as first-line therapy. 5 patients were treated with HERi as first-line therapy, achieving a median PFS of 192 days (ranged from 60-515days), comparing to patients treated with chemotherapy (71.7±53.3days). 1 patient who was treated with different HERi sequentially in the order of lapatinib, afatinib, TDM-1, achieving an overall PFS of 515 days. Subsequently, she was treated with pyrotinib and had a PFS of 92 days. Molecular docking simulation showed the covalent inhibitors Afatinib and Pyrotinib are more favorable for blocking HER2 KD than non-covalent inhibitor Lapatinib. Between the two covalent inhibitors, Pyrotinib (∆GPyrotinib = -65.92kcal/mol) shows stronger non-covalent binding ability than Afatinib (∆GAfatinib = -59.71 kcal/mol) (p < 0.001). Conclusions: To the best of our knowledge, this is the largest-reported HER2 V659E mutation cohort. We revealed the prevalence of ERBB2 V659E in Chinese LUAD patients and elucidated the genomic profile of ERBB2 V659E mutant. This study paves avenue for the utilization of the novel HER2 inhibitors pyrotinib in ERBB2 V659E mutant LUAD patients.
Major pathologic response of EGFR mutated non-small cell lung cancer (NSCLC) on 1-3 G TKI.
Authors: Moiseenko Fedor Vladimirovich , Kryukov Kirill , Myslik Alexander , Levchenko Nikita , Ivantsov Alexander , Aleksakhina Svetlana , Volkov Nikita , Gabina Albina , Shelekhova Ksenia , Artem'eva Elizaveta , Moiseyenko Vladimir 
Published: May 2020

e21528 Background: Despite impressive clinical efficacy in response rate, increase in PFS and sometimes in OS EGFR TKI rarely cure cancer patients, as all of them inevitably develop resistance. Small fractions of residual cells appear to be a reservoir of further clones with acquired resistance. For this moment morphological characteristics of “persister” population are not well defined. Methods: We screened hospital data-base containing > 200 pts for EGFRmut NSCLC who underwent cytoreductive surgical treatment during treatment with either TKI and before radiographic disease progression. We obtained 18 pairs of pretreatment biopsy and surgical specimen. 7/18 were male, median age 60.5 yo (45-79). 15/18 had ex19del; 3/18 – L858R. 12/3/2/1 received gefitinib/erlotinib/afatinib/osimertinib before surgery. Median time from treatment initiation to surgery was 8.9 mon (0.7 – 24.3). None of the pts had evidence of increase in any dimension of tumor lesions before surgery. According to RECIST 6/18 pts had SD, 12/18 – PR. 6/18 pts had complete cytoreduction, 4/18 – partial, 8/17 – metastasectomy. All pathologic responses (MPR) were graded according to Hellmann MD et al., 2014. Results: Pathologic response with > 50% of residual tumor – 2/18; 10-50% – 7/18; < 10% – 4/18; pCR – 3/18. Median observation time is 15.4 mon (8.4 – 37.2+). Disease progression after surgery was registered in 6/18 pts. No significant correlations between PFS, MPR, RR, TKI generation, time to surgery were seen. Conclusions: In our serie MPR rate ( < 10% of viable tumor cells according to Hellmann MD et al, 2014) for NSCLC treated with various TKI was 38%, that is higher than in other reports (10.2% in CTONG 1103 for example). Further characterization of the “persister” tumor cells may help to determine mechanisms of intrinsic resistance and direct more efficient antitumor activity.
Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertions.
Authors: Chen Kaiyan , Pan Guoqiang , Xu Yanjun , Fan Yun 
Published: May 2020

e21540 Background: This study aimed to investigate the immune microenvironment features and efficacy of PD-1/PD-L1 blockade of NSCLC with insertions in exon 20 (Ex20ins) of EGFR or HER2. Methods: Molecular spectrum, tumor mutational burden (TMB), PD-L1 protein expression, and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) were reviewed for NSCLC patients with Ex20ins of EGFR or HER2. Results: Thirty-five patients carrying EGFR Ex20ins and 21 patients harboring HER2 Ex20ins were retrospectively enrolled between April 2016 and September 2018. The average TMB was 3.3 mutations/megabase. PD-L1 expression in patients with EGFR Ex20ins was significantly higher than those with HER2 mutations (48.6% vs. 19.0%, P=0.027). High TMB and PD-L1 expression was independently associated with considerably poor prognosis (P=0.025, P=0.045; respectively). Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD-1/PD-L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins. Conclusions: NSCLC patients with EGFR/ HER2 Ex20ins had distinct immune features. Patients with EGFR Ex20ins had significantly higher PD-L1 expression than those with HER2 mutations, which may be the underlying reason for the different responses to PD-1/PD-L1 blockage.
Correlation between tissue PD-L1, TMB, and blood PD-L1, MSI biomarkers in patients with advanced-stage non-small cell lung cancer (NSCLC).
Authors: Nandimandalam Sujitha , Sharma Nitika 
Published: May 2020

e21564 Background: Tissue biomarkers like programmed cell death ligand-1 (PD-L1), microsatellite instability (MSI) and high tumor mutational burden (TMB) are surrogates in identifying patients with non-small cell lung cancer (NSCLC) for treatment with immune checkpoint blockade (ICB) therapy. Although tissue biopsy is widely used for identifying the tumor biology, the invasive nature as well as insufficiency of tissue biopsy specimens limits its application. Liquid biopsy is a minimally invasive procedure and has gained interest in recent times for profiling cancer. We sought to study the correlation in the molecular tumor profile specifically PD-L1, MSI and TMB markers between the tissue and liquid biopsies. Methods: We conducted a retrospective review of patients with Stage 3, 4 and recurrent NSCLC that underwent tissue next generation sequencing (NGS) using Caris life sciences and liquid biopsy using Circulogene molecular diagnostics from January 2018 to December 2019 at East Carolina University. A total of 524 patients were reviewed out of which 199 patients had both liquid and tissue NGS performed at the time of initial diagnosis. TMB high was defined as greater than 10 mut/Mb whereas TMB low as less than or equal to 10 mut/Mb. PD-L1 was divided into negative (0%), 1-49% and ≥50%. The blood MSI was classified as positive or negative. We used frequency table, logistic regression and Pearson bivariate correlation for statistical analysis using SPSS platform. Results: The study cohort had 60% (n = 119) male and 40% (n = 80) female patients of which 53% (n = 105) were Caucasians and 45% (n = 89) were African Americans. A total of 87 patients (44%) had negative tissue PD-L1, 59 patients (30%) had tissue PD-L1 ≥ 50%. A linear correlation was seen between negative tissue PD-L1 and negative blood PD-L1 in 92% of patients (n = 80). However, only 15.3% (n = 9) had correlating tissue PD-L1 and blood PD-L1 ≥ 50%, p = 0.024. The negative blood MSI correlated to low tissue TMB in 83% ( n = 60) whereas positive blood MSI correlated to high tissue TMB in 25% (n = 19), p = 0.023. Conclusions: Our results indicate a linear correlation between tissue PD-L1 and blood PD-L1. Similarly, a linear correlation was seen between blood MSI and tissue TMB. Further studies are needed to elucidate the efficacy of ICB therapy using blood MSI and blood PD-L1 as biomarkers for response to therapy.
Assessing the risk of serious adverse events (SAEs) and death in non-small cell lung cancer (NSCLC) trials.
Authors: Marvania Nirali , Chan Abigail Sy , Abraham Joseph , Miller Kenneth David 
Published: May 2020

e21576 Background: Lung cancer is a leading cause of morbidity and mortality despite advances in targeted therapy and immunotherapy. Clinical trials play a critical role in improving treatment options however, pose significant known and unknown risks. The purpose of this study was to analyze the risk of SAEs (Grade 3 and 4 toxicity) and deaths in advanced NSCLC patients participating in phase I/II and III clinical trials. Methods: A literature search using Clinicaltrials.gov was conducted to identify published phase I/II and III clinical trials in advanced NSCLC patients. The data extracted included study name, total number of participants, SAEs, and deaths attributable to a study drug. A fixed-effects model was implemented to estimate summary proportions of SAEs among participants. The Freeman-Tukey double arcsine transformation was applied to stabilize the variances of SAEs and mortality proportions. Results: We evaluated 112 studies, of which 87% were phase I/II, and 13% were phase III clinical trials. Study sample sizes ranged from 7 to 659 patients for phase I/II studies and from 186 to 1391 for phase III studies. 107 studies had SAEs while 5 phase I/II studies had no SAEs reported. The overall estimated percentage of SAEs was 39.5% (95% Confidence Interval, CI: 38.8%, 40.2%). The estimated percentages of patients with SAE in phase I/II and phase III trials were 40.9% (95%CI: 39.8%, 42.0%) and 38.7% (95%CI: 37.8%, 39.6%), respectively (p = 0.001). The estimated percentages of deaths among patients were 1.1% (95%CI: 0.90%, 1.3%) overall, 1.1% (95%CI: 0.7%, 1.5%) in phase I/II trials and 1.7% (95%CI: 1.5%, 2.0%) in phase III trials. The difference in mortality between phase I/II and phase III trials was not statistically significant (p = 0.408). Conclusions: Patients with advanced stages (III/IV) of NSCLC have a high risk of morbidity and mortality from their primary disease and also from their treatment. Our study demonstrated SAEs and toxic deaths attributable to the treatment of approximately 40% and 1%, respectively. Phase I/II trials patients are at a slightly higher risk of SAEs compared to patients participating in phase III trials, although the differences might not be clinically significant.
Prevalence of ALK mutations in advanced NSCLC patients in the United States: Analysis with a real world oncology database.
Authors: Allen Timothy , Xiao Yan , Abraham Anup , Redpath Stella , Engstrom-Melnyk Julia , Croix Denise , Yang Baiyu , Shah Roma , Madala Jaya , Bernicker Eric 
Published: May 2020

e21586 Background: ALK mutation rate is widely reported to be 3-7% of advanced non-small cell lung carcinoma (aNSCLC) patients. A cross-sectional study to assess the prevalence of ALK mutations in the real world was performed on the nationwide Flatiron Health electronic record-derived de-identified database. Methods: Patients with aNSCLC (stage IIIB-IV) diagnosed between 1 Jan 2015 – 31 May 2019, age ≥18 at the time of aNSCLC diagnosis, known ALK result and smoking status were included in the analysis. The included patient cohort had 19,895 eligible patients, with a mean age of 68.5 (Standard deviation = 10.0), most of them were ever-smokers (85.5%) and from community centers (92.2%). Results: The overall ALK mutation prevalence was 2.6%. Prevalence of ALK mutation was calculated by age, gender, race, ECOG status and cancer type. Non-smokers had the greatest mutation rate (9.3% non-squamous histology, 6.3% NSCLC histology not otherwise specified [NOS], 3.3% squamous) vs smokers (1.7% non-squamous, 1.4% NSCLC NOS, 0.7% squamous). Differences in ALK status varied by age and race with young patients (18-44 yrs) having a greater mutation rate (16.2%) vs older patients (age 45-64 = 4.5%, age ≥ 65 = 2.2%) and Asian patients having a mutation prevalence of 6.3%. Patients that were positive for other biomarkers (EGFR, ROS1, KRAS or BRAF) had a lower ALK positivity rate (0.5%) while patients reported to be positive for PD-L1 had an ALK mutation rate of 3.0%. Conclusions: While this data overwhelmingly represented testing in the community setting vs academic medical centers, it provides insight into the ALK mutation prevalence across the US. The prevalence of ALK mutations in smokers suggests that a smoking patient (with non-squamous, mixed histology or small biopsy) should not be excluded from testing. This also highlights the need to capture smoking histories as accurate pack-year histories