bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of systemic treatment on brain metastasis in patients with non-small-cell lung cancer: A retrospective nationwide population-based cohort study.
Authors: Ko Yoon Ho , Hong Ji Hyung , Sun Der Sheng , Won Hye Sung , Kang Seok Yun , Lee Jung Soo , Lee Hyun Woo 
Published: May 2019

e20572 Background: We performed a large-scale, retrospective, nationwide, cohort study of the incidence of brain metastasis in patients with advanced non-small-cell lung cancer (NSCLC) according to the systemic treatment administered. Methods: The data were extracted from the Health Insurance Review and Assessment Service of Korea database from January 1, 2011 to November 30, 2016. Of the 29,224 patients newly diagnosed with stage IIIB or IV NSCLC who received first-line cytotoxic chemotherapy (CC group) or targeted therapy (TT group), 22,508 patients without brain metastasis were analyzed. Results: In total, 1,131 (5.0%) patients subsequently developed brain metastasis. The overall cumulative incidence of brain metastasis was significantly higher in the TT group than in the CC group (1-year cumulative incidence: 8.7 ± 0.6% vs. 3.8 ± 0.3%; 3-year: 17.2 ± 0.7% vs. 5.0 ± 0.3%, respectively; P < 0.001), despite the higher rate of brain metastasis in the CC group at < 3 years after diagnosis. Younger age, female sex, living in a rural area, anticoagulant use, and first-line TT (relative risk, 2.17 ± 0.03; 95% confidence interval, 1.92–2.50, P < 0.0001) retained significant associations with subsequent brain metastasis after adjusting for all variables. Conclusions: In the Korean population, the overall cumulative incidence of brain metastasis was significantly higher in patients in the TT group than in those in the CC group; the former could be regarded as having mutations in the EGFR or ALK gene.
The impact of steroid use on efficacy of immunotherapy among patients with lung cancer who have developed immune-related adverse events.
Authors: Wakuda Kazushige , Miyawaki Taichi , Miyawaki Eriko , Mamesaya Nobuaki , Kawamura Takahisa , Kobayashi Haruki , Omori Shota , Nakashima Kazuhisa , Ono Akira , Kenmotsu Hirotsugu , Naito Tateaki , Murakami Haruyasu , Mori Keita , Endo Masahiro , Takahashi Toshiaki 
Published: May 2019

e20583 Background: Systemic steroids use before starting immune checkpoint inhibitors (ICI) has negative impacts on survival. The aim of this study was to evaluate whether steroid against immune-related adverse events (irAE) reduces efficacy in patients with non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed patients who had advanced NSCLC and undergone ICI therapy between December 2015 and June 2018. Patients whose irAE was treated with ≥ 10mg/day of predonisone were classified into steroid group (S), otherwise into non-steroid group (N). Results: A total of 257 patients (pts) were treated with ICI and irAEs was observed in 103 pts (40%). Twenty-eight pts were S-group and 75 patients were N-group. There was no significant difference in age, sex, stage, performance status, histology, smoking status, gene alteration, expression of PD-L1, or treatment line between the groups. Main irAEs included pneumonitis (43% in S-group / 12% in N-group), diarrhea or colitis (25% / 9%), rash (21% / 20%), and hypothyroidism (14% / 37%). Grade 2 or higher irAEs were pneumonitis in 39% / 0%, diarrhea or colitis in 21% / 5%, hypothyroidism in 7% / 19%. Among S-group, steroids were used for pneumonitis in 11 pts, diarrhea or colitis in 7 pts, stomatitis in 2 pts, and rash in 2 pts. There was no significant difference in overall survival (median; 14.5 vs 30.0 months, P = 0.30, Hazard ratio, 0.69), progression-free survival (median; 7.8 vs 9.6 months, p = 0.11, Hazard ration, 0.65), and objective response rate (46% vs 41%, p = 0.64), respectively. Conclusions: Systemic steroid was mainly used in pts with ≥Gr2 pneumonitis or colitis. This study indicated that steroids use did not reduce efficacy of ICI. Thus, steroid should not be avoided in patients with moderate to severe irAEs with concern over reducing efficacy.
EGFR-A763_Y764insFQEA: A unique exon 20 insertion mutation that displays sensitivity to all classes of approved lung cancer EGFR tyrosine kinase inhibitors.
Authors: Gergis Carol , Rangachari Deepa , Fujii Masanori , Varkaris Andreas , VanderLaan Paul A , Kobayashi Susumu , Costa Daniel Botelho 
Published: May 2019

e20593 Background: The epidermal growth factor receptor (EGFR)-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation (accounting for ~10-20% of all EGFR exon 20 insertions) that more closely resembles EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants (i.e. EGFR-exon 19 deletions and L858R) at the structural and enzymatic level as compared to other non-classical mutations. A limited number of preclinical models and clinical reports have detailed the response of EGFR-A763_Y764insFQEA-driven lung tumors to approved or in-development TKIs. Methods: Multiple preclinical models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations were used to probe representative 1st generation (gefitinib, erlotinib), 2nd generation (afatinib, dacomitinib), 3rd generation (osimertinib), and in-development EGFR exon 20 specific (poziotinib, others) TKIs. Clinical outcomes and prior reports of EGFR-A763_Y764insFQEA mutated lung adenocarcinomas treated with EGFR TKIs were compiled. Results: Cell lines driven by EGFR-A763_Y764insFQEA were consistently sensitive to 1st, 2nd and 3rd generation EGFR TKIs, while models driven by other EGFR exon 20 insertions (i.e. D770_N771insSVD and H773_V774insH) were only inhibited by in-development EGFR TKIs and at doses below those affecting the wild-type receptor. The majority of patients with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinical doses of 1st, 2nd, and 3rd generation EGFR TKIs; and lung cancers with these mutants are currently enrolled in clinical trials of in-development EGFR exon 20 specific TKIs. Conclusions: This is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation sensitive to 1st, 2nd, 3rd generation and in-development EGFR exon 20 specific TKIs. Mechanisms of acquired resistance of this mutant to different EGFR TKIs remain unreported.
Chemoimmunotherapy combination: Potential option for metastatic NSCLC patients with EGFR mutation resistant to osimertinib.
Authors: Yang Bo , Long Yaping , Hu Yi 
Published: May 2019

e20618 Background: Osimertinib has been emerged as the standard selection in EGFR T790M-positive NSCLC patients who failed prior treatment with EGFR TKIs. However, acquired resistance to osimertinib is a growing clinical challenge. Despite the significant antitumor activity of Chemoimmunotherapy (CIT) combinations in NSCLC, clinical benefit in patients with EGFR mutations has not been shown obviously. Our objective was to assess the effectiveness and tolerability of CIT for metastatic EGFR-mutant NSCLC patients with acquired resistance to Osimertinib. Methods: We conducted a retrospective study in patients with sensitizing EGFR-mutant NSCLC who were resistant to Osimertinib and received anti-PD1 immunotherapy combined with chemotherapy at Chinese PLA General Hospital. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities were examined. Results: Between Oct 2015 and Nov 2018, 11 patients were available for analysis, 45.5% male, 45.5% ECOG PS 0-1, median age 54 years, all pts who failed treatment with Osimertinib had received previously targeted therapies. In this CIT combination group, 6 [54.5%] of 11 pts received pembrolizumab and 5[54.5%] of 11 pts received Nivolumab anti-PD1 therapy, 8 [72.7%] of 11 pts received mono-chemotherapy and 3 [27.3%] of 11 pts received platinum-based doublet chemotherapy. The median PFS was 7.47 months (95% CI 3.04 to 11.89). Despite Median OS was not reached, the OS rate at one year was 6 [54.5%] of 11. The ORR was 5 [45.5%] of 11. Treatment-related adverse events (TRAE) of grade 3 or higher were reported in 6 [54.5%] of 11 patients. The most common grade 3 or worse TRAEs were fatigue (3 [27.3%] of 11) and anemia (3 [27.3%] of 11); The following ≥Grade 3 TRAEs occurred once: decreased neutrophil count, acute kidney injury, gastrointestinal bleeding. One patient discontinued treatment because of immune-associated gastroenteritis. Conclusions: In metastatic NSCLC patients with activating EGFR mutation resistant to Osimertinib, our single institution real-world experience in Chemoimmunotherapy combination shows promising activity and acceptable toxicity profile. Given the small number of patients studied, further clinical trials are warranted.
Effect of immunotherapy at any line of treatment on survival in Hispanic patients with advanced metastatic non-small cell lung cancer (NSCLC) compared with chemotherapy (Quijote-CLICaP).
Authors: Cardona Zorrilla Andres Felipe , Ruiz-Patiño Alejandro , Arrieta Oscar , Martin Claudio , Raez Luis E. , Zatarain Barrón Zyanya Lucia , Barron Feliciano Barron , Ricaurte Luisa , Bravo Maria , Mas Luis , Rojas Leonardo , Lupinacci Lorena , Perazzo Florencia , Puparelli Carmen , Rizzo Manglio Miguel , Rolfo Christian Diego , Rodriguez July , Sotelo Rodríguez Diana Carolina , Carranza Hernan , Rosell Rafael ,   ONCOLGroup
Published: May 2019

e20637 Background: To compare survival outcomes of patients with advanced or metastatic NSCLC who received immunotherapy at first, second or beyond versus matched patients receiving standard chemotherapy. Methods: A retrospective multicenter international cohort study of 296 patients with unresectable/ metastatic NSCLC treated with immunotherapy either as first, second, third or fourth line was conducted. A matched comparison with a historical cohort of first line chemotherapy was conducted. Results: Median age was 64 years (Range 34-90) and 40.2% were female patients. 91.2% of patients had an ECOG performance score ≤ 1. Immunotherapy as first line was given to 39 patients (13.7%), second line to 140 (48.8%), and as third line and beyond to 108 (37.6%). Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival was 4.27 months (95% CI 3.97-5.0). Factors associated with increased survival included treatment as first-line (p < 0.001), type of response (p < 0.001) and PD-L1 status (p = 0.0039). Compared to the historical cohort, immunotherapy proved to be superior in terms of OS (p = 0.05) but not PFS (p = 0.2). Conclusions: Patients who receive immune checkpoint inhibitors as part of their treatment for NSCLC have better OS compared with matched patients treated with standard chemotherapy, regardless treatment line.
Autoantibodies indicating diagnostic or prognostic value in NSCLC patients were identified by protein microarrays.
Authors: Luo Rongrong , Liang Caixia , Yao Jiarui , Wu Di , Zhang Zhishang , Shi Yuankai , Han Xiaohong 
Published: May 2019

e20638 Background: Autoantibodies(AAbs) have been recently recognized as auxiliary diagnostic biomarkers in lung cancer. Applying high-throughput protein microarrays to address AAbs profile of non-small cell lung cancer(NSCLC) is rarely studied. Herein, we aimed to discover AAbs possessing diagnostic or prognostic value in NSCLC patients. Methods: We collected pretreatment plasma samples and survival data of 258 NSCLC patients and 343 controls. The advanced NSCLC patients were divided into subgroups according to different epidermal growth factor receptor(EGFR) gene status, therapies and therapeutic response. We utilized human proteomic(HuprotTM) microarrays to screen differential AAbs and customized microarrays to validate. Statistical methods were Chi-square test and ROC analysis. Results: We found 8 AAbs(p < 0.05 or AUC > 0.6) with underlying diagnostic or prognostic value of NSCLC patients after screening and validation. The positive rate of 4 AAbs including anti-TP53, XAGE1A1,2 and KCNAB1 in NSCLC group were higher than that in controls. Among them, anti-KCNAB1 increased in early-stage group compared with controls, indicating early diagnostic value. The other three AAbs level raised as disease progressed to advanced-stage. For advanced NSCLC patients, the differential AAbs of EGFR+ patients receiving either first generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy or chemotherapy were identified with higher positive rate in poor response subgroups compared with good response subgroups(Table1). However, for EGFR- patients with chemotherapy, the differential AAbs in different response subgroups were not found. Conclusions: We found AAbs with underlying diagnostic or prognostic value for advanced NSCLC patients receiving EGFR-TKI or chemotherapy, which should be further investigated to confirm their clinical value. [Table: see text]
Impact of antibiotics (ABX) on overall survival (OS) in patients (pts) with advanced non-small-cell lung cancer (aNSCLC) and melanoma (aMel) treated with first-line immune checkpoint inhibition (ICI).
Authors: Bagley Stephen Joseph , Dhopeshwarkar Neil , Narayan Vivek , Meropol Neal J. , Mamtani Ronac , Boursi Ben 
Published: May 2019

e20643 Background: Recent data suggest that modulating the microbiome may affect response to ICI. Using electronic health record (EHR) data, we examined whether use of ABX influences OS in pts with aNSCLC and aMel treated with ICI. Methods: We performed two retrospective cohort studies (aNSCLC, aMel) of pts who received ICI +/- chemotherapy as first-line treatment in the nationwide Flatiron Health EHR-derived database. The impact of ABX exposure on OS was assessed using Cox regression, adjusting for age, sex, body mass index (BMI), performance status (ECOG PS), Elixhauser Comorbidity Index, glucocorticoid (GC) use, and smoking. In the primary analysis, ABX exposure was defined as use from -6 to +4 weeks around start of ICI. In secondary analyses, we separately evaluated ABX use within 6 weeks pre- and 4 weeks post-initiation of ICI. Results: Baseline characteristics are displayed (Table). In the primary analysis, there was no association between ABX use and OS in aNSCLC (HR 1.16, 95% CI 0.54-2.47, p = 0.7) or in aMel (HR 0.70, 95% CI 0.17-2.81, p = 0.6). The only secondary analysis to reveal a negative impact of ABX on OS was the time window of 0 to +4 weeks after ICI start in aNSCLC (HR 3.41, 95% CI 1.38-8.39, p = 0.008). Conclusions: In this large, real-world dataset, ABX exposure around the start of front-line ICI did not influence OS in pts with aNSCLC or aMel. However, ABX exposure was associated with inferior OS in the subgroup of aNSCLC pts who received ABX within 4 weeks following start of ICI. Further characterization of completeness of ABX exposure data in the oncology EHR will assist with interpretation of these results. [Table: see text]
Cross-sectional imaging utilization for EGFR, EML/ALK, and KRAS mutant non-small cell lung cancer.
Authors: Bomberger Thomas , Kikano Elias , Laukamp Kai , Smith Daniel Arnold , Gupta Amit , Ansari-Gilani Kianoush , Dowlati Afshin , Ramaiya Nikhil H. 
Published: May 2019

e20663 Background: Targeted therapies for specific genotypic subsets of non-small cell lung cancer (NSCLC) patients have had drastic effects on overall survival at all stages. However, the NCCN guidelines have remained relatively static with respect to initial evaluation, staging, response, and imaging surveillance. In this study we evaluated 3 cohorts of patients, two with a specific targetable mutation (EGFR and EML/ALK) and one without a targetable mutation available (KRAS), for cross-sectional imaging utilization in the initial presentation and surveillance of disease. Methods: Retrospective analysis of imaging studies for patients with NSCLC who received treatment and follow-up between 2007 and 2018 was completed. CT, MRI, and PET imaging data were collected from the picture archiving system. Additional clinical data collected included age, race, smoking history, and dates of diagnosis and death. Results: 153 NSCLC patients were identified with positive EGFR (n = 65), EML/ALK (n = 15), or KRAS (n = 73) mutations. Patients averaged an age of 64 at diagnosis, with a distribution of 38% male, 62% female, 29% current smokers, 48% former smokers, and 23% never smokers. Mean duration between date of diagnosis and death for each group was 1099 ± 770 days (EGFR), 1139 ± 924 days (EML/ALK), and 542 ± 602 days (KRAS). Compared to the KRAS group, the EML/ALK group had higher utilization of chest CTs (p = 0.044), pulmonary embolus CTs (p = < 0.001), abdominopelvic CTs (p = 0.004), and PET CTs (p = 0.006). The EGFR group had significantly fewer pulmonary embolus CTs (p = < 0.001) and higher numbers of non-brain MRIs (p = 0.004) compared to the KRAS group, as well as fewer abdominopelvic CTs (p = 0.034) compared to the EML/ALK group. Conclusions: Different genotypes of NSCLC with available targetable mutations show statistically significant differences in cross-sectional imaging utilization compared to those without targetable mutations. [Table: see text]
Diverse RB1 mutations and co-occurring molecular alterations in advanced NSCLC.
Authors: Huang Jie , Peng Lun-Xi , Yang Jin-Ji , Wu Yi-Long 
Published: May 2019

e20672 Background: Retinoblastoma transcriptional corepressor 1 (RB1) mutation is strikingly more frequent in non-small cell lung cancer (NSCLC) with SCLC transformation (SCLC-T) than that remain NSCLC. However, NSCLC patients harboring RB1 mutations do not necessarily transform to SCLC. Thus, exploring RB1 mutation frequency and co-occurring genomic alterations is potentially important to understand the SCLC-T mechanism. Methods: We investigated 47 NSCLC pts with RB1 aberrations at our institution. Submitted samples (tissue, plasma, cerebrospinal fluid and pleural effusion) were analyzed using next-generation sequencing across at least 139 genes (139-520). Demographics, molecular features and outcomes were analyzed. Results: Among 47 pts (27F/20M), median age was 58. Twenty (47%) had brain metastases and 7 (15%) underwent SCLC-T. A total of 39 types of RB1 mutations were identified, in which copy number deletion is the most common (40%). RB1 mutations were present from early NSCLC and were detected in 88%(29/33), 82%(9/11), 70%(9/13) and 42% (20/48) of tissue, pleural effusion, CSF and plasma samples, respectively. The most frequent co-occurring alterations were TP53 (100%, 95%) and EGFR (100%, 93%) in both SCLC-T group and non-transformed group. Besides, mutations involving in the PI3K pathway were often detected: PIK3CA (57%, 20%), AKT (43%, 10%), PTEN (14%, 15%), MET (14%, 15%), NTRK1 (14%, 13%). Notably, RB1 also co-occurred with ALK fusion (1/47). Moreover, SCLC-T group harbored significant higher frequency of RB1 mutation compared with non-transformed group. Conclusions: RB1 mutations in NSCLC are associated with a trend toward SCLC-T, and the mechanisms may be increased frequency of RB1 mutations and co-occurring similar molecular alterations to those in SCLC.
Association of allele frequency of EGFR mutation with efficacy of EGFR TKIs in advanced non-small cell lung cancer.
Authors: Li Xiang-Meng , Yang Jin-Ji , Wu Yi-Long 
Published: May 2019

e20678 Background: Next-generation sequencing (NGS) is beneficial to precision medicine. However, it remains elusive whether the epidermal growth factor receptor ( EGFR) mutant allele frequency (MAF) tested by NGS is predictive for tyrosine kinase inhibitors (TKIs) therapy in advanced non-small-cell lung cancer (NSCLC). Methods: We enrolled 194 advanced NSCLC EGFR mutant patients receiving erlotinib or gefitinib orally. A total of 196 baseline tissue samples from a phase III clinical trial (CTONG 0901; clinicaltrials.gov No.NCT01024413) between July 2009 and 2014 were analyzed by a panel of 168 lung cancer-related genes NGS. The median EGFR MAF was 25.8% (range, 1.4%-86.2%). Patients were divided into MAF low group (1.4%-25.8%) and high group (25.8%-86.2%). We defined PFS as the time of randomization to confirmed disease progression or death from any cause. OS was calculated from randomization to the last visit or death from any cause. Tumor response was assessed by investigators according to RECIST version 1.1. Survival was estimated using the Kaplan-Meier method. The relationship between the response of TKIs and EGFR MAF were evaluated by Pearson Chi-square test or Fisher’s exact test. Results: The median age was 58.7 years (range,31.2- 85.1), 92 (47.4%) were male, 41(21.1%) were smokers,189 (97.4%) had adenocarcinoma, 105 (54.1%) patients were identified as carrying EGFR exon 19 deletion, while one patient with the co-existence of T790M mutation. 85 (43.8%) patients harbored EGFR exon 21 L858R mutation. After 5 weeks of treatment, the initial response was assessed. No significant difference was observed in initial response between the high and low groups ( P = 0.502). The difference in best response to EGFR-TKIs between the groups was not significant ( P = 0.557). Objective response rate (ORR) was 56.2% and 57.5% respectively. There was no significant difference in median PFS [11.2 (95% CI,10.0 -12.3) vs 12.4 (95% CI,10.3-14.5) months, P = 0.509] between the groups. The high group was not significantly superior to the low group in median OS[20.5 (95% CI,18.0-23.0) vs 23.1 (95% CI,19.3-27.0) months, P = 0.500]. Conclusions: EGFR mutant allele frequency tested by NGS is not associated with the efficacy of EGFR TKIs in advanced NSCLC.
TP53 mutations in EGFR mt+ NSCLC IV as a predictive factor for ORR, PFS, and OS irrespective of T790M.
Authors: Roeper Julia , Lueers Anne Christina , Falk Markus , Tiemann Markus , Otto-Sobotka Fabian , Griesinger Frank 
Published: May 2019

e20679 Background: The impact of TP53 mutations in EGFR mt+ pts on PFS and OS is controversial, and different classifications of TP53 mt+ with respect to functional and potential predictive impact have been published. Therefore, we retrospectively analyzed the impact of TP53 aberrations on ORR, PFS and OS in a cohort of EGFR mt+ NSCLC IV pts (UICC 7) using different classifications of TP53 mutations. Methods: 75 EGFR mt+ NSCLC IV pts were analyzed for TP53 co-mutations. TP53 mt+ were classified according to Poeta et al. into (1) disruptive vs. non-disruptive, according to structural prediction and biophysical characteristics into (2) pathogenic vs. non-pathogenic and finally into (3) exon 8 vs. non-exon 8 mutations according to Crino et al.. The endpoints ORR according to Recist 1.1, PFS and OS were calculated by Kaplan Meier. Results: 69 of the 75 EGFR mt+ pts (92%) had a common mutation in EGFR E19/21. In 59/75 pts (79%) material was sufficient for successful TP53 analysis. TP53 mt+ were found in 29/59 pts (49%), 16/59 (27%) had a TP53 disruptive mt+, 13/59 (22%) a TP53 non-disruptive mt+ and 30/59 a TP53 WT configuration. Using the structural/biophysical classification, 7/59 (12%) had a TP53 non-pathogenic and 22/59 (37%) a TP53 pathogenic mt+. Of the 29 mutated pts, 6 had a TP53 Exon 8 mt+. Median PFS on 1st line TKI was 12 vs. 18 months for non-disruptive/disruptive mt+ vs. WT (p < 0.004), 11 vs. 17 months for pathogenic vs. non-pathogenic/WT (p < 0.0001), and 7 vs. 12 vs. 18 months for exon 8 vs. non-exon 8 vs. WT (p < 0.006). Median OS was 24 vs. 42 months in non-disruptive/disruptive mt+ vs. WT (p < 0.0009), 23 vs. 42 months in pathogenic vs. non-pathogenic/WT (p < 0.001) and 12 vs. 28 months for TP53 exon 8 vs. non-exon 8 mt+ (p < 0.024). Additionally ORR was significantly impacted by TP53 mt+. In rebiopsy samples on acquired resistance, no new TP53 mutations were observed and there were no correlations of TP53 mutations with clinical factors and the EGFR mt+ type including T790M. Conclusions: TP53 seems to be a frequent co-mutation in EGFR mt+ NSCLC and has a strong impact on all clinical endpoints on TKI therapy. These data might have an impact on the management and follow up of pts with TP53 mt+. Furthermore, there is an urgent need for further therapeutic approaches in this patient group.