bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic alterations profiling by liquid biopsy and their association to immune checkpoints inhibitors (ICI) response in a cohort of non-small cell lung cancer (NSCLC) patients.
Authors: Callejo Ana , Carbonell Caterina , Iranzo Patricia , Pardo Aranda Nuria , Navarro Alejandro , Martinez-Marti Alex , Cedres Perez Susana , Gutierrez Raquel , Recasens Sergi , Madrenas Raquel , Sanchez Laura , Saoudi Nadia , Assaf Juan David , Masnou Mar , Frigola Joan , Amat Ramon , Felip Enriqueta 
Published: May 2020

e21524 Background: In metastatic NSCLC, identification of biomarkers of response to immune checkpoint inhibitors (ICI) is still an unmet need. Liquid biopsy, including the detection of circulating tumor DNA (ctDNA) in patients’ bloodstream, is an emerging tool for detecting and monitoring genetic alterations. Mutations in specific genes as KRAS or STK11, in combination with PDL1, have been suggested as potential biomarkers to select responders to ICI. Methods: Digital NGS of ctDNA was analyzed by Guardant360 in samples from 89 patients with advanced NSCLC treated with ICI between 2017 to 2019. Plasma samples after progression to ICI were obteined from 40 patients and we focus in this subgroup to explore mutations of genes commonly alterated in lung cancer and correlate them with clinical outcomes. Results: Forty patients were included in the analysis with a median age of 64.5 years and 62.5% were diagnosed with adenocarcinoma. Fourteen patients were treated with single agent ICI as first line, 19 patients as second line and 7 in third line. A median of 4 mutations per patient were detected (range 0-13). Mutations (mut) in TP53 were found in 85% of the patients, KRAS in 34%, STK11 in 22% and both genes KRAS and STK11 were alterated in 12.5% of the patients. Globally, median PFS (mPFS) of the patients treated with ICI was 7.5 months. mPFS in patients harboring KRAS mutations was 4.9 m ( vs 10.1 m in patients without KRASmut, logrank test p-value = 0.031) and 4.1 m in those patients with STK11 mutations (vs 9.5 m in patients without STK11mut, logrank test p-value = 0.034). Additionally, mutations in both genes were also associated to statistically significant shorter mPFS 3.9 m vs 9.5 m (logrank test p-value < 0.01). Conclusions: Our results support the idea that tumor alterations identified by liquid biopsy panels can potentially contribute as biomarkers of response to ICI in NSCLC. When analyzing the mutational panorama after ICI treatment, we find that those patients exhibiting KRAS and/or STK11 mutations in their ctDNA have a shorter PFS.
Concurrent somatic alterations of TP53 and RB1 in Chinese lung adenocarcinoma with or without EGFR mutations.
Authors: WANG JUN , Chen Gang , Zhang Bicheng , Sun Jianguo , Liang Jing , Liu Xiaolin , Li Yan , Wang Baocheng 
Published: May 2020

e21526 Background: Endothelial growth factor receptor (EGFR)-mutant lung adenocarcinoma displays diverse responses to tyrosine kinase inhibitor therapy. Concurrent somatic alterations represent different biological substantial proportion of patients with EGFR mutations and impacts their prognosis. Methods: We conducted this retrospective study to clarify the comprehensive concurrent genetic alterations of TP53 and RB1 and tumor mutational burden (TMB) in 712 EGFR-mutant or EGFR-wild type lung adenocarcinoma by next generation sequencing-based gene panel tests. Results: EGFR was the most frequently mutated gene altered in 58.0% (413/712) of lung adenocarcinoma, followed by TP53 altered in 56.7%, KRAS altered in 13.3%, and RBM10 altered in 11.2% of all patients. Concurrent genetic alteration of TP53 and RB1 is more likely to be found in EGFR-mutant patients than in EGFR-wild type patients, with a frequency of 11.4% (45/413) and 4.3% (13/299), respectively (p = 0.003). However, the frequency of TP53 and RB1 concurrent alteration was similar in lung cancer with sensitive EGFR mutation compared to those with non-sensitive mutation (10.5% versus 11.6%). TP53 mutation was most frequently found in patients with RB1 mutation (58/61), irrespective of EGFR mutational status. Furthermore, significant difference was found regarding median TMB in patients with mutant EGFR compared to those with non-mutant EGFR (3.8 versus 4.3; p < 0.001). Median TMB was higher for patients with TP53 and RB1 concurrent alteration than those without concurrent alteration in all patients (5.4 versus 4.3, p = 0.018). Conclusions: Our data showed that high prevalence of concurrent somatic alterations of TP53 and RB1 genes among lung adenocarcinoma patients with EGFR mutations, which might help understand several key biological processes and develop potential therapeutic strategies.
Expression of immune response markers in Arab patients with lung cancer.
Authors: Jazieh Abdul Rahman , Bounedjar Adda , Bamefleh Hanaa , Al-Fayea Turki , Almaghraby Hatim Q. , Belarabi Ayed , Ouahioune Wahiba , Derbouz Zoubir , Alkaiyat Mohammad , Alkattan Khaled , Damlaj Moussab , Khalbuss Walid 
Published: May 2020

e21543 Background: Programmed death-ligand 1 (PD-L1) is a marker for checkpoint inhibitors use in management of solid tumor especially non-small cell lung cancer (NSCLC). Our study aimed at determining the patterns of PD-L1 expression and CD8 immunostains in patients with NSCLC in Arab population. Methods: Archival tumor tissue form patients with confirmed diagnosis of NCSLC were obtained and stained for PD-L1 using antibody 22C3 by Dako using Immuno-histochemistry stain (IHC) and giving Tumor Proportion Score (TPS) a percentage number from 0 to 100% of stained tumor cells. Tumors were categorized into negative expressers (TPS<1%), low positive (TPS 1-49%), and high positive (TPS 50% -100%). Correlation of expression with clinical and pathological features including CD8+ lymphocyte density was analyzed. Results: Two hundred NSCLC cases were included in the study from 6 centers in Saudi Arabia and Algeria. Median age was 65 years (28-93) and majority were males (75%) with stage 4 NSCLC (64%). The TPS was high in 37 patients (18%), low in 60 patients (30%), and negative in 103 patients (52%). In a univariate analysis, the following were significant predictors of any PD-L1 expression (>1%): male gender, being Saudi national patients, high expression of CD8+ and the presence of tumor infiltrating lymphocytes. In the multivariate analysis, only high expression of CD8+ cells (>2+) was significant with Odd Ratio (OR) of 4.4 (95% Confidence interval 1.5-12.9, p value of 0.003). Conclusions: PD-L1 expression in our population is similar to the published literature and correlated with the density of CD8+ cells. Validation of the predictive value of this marker in our population and identifying easier and reliable methods to test for it is warranted.
Human skin biomarkers and his relation with the response to treatment to tyrosine kinase inhibitors in advanced EGFR mutated lung adenocarcinoma.
Authors: Rodriguez Cid Jeronimo Rafael Rafael , Castañeda-Zárraga Anahi , Flores-Mariñelarena Rodrigo Rodrigo , Vega-Memije María Elisa , Fernández Garibay Valeria Michelle , Trinidad-Bibiano Héctor , Martínez-Herrera José Fabián , Sánchez-Ríos Carla Paola , Alatorre-Alexander Jorge , Martinez Luis Manuel , Santillan-Doherty Patricio 
Published: May 2020

e21544 Background: A relationship between EGFR signaling pathway expression in skin and the use of targeted cancer therapies has been consistently demonstrated. Nonetheless, consistent evidence to support the use of skin biopsies as a surrogate for therapeutic evaluation. Methods: The present study is a prospective single-blind analysis of skin biopsies of patients with confirmed advanced EGFR mutated lung adenocarcinoma. Immunohistochemistry was performed with EGFR, p27, Ki67, STAT3, and MAPK, as well as an H&E histopathological analysis, looking for their relationship with the response to treatment with tyrosine kinase inhibitors. ROC curve analysis was used to determine the cutoff value for each biomarker selected dichotomizing the response to treatment as mentioned in the tissue samples section (adequate response or no response). Kaplan Meier analysis for progression-free survival was performed. Results: From the 35 biopsies obtained, 21 (60%) of the patients were women and 14 (40%) men; the mean age of participants was 60.6±11.7 years. Twelve patients (34.3%) were at the pre-treatment group, 12 (34.3%) had an adequate response to treatment and 11 (31.4%) were at the no response to treatment group. The median progression-free survival was 9 months. The next biomarkers were significantly related to an adequate response to treatment by using a bivariate correlation test: EGFR (p = 0.025), Ki67 (p = 0.015), STAT3 (p = 0.017), stratum corneum thickness (p = 0.039) and the number of layers of the stratum corneum(p = 0.041). A better median of progression-free survival was obtained on those with a value above of the cutoff preestablished of EGFR (21 months versus 7 months, 95% CI 0-46 versus 4.23-9.77, p = 0.025) and number of layers of the stratum corneum (21 months versus 8 months, 95% CI 0-43.81 versus 6.72-9.28, p = 0.030), however, for p27 a better median of progression-free survival was shown in those with a value below the cutoff before mentioned (21 months versus 8 months, 95% CI 8.17-33.83 versus 6.87-9.13, p = 0.031). Conclusions: We found a relationship between EGFR, Ki67, STAT3, stratum corneum, number of layers of stratum corneum, with the response to treatment, and better progression-free survival for high expression EGFR, number of layers of the stratum corneum and low expression for p27. The present study should incite to perform a further investigation to validate these markers as potential prognostic and predictive factors.
STK11/LKB1 revisited: A prognostic rather than predictive biomarker for immune checkpoint inhibitor in EGFR/ALKWT nonsquamous non-small cell lung cancer (NSCLC).
Authors: Zhao Hui , Qi Nan , Chen Dianjun , Li Donghui , Fu Yan , Xu Yu , Wang Guoqiang , Bai Yuezong , Du Nan 
Published: May 2020

e21548 Background: Previous retrospective studies identified the mutation of serine/threonine-protein kinase (STK11, also known as Liver Kinase B1 [LKB1]) as predictor to the benefit from immune checkpoint inhibitor (ICI) in KRAS-mutant lung adenocarcinoma. This conclusion was drawn from merely the patients receiving ICI, lacking the indispensable control group undergoing chemotherapy. Therefore, we hereby revisit the impact of STK11 mutation in both immunotherapeutic and chemotherapeutic cohorts, in addition to TCGA database as a control cohort representing prognosis. Methods: 6 immunotherapeutic cohorts involving 807 patient-level data (Van Allen, Rizvi-34, Rizvi-240, MSKCC-75, MSKCC-350, and POPLAR/OAK-atezolizumab), 1 chemotherapeutic cohort (POPLAR/OAK-docetaxel, n = 244), and TCGA database (n = 485) were included to comprehensively re-examine the questionably predictive effect of STK11 mutation on the benefit from immunotherapy in patients with EGFR/ALKWT non-squamous NSCLC. Results: In the 6 immunotherapeutic cohorts, STK11 mutation was associated with shorter progression-free survival (PFS, HR = 1.54, 95%CI 1.17-2.03, P = 0.002) and overall survival (OS, HR = 1.57, 95%CI 1.16-2.11, P = 0.003), but no statistically lower overall response rate (ORR, RR = 0.71, 95%CI 0.39-1.28, P = 0.251). Similarly, in the patients receiving docetaxel, worse ORR and PFS at borderline level and significantly reduced OS (HR = 1.82, 95%CI 1.18-2.80, P = 0.006) were observed. Specifically, in the POPLAR/OAK cohort retrieved from two randomized controlled trials comparing atezolizumab and docetaxel, STK11 mutation and treatment choice separately impacted on OS, but the interaction between these two variables was barely profound (HR 1.10, 95%CI 0.60-2.01, P = 0.766), indicating the prognostic, but not predictive utility of STK11 mutation. Furthermore, in TCGA database, STK11 mutation was linked with poorer prognosis, with the similar hazard ratio in immunotherapeutic cohorts. Conclusions: Genomic abberation of STK11 remarkably worsens prognosis among 6 immunotherapeutic cohorts, 1 chemotherapeutic cohort, and TCGA database, demonstrating the prognostic, but not predictive utility of STK11 mutation in patients with EGFR/ALKWT non-squamous NSCLC.
Characterization of ERBB2 alterations in non-small cell lung cancer.
Authors: Singh Vijendra , Feldman Rebecca , Sukari Ammar , Kim Chul , Mamdani Hirva , Spira Alexander I. , Bepler Gerold , Kim Edward S. , Raez Luis E. , Pai Sachin Gopalkrishna , Ikpeazu Chukwuemeka , Vanderwalde Ari M. , Xiu Joanne , Wozniak Antoinette J. , Borghaei Hossein , Liu Stephen V. , Nagasaka Misako 
Published: May 2020

e21553 Background: ERBB2 alteration (mutation and/or amplification) is associated with poor survival in non-small cell lung cancer (NSCLC) and is commonly reported as a resistance mechanism to EGFR tyrosine kinase inhibitors. Several clinical trials are ongoing for the management of ERBB2-altered NSCLC. Here we report the prevalence of different ERBB2 alterations in NSCLC. Methods: We retrospectively analyzed ERBB2 alterations in NSCLC tumors that underwent next-generation sequencing (NGS) with Caris Life Sciences. De-identified pathological and molecular information was collected. ERBB2 copy number of greater than 6 was defined as amplification; mutations were classified among 7 groups based on their mechanism of action. Results: A total of 12946 NSCLC tumors with ERBB2 NGS results were available. Among them, 12492 had ERBB2 copy number alteration (CNA) data available. 321 tumors (2.5%) had ERBB2 alteration (mutation or amplification). Among them, ERBB2 was mutated in 197 tumors (1.5%) and amplified in 134 (1.1%) tumors. Type of ERBB2 mutation, respective median age and distribution among sex is in the table. 10 tumors with ERBB2 mutation (7.46%) also showed ERBB2 amplification. Six percent of tumors (8/135) with ERBB2 exon 20 insertion mutations had co-occurring ERBB2 amplification. One tumor for each extracellular domain (ECD) and transmembrane group had co-occurring ERBB2 amplification. Eight tumors with ERBB2 mutation had an overlapping EGFR L858R or exon19del mutation. Seven of these 8 tumors were from the ECD group (7/21) and all had mutations in the S310 locus. One tumor was from the transmembrane group. Conclusions: Exon 20 insertion mutation is the most commonly found ERBB2 mutation among NSCLC, a few of them had co-occurring ERBB2 amplification. One third of tumors with extracellular domain ERBB2 mutation had EGFR mutation. Tarloxitinib (NCT03805841), trastuzumab deruxtucan (NCT03505719), pyrotinib (NCT02500199), poziotinib (NCT03318939) are just a few of the novel ERBB2 inhibitors available in clinical trials. It will be critical to utilize next generation sequencing to effectively capture uncommon mutations and amplifications in ERBB2 so that patients may be offered therapy directly targeted to their genomic alterations. [Table: see text]
Association between inflammatory markers and progression-free survival in patients with advanced EGFR-mutated non-small cell lung cancer under treatment with tirosin kinasa inhibitors: Real-world data from Peru.
Authors: Motta Guerrero Rodrigo , Aliaga Macha Carlos , Carracedo Carlos F. , Runciman Thanya 
Published: May 2020

e21568 Background: Tirosine Kinasa Inhibitors (TKI) are the standard treatment in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutation. However, eventually patients will progress to TKI. The aim of this study is to determinate if neutrophil-lymphocyte ratio (NLR), RDW-CV and platelet-lymphocyte ratio (PLR) are associated with progression free survival (PFS). Methods: This is a retrospective observational study of a single patient cohort. Clinical records of advanced NSCLC patients that received TKI as first line therapy in ALIADA cancer center since January 2015 and December 2019 were evaluated. NLR, RDW-CV and PLR were calculated from blood counts before beginning of TKI. The statistical analysis was performed with SPSS version 20 and MINITAB 14. Results: 182 patients were diagnosed with advanced NSCLC and 30% of them harbor a EGFR mutation. 43 patients were finally included, 55.8% were women and mean age was 58 years. The 65% of patients had exon19 deletion, 25% exon21 L858R substitution, 7% exon20 T790 mutations and 3% exon18 G719X substitution. 44% of patients received erlotinib, 38% afatinib and 18% osimertinib. The 61.5% of patients achieved partial response; they had a mean NLR, PRL and RDW-CV of 2.98 (0.93–7.41), 238.59 (101.63–863.01) and 13.8 (12.6–15.5) respectively. 17.3% achieved complete response, with a mean NLR, PRL and RDW-CV of 2.93 (1.22–4.64), 204.37 (109.21–417.46) and 13.7 (12.8–15.4). Finally, 9.6% maintain stable disease; with a mean NLR, PRL and RDW-CV of 4.25 (3.6-4.91), 200.7 (196.4-205) and 14.35 (14.3-14.4). 74% of patients progressed. The mean PFS was 24.33 months (95% CI 16.05 - 32.6). Patients that developed progressive disease and those who did not, had no significant difference in the mean NLR (3.98 vs 3.68, p = 0.706) and mean RDW-CV (14.12 vs 14.3, p = 0.655). However, patients with clinical benefit during TKI had a mean PLR of 163.68, meanwhile patients with progressive disease had a mean PLR of 276.54 (T of Student, p = 0.03). Conclusions: In patients with advanced EGFR mutated NSCLC, a high level of PLR is associated with a lower PFS. It is necessary to carry out studies with a bigger amount of population to validate the PLR as a predictive biomarker. To our knowledge this is the first study that analyzes these characteristics in Latin American population.
Human papillomavirus infection in metastatic lung adenocarcinoma is associated with better outcomes with immune checkpoint inhibitor treatment.
Authors: Rojas Puentes Luis Leonardo , Ruiz-Patiño Alejandro , Mayorga Gonzalez Diana Carolina , Rodríguez July Katherine , Ávila Coy Jenny Mireya , Bravo Espinosa Melissa Andrea , Zatarain-Barron Zyanya Lucía , Arrieta Oscar , Barron Feliciano Barron , Carranza Hernan , Otero Jorge Miguel , Vargas Carlos Alberto , Archila Pilar , Sotelo Rodríguez Diana Carolina , Martin Claudio Marcelo , Pino Luis Eduardo , Rolfo Christian Diego , Rosell Rafael , Cardona Zorrilla Andres Felipe , Recondo Gonzalo 
Published: May 2020

e21569 Background: Human papilloma virus (HPV) is associated with the development of several primary tumors. Recent studies have shown that HPV-positive tumors tend to be sensitive to immune checkpoint inhibitors (ICI), owing to the presence of xenobiotic genomes in cancer cells. The objective of this study was to explore this relationship in patients with lung adenocarcinoma. Methods: A retrospective cohort analysis in patients with advanced lung adenocarcinoma treated in a reference center in Bogota, Colombia was conducted. Demographic as well as treatment variables were collected between January 2018 and December 2019. Besides clinical outcomes, HPV infection status was determined by PCR amplification and reverse line hybridization directly on formalin-fixed paraffin-embedded tumor samples. Statistical analyses included stratified survival analysis based on HPV status and response. Results: A total of 133 patients were included. Male predominance (51.1%) with Karnofsky performance scores (KPS) greater than 80, and 19% of prior cigarette exposure (26 patients) was identified in the cohort. HPV positivity was identified in 25.6% of patients (33 cases, [95%CI 17.5-32.2%]), in addition to 29.8% EGFR mutation positivity (29 cases [[95%CI 14.8-28.8%]), 6% ALK positivity (8 cases [95%CI 1.9-10]) and positive PD-L1 expression in 49 samples (36.8% [95%CI 28.6-45%]). In immune checkpoint inhibitor (ICI) exposed patients, HPV+ patients had significantly higher PD-L1 expression compared with HPV- individuals (p < 0.001). In terms of overall survival, ICI treated patients achieved an OS of 27.1 months (95%CI 22.1-NA) and a PFS of 19.4 months (95%CI 18-24.5 months). HPV infection status was associated with prolonged OS (median OS not reached, [95%CI 27.7 months – no reached], p = 0.0089) and better response to ICI (p < 0.001). Conclusions: HPV infection is prevalent in patients with lung adenocarcinoma and is associated with better response to ICIs as well as better survival outcomes. Its identification could serve as a prognostic marker, especially in female non-smoker patients.
Clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine tumors: A population-based analysis.
Authors: Fuentes Harry E , Zhu Mojun , Gile Jennifer , Leventakos Konstantinos , Sonbol Mohamad Bassam , Schild Steven E. , Starr Jason Scott , Halfdanarson Thorvardur Ragnar , Molina Julian R. 
Published: May 2020

e21575 Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p < 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]